Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period.

Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal-fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients.

The iTreAD project: a study protocol for a randomised controlled clinical trial of online treatment and social networking for binge drinking and depression in young people.

BACKGROUND: Depression and binge drinking behaviours are common clinical problems, which cause substantial functional, economic and health impacts. These conditions peak in young adulthood, and commonly co-occur. Comorbid depression and binge drinking are undertreated in young people, who are reluctant to seek help via traditional pathways to care. The iTreAD project (internet Treatment for Alcohol and Depression) aims to provide and evaluate internet-delivered monitoring and treatment programs for young people with depression and binge drinking concerns. METHODS: Three hundred sixty nine participants will be recruited to the trial, and will be aged 18-30 years will be eligible for the study if they report current symptoms of depression (score 5 or more on the depression subscale of the Depression Anxiety Stress Scale) and concurrent binge drinking practices (5 or more standard drinks at least twice in the prior month). Following screening and online baseline assessment, participants are randomised to: (a) online monthly self-assessments, (b) online monthly self-assessments + 12-months of access to a 4 week online automated cognitive behaviour therapy program for binge drinking and depression (DEAL); or (c) online monthly assessment + DEAL + 12-months of access to a social networking site (Breathing Space). Independent, blind follow-up assessments occur at 26, 39, 52 and 64-weeks post-baseline. DISCUSSION: The iTreAD project is the first randomised controlled trial combining online cognitive behaviour therapy, social networking and online monitoring for young people reporting concerns with depression and binge drinking. These treatments represent low-cost, wide-reach youth-appropriate treatment, which will have significantly public health implications for service design, delivery and health policy for this important age group. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000310662. Date registered 24 March 2014.

Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses.

Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.

Digitizing clinical trials.

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring.

BACKGROUND: In patients with advanced ovarian cancer (OvCa), microscopic residual tumour nodules that remain after surgical debulking frequently escape detection by current treatment assessment methods and lead to disease recurrence. The aim of this study was to evaluate the use of high-resolution fibre-optic fluorescence imaging of the clinically approved photodynamic therapy (PDT) agent benzoporphyin-derivative monoacid ring A (BPD-MA) for detection of microscopic OvCa and for monitoring treatment response. METHODS: Our fluorescence microendoscope consists of a flexible imaging fibre coupled to a custom epi-fluorescence system optimised for imaging BPD-MA, which, after a single administration, serves as both an imaging agent and a light-activated therapeutic agent. After characterisation in an in vitro OvCa 3D model, we used the flexible imaging fibre to minimally invasively image the peritoneal cavity of a disseminated OvCa murine model using BPD-MA administered intraperitoneally (i.p.). To evaluate longitudinal changes in response to treatment, we compared sets of images obtained before and after PDT with those from untreated mice imaged at the same time points. RESULTS: By comparison with histopathology, we report an 86% sensitivity for tumour detection in vivo using the microendoscope. Using a custom routine to batch process-image data in the monitoring study, treated mice exhibited an average decrease of 58.8% in tumour volumes compared with an increase of 59.3% in untreated controls (P<0.05). CONCLUSIONS: Our findings indicate the potential of this approach as a reporter of treatment outcome that could aid in the rational design of strategies to mitigate recurrent OvCa.

Image analysis for denoising full-field frequency-domain fluorescence lifetime images.

Video-rate fluorescence lifetime-resolved imaging microscopy (FLIM) is a quantitative imaging technique for measuring dynamic processes in biological specimens. FLIM offers valuable information in addition to simple fluorescence intensity imaging; for instance, the fluorescence lifetime is sensitive to the microenvironment of the fluorophore allowing reliable differentiation between concentration differences and dynamic quenching. Homodyne FLIM is a full-field frequency-domain technique for imaging fluorescence lifetimes at every pixel of a fluorescence image simultaneously. If a single modulation frequency is used, video-rate image acquisition is possible. Homodyne FLIM uses a gain-modulated image intensified charge-coupled device (ICCD) detector, which unfortunately is a major contribution to the noise of the measurement. Here we introduce image analysis for denoising homodyne FLIM data. The denoising routine is fast, improves the extraction of the fluorescence lifetime value(s) and increases the sensitivity and fluorescence lifetime resolving power of the FLIM instrument. The spatial resolution (especially the high spatial frequencies not related to noise) of the FLIM image is preserved, because the denoising routine does not blur or smooth the image. By eliminating the random noise known to be specific to photon noise and from the intensifier amplification, the fidelity of the spatial resolution is improved. The polar plot projection, a rapid FLIM analysis method, is used to demonstrate the effectiveness of the denoising routine with exemplary data from both physical and complex biological samples. We also suggest broader impacts of the image analysis for other fluorescence microscopy techniques (e.g. super-resolution imaging).

[Role of endovascular therapy for redo surgery in patients after aortoiliac aneurysm exclusion]. / Stellenwert der endovaskulären Therapie bei Reeingriffen nach Ausschaltung aortoiliakaler Aneurysmata.

INTRODUCTION: Redo surgery or reintervention following conventional or endovascular aortoiliac reconstruction often requires exclusion of new aneurysms. In the present study the potentials of endovascular management of such lesions are investigated. METHODS: All patients with endovascular reoperation for of newly developed aortoiliac aneurysms were identified from a prospectively run data-base. The indications and results of endovascular therapy were analysed retrospectively. In detail, data were analysed for the type of original operation, interval until and kind of reoperation, and results concerning survival, technical success and complications. RESULTS: From 12 / 2003 through 3 / 2007 195 patients with aortoiliac aneurysms were operated. Endovascular repair was performed in 15 cases of previously excluded aneurysms. Mean age of these 15 patients (12 men) was 73 (64-85) years. Ten patients had a primary conventional (group A) and 5 patients had a primary endovascular (group B) aneurysm repair. The mean time interval between the first and second operation was 8.9 (1-26) years. The secondary endovascular therapy in group A was successful in all cases. In group B endoleaks type I a (n = 1), I a / b (n = 1), II (n = 2) and III (n = 1) were treated. One type II endoleak could only be treated successfully by conversion to open repair, the other one was successfully treated by reintervention. All but one patient are alive and -remained free of pathological findings during a median follow-up of 13 (2-39) months. DISCUSSION: Because of the clearly elevated operation risk of redo surgery after conventional or endovascular aneurysm repair, endovascular aneurysm exclusion represents the method of first choice. The reasonable selection and combination of procedures allows for an optimal adaptation of therapy to the individual case.

Psychobiological effects of carbohydrate- and protein-rich meals in patients with seasonal affective disorder and normal controls.

Patients with seasonal affective disorder (SAD) frequently report carbohydrate craving and note that carbohydrate ingestion energizes them. Bright artificial light has been shown to reverse the symptoms of SAD, including carbohydrate craving. In this study, 16 depressed SAD patients and 16 matched controls were fed two different isocaloric meals, one rich in protein and one rich in carbohydrates, in a crossover design. Although their biochemical response in terms of plasma large neutral amino acid concentrations was identical, SAD patients reported activation following carbohydrate ingestion, whereas normal controls reported sedation. Marked ordering effects on psychological parameters were noted, suggesting that order should be taken into account as a methodological consideration in meal studies.

Effects of amantadine and trihexyphenidyl on memory in elderly normal volunteers.

Anticholinergic drugs impair one's ability to learn new material, even at routine clinically used doses. During the trihexyphenidyl phase of this double-blind crossover trial, elderly normal subjects complained of confusion and memory impairment and demonstrated a pattern of deficits in memory function compatible with that previously reported to result from anticholinergic drugs. The subjects neither complained of nor demonstrated memory impairment while taking amantadine, which is believed to exert its pharmacological effects upon extrapyramidal disorders via dopaminergic mechanisms and does not appear to be associated with memory impairment. Anticholinergic drugs should be avoided whenever possible in the elderly and especially in those suffering dementia.

Efficacies of dexfenfluramine and fluoxetine in preventing weight gain after smoking cessation.

We tested whether 14 wk of dexfenfluramine (30 mg) or fluoxetine (40 mg) treatment would prevent weight gain after subjects quit smoking. Normal-weight women (n = 144) were randomly assigned to drug or placebo on a double-blind basis for 2 wk before quitting smoking and 12 wk thereafter. The fluoxetine group had more dropouts (28/49, 57.1%) than the dexfenfluramine group (17/47, 36.2%), with an intermediate number of dropouts from the placebo group (21/48, 43.8%). All groups gained weight during treatment, but their amount and pattern of weight gain differed. In the first month after quitting smoking, the placebo group gained more weight than either the dexfenfluramine or fluoxetine group (P < 0.05). By 2 mo postcessation, dexfenfluramine still suppressed weight gain in comparison with placebo (P < 0.05); weight gain with fluoxetine was not differentiable from either dexfenfluramine or placebo. By 3 mo postcessation, the dexfenfluramine group had gained 1.0 +/- 0.7 kg, significantly less than either the placebo (3.5 +/- 0.7 kg) or fluoxetine (2.7 +/- 0.5 kg) groups. Three months after drug discontinuation, formerly medicated, but not placebo patients, showed additional weight gain, eliminating differences between groups. Results indicate that weight gain, an adverse accompaniment of smoking cessation, can be minimized to some degree by serotoninergic drugs, although only for the duration of drug treatment.

The effects of dietary neurotransmitter precursors on human behavior.

The neurotransmitter precursors tryptophan and tyrosine are present in a variety of foods. In order to document possible effects of tryptophan and tyrosine on human behavior, single oral doses of these substances and matched placebos were administered to 20 men in a double-blind, crossover study. Various tests of mood state and performance were then administered. Tryptophan increased subjective fatigue and decreased self-ratings of vigor and alertness, but did not impair performance on any of the tests. Tyrosine produced no effects in our young population compared with placebo, but did decrease reaction time relative to tryptophan. It may be concluded that tryptophan has significant sedative-like properties, but unlike other sedatives may not impair performance.

Tardive dyskinesia exacerbated after ingestion of phenylalanine by schizophrenic patients.

Despite continued research, the influences that promote or exacerbate tardive dyskinesia (TD) symptoms remain incompletely understood. Recent findings (Gardos et al. 1992; Richardson et al. 1989) suggest that ingestion of the dietary constituent, phenylalanine, might exacerbate TD symptoms, but a double-blind, placebo-controlled challenge had not previously been conducted in schizophrenic patients. On two different mornings, in counterbalanced order, 18 male schizophrenic patients with TD were challenged with either 100 mg/kg phenylalanine or placebo. Effects on abnormal involuntary movements, recall memory, and plasma phenylalanine were measured 90 minutes post-challenge. The results supported the hypothesis in that involuntary movements increased to a statistically and clinically meaningful degree after the phenylalanine challenge, but not after placebo. No effects on memory were detected. Significant order effects characterized the plasma findings but not the behavioral data. Results indicate that a dietary constituent, the amino acid phenylalanine, can potentially exacerbate tardive dyskinesia symptoms in schizophrenic patients. The influence of phenylalanine and other ingested substances on clinical symptomatology warrants further investigation.

Schizophrenia, monoamine oxidase activity, and cigarette smoking.

Reduced monoamine oxidase activity has been proposed as a marker for vulnerability to schizophrenia. Reduced monamine oxidase activity has also been shown to occur in cigarette smokers. This study compared monamine oxidase activity level in a matched group of patients with schizophrenia who smoked with a group who did not. Lower levels of monoamine oxidase activity were found in the smokers and this is the likely explanation for the low levels hypothesized as a marker for schizophrenia.

Psychobiological effects of carbohydrates.

The authors studied whether the fatiguing effects of eating lunch are greater for carbohydrate-rich meals than for other meals, and related the time course of behavioral change to plasma glucose, insulin, and amino acids. On different occasions, in counterbalanced order, normal women (N = 7) fasted overnight, ate a standard breakfast, and at lunch either continued to fast or ate a high-carbohydrate, low-protein meal; a hedonically similar meal containing both carbohydrate and protein; or a high-protein, low-carbohydrate meal. Meals were isocaloric and equated for fat content. Only the carbohydrate meal significantly increased fatigue, which could not be attributed to hypoglycemia because plasma glucose remained elevated. Fatigue began approximately, when the carbohydrate meal elevated the plasma tryptophan ratio but ended even though the ratio remained elevated. Fatigue after a high-carbohydrate lunch could not be explained by reactive hypoglycemia or sweet taste, and could partially be explained by the hypothesis that fatigue parallels an elevation of the tryptophan ratio.

Effects of two antidepressants on memory performance in depressed outpatients: a double-blind study.

Forty outpatients with primary depression were randomly assigned on a double-blind basis to treatment with amitriptyline (a tricyclic antidepressant) or clovoxamine (a nontricyclic, experimental antidepressant). Memory and depression were assessed during a pretreatment baseline period and at the end of days 4, 7, and 28 of drug treatment. A signal detection recognition memory task and conventional memory measures (including the Benton Visual Retention, Wechsler Logical Memory, and verbal learning tests) were used to assess memory. Although both drugs led to comparable clinical improvement in depression, they affected memory performance differently. The signal detection recognition memory task detected an impairment in memory after chronic amitriptyline administration, as contrasted with an improvement in memory after chronic administration of clovoxamine. The memory impairment in the amitriptyline group and improvement in the clovoxamine group were the result of changes in sensitivity [P(A)]. No changes in response bias (B) were detected. Conventional memory tests failed to detect drug-related differences in memory between the two groups. On the Benton, errors decreased over time within both drug treatment groups, whereas correct reproductions increased within the amitriptyline group only. However, between-group differences on the Benton did not reach significance. Results from the signal detection task suggest an amitriptyline-associated memory impairment. However, this interpretation is tempered by the finding that conventional memory measures failed to detect differences in memory performance between the two groups. We discuss the limitations of traditional memory measures and the utility of a signal detection approach in studies of psychopharmacologic influences on memory.

Amitriptyline, clovoxamine and cognitive function: a placebo-controlled comparison in depressed outpatients.

No longer prescribed only for vegetative signs of depression, tricyclic antidepressants also lessen depressive cognitive distortions. Less clear is whether they ameliorate depressed patients' other cognitive deficits in memory, information processing speed, and psychomotor performance. We tested the alternative hypothesis that amitriptyline, because of its anticholinergic and sedative properties, would exacerbate depressed patients' cognitive disturbances. Depressed outpatients received double-blind placebo (n = 15), amitriptyline (n = 10), or clovoxamine fumarate (n = 10), a serotonin reuptake inhibitor relatively lacking in anticholinergic properties. Depression, memory, and psychomotor performance were assessed at baseline and after 7 and 28 days of drug treatment. Depression was alleviated after all treatments, including placebo. Only amitriptyline impaired performance on tests of memory, producing a significant decrement, relative to placebo, after 4 weeks of treatment. None of the treatments adversely affected performance on psychomotor tasks. These findings add to the evidence that antidepressant drugs with high anticholinergic activity can impair memory, despite alleviation of depression.

Effects of protein and carbohydrate meals on mood and performance: interactions with sex and age.

Normal adult subjects (n = 184) consumed a high-protein or high-carbohydrate meal. Two hours later their mood and performance were tested. The effects of meal composition on mood were different for men and women, and for older and younger subjects. Females, but not males, reported greater sleepiness after a carbohydrate as opposed to a protein meal. Male subjects, but not females, reported greater calmness after a carbohydrate as opposed to a protein meal. Older subjects responded differently to meals depending upon the time of day when these were consumed. When meals were eaten for breakfast (but not for lunch) individuals 40 yr of age or older felt more tense and less calm after a protein than after a carbohydrate meal. Although older subjects reported subjective discomfort after a morning protein meal, they displayed objective performance impairments after a carbohydrate lunch. Subjects 40 yr of age or older were impaired on a test of sustained selective attention (dichotic shadowing) after consuming a high-carbohydrate lunch. The shadowing impairment after carbohydrate consumption was as pronounced without distraction as with distraction and resulted mostly from increased omission errors. Our findings suggest negative effects on concentration when older subjects consume a high-carbohydrate, low-protein lunch. These negative effects of carbohydrate consumption appear to arise predominantly from lapses of attention rather than from intrusion of distractors.

Mood, performance, and pain sensitivity: changes induced by food constituents.

We examined the behavioral effects of the dietary constituents tryptophan and tyrosine on human mood, sensorimotor performance and pain sensitivity. Tryptophan and tyrosine are neurotransmitter precursors present in varying amount in protein-containing foods. Tryptophan (50 mg/kg) increased subjective drowsiness and fatigue but unlike many hypnotics did not impair sensorimotor performance. Tryptophan also decreased human pain sensitivity in a manner that was more specific than certain analgesic drugs.

Stress and schizophrenia: some definitional issues.

This article discusses definitional ambiguities in research on the role of stress in the etiology of schizophrenia. Implications of the change to DSM-III criteria are considered, as is the question of whether prior research samples have overincluded acute schizophrenics. It is suggested that the problem of defining schizophrenia's time of onset is one of the thorniest in this literature. Three different operational definitions of stress are examined. Stress may be considered a response involving disruption in homeostasis, or as a stimulus with objectively specifiable properties. Stress is also defined interactionally with reference to characteristics of the individual and the surrounding life context. Relative merits of the three definitions are evaluated, and an attempt is made to clarify the differentiation between formative and triggering effects of stress. Further study of the impact of remote life events on vulnerability is encouraged.