Catechol derived from aronia juice through lactic acid bacteria fermentation inhibits breast cancer stem cell formation via modulation Stat3/IL-6 signaling pathway.

Cancer stem cells (CSCs) as a subpopulation of cancer cells are drug-resistant and radiation-resistant cancer cells to be responsible for tumor progress, maintenance and recurrence of cancer, and metastasis. This study isolated and investigated a new cancer stem cell (CSC) inhibitor derived from lactic acid fermentation products using culture broth with 2% aronia juice. The anti-CSC activity of aronia-cultured broth was significantly higher than that of the control. Activity-guided fractionation and repeated chromatographic preparation led to the isolation of one compound. Using nuclear magnetic resonance and ESI mass spectrometry, we identified the isolated compound as catechol. In this study, we report that aronia-fermented catechol has a novel inhibitory effect on human breast CSCs. Catechol inhibited breast cancer cell proliferation and mammosphere formation in a dose-dependent manner. This compound reduced the CD44high /CD24low subpopulation, ALDH-expressing cell population and the self-renewal-related genes nanog, sox2, and oct4. Catechol preferentially reduced mRNA transcripts and protein levels of Stat3 and did not induce c-Myc degradation. These findings support the novel utilization of catechol for breast cancer therapy via the Stat3/IL-6 signaling pathway. Our results suggest that catechol can be used for breast cancer therapy and that Stat3 expression is a marker of CSCs. Catechol inhibited Stat3 signaling by reducing Stat3 expression and secreted IL-6, a CSC survival factor. These findings support the novel utilization of catechol for breast cancer therapy via Stat3/IL-6 signaling.

Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence.

Psoriasis is a chronic, systemic inflammatory disorder manifesting primarily in skin and potentially in joints, frequently necessitating treatment with conventional systemic therapies, phototherapy or biological agents. Patients with moderate to severe disease suffer a diminished quality of life, experience significant comorbidities and have a higher mortality. Although traditional treatments are effective in the short-term, their use is often limited by concerns over long-term toxicity, including end-organ damage and risk of malignancy. Combination therapy is a commonly used approach and is often more effective than any single agent. Lower doses of two treatments in combination can also minimize potential side effects from a single agent at higher doses. Etanercept is a recombinant human tumour necrosis factor (TNF)α receptor (p75) protein fused with the Fc portion of IgG1 that binds to TNFα. This article reviews the evidence on the efficacy and safety of etanercept in combination with methotrexate, acitretin, narrowband UVB and cyclosporin. The largest body of evidence assesses the combination with methotrexate, although evidence is available for the other combinations. Data suggest that although highly effective as monotherapy, etanercept in combination with a conventional systemic agent can enhance efficacy and allow drug sparing. Potentially, the combination may also result in faster treatment responses and permit safe transitioning from one systemic agent to another. Evidence to date suggests that these benefits can be achieved without significant additional toxicity, although long-term data on the efficacy and safety of the combination in psoriatic populations is limited and further evaluation is warranted.

Tetanus toxin induces long-term changes in excitation and inhibition in the rat hippocampal CA1 area.

Intrahippocampal tetanus toxin induces a period of chronic recurrent limbic seizures in adult rats, associated with a failure of inhibition in the hippocampus. The rats normally gain remission from their seizures after 6-8 weeks, but show persistent cognitive impairment. In this study we assessed which changes in cellular and network properties could account for the enduring changes in this model, using intracellular and extracellular field recordings in hippocampal slices from rats injected with tetanus toxin or vehicle, 5 months previously. In CA1 pyramidal neurones from toxin-injected rats, the slope of the action potential upstroke was reduced by 32%, the fast afterhyperpolarisation by 32% and the slow afterhyperpolarisation by 54%, suggesting changes in voltage-dependent conductances. The excitatory postsynaptic potential slope was reduced by 60% and the population synaptic potential slope was reduced at all stimulus intensities, suggesting a reduced afferent input in CA1. Paired-pulse stimulation showed an increase of the excitability ratio and an increase of cellular excitability only for the second pulse, suggesting a reduced inhibition. The polysynaptic inhibitory postsynaptic potential was reduced by 34%, whereas neither the inhibitory postsynaptic potential at subthreshold stimulus intensities,nor the pharmacologically isolated monosynaptic inhibitory postsynaptic potential were different in toxin-injected rats, suggesting a reduced synaptic excitation of interneurones. Stratum radiatum stimuli in toxin-injected rats, and not in controls, evoked antidromic activation of CA1 neurones, demonstrating axonal sprouting into areas normally devoid of CA1 pyramidal cell axons.We conclude that this combination of enduring changes in cellular and network properties, both pro-epileptic (increased recurrent excitatory connectivity, reduced recurrent inhibition and reduced afterhyperpolarisations) and anti-epileptic (impaired firing and reduced excitation), reaches a balance that allows remission of seizures, perhaps at the price of persistent cognitive impairment.

Dynamic modulation of excitation and inhibition during stimulation at gamma and beta frequencies in the CA1 hippocampal region.

Fast oscillations at gamma and beta frequency are relevant to cognition. During this activity, excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) are generated rhythmically and synchronously and are thought to play an essential role in pacing the oscillations. The dynamic changes occurring to excitatory and inhibitory synaptic events during repetitive activation of synapses are therefore relevant to fast oscillations. To cast light on this issue in the CA1 region of the hippocampal slice, we used a train of stimuli, to the pyramidal layer, comprising 1 s at 40 Hz followed by 2--3 s at 10 Hz, to mimic the frequency pattern observed during fast oscillations. Whole cell current-clamp recordings from CA1 pyramidal neurons revealed that individual stimuli at 40 Hz produced EPSPs riding on a slow biphasic hyperpolarizing-depolarizing waveform. EPSP amplitude initially increased; it then decreased concomitantly with the slow depolarization and with a large reduction in membrane resistance. During the subsequent 10-Hz train: the cells repolarized, EPSP amplitude and duration increased to above control, and no IPSPs were detected. In the presence of GABA(A) receptor antagonists, the slow depolarization was blocked, and EPSPs of constant amplitude were generated by 10-Hz stimuli. Altering pyramidal cell membrane potential affected the time course of the slow depolarization, with the peak being reached earlier at more negative potentials. Glial recordings revealed that the trains were associated with extracellular potassium accumulation, but the time course of this event was slower than the neuronal depolarization. Numerical simulations showed that intracellular chloride accumulation (due to massive GABAergic activation) can account for these observations. We conclude that synchronous activation of inhibitory synapses at gamma frequency causes a rapid chloride accumulation in pyramidal neurons, decreasing the efficacy of inhibitory potentials. The resulting transient disinhibition of the local network leads to a short-lasting facilitation of polysynaptic EPSPs. These results set constraints on the role that synchronous, rhythmic IPSPs may play in pacing oscillations at gamma frequency in the CA1 hippocampal region.

Pediatric psychotropic medication compliance: a literature review and research-based suggestions for improving treatment compliance.

Without good compliance the best psychiatric treatment is ineffective. This article reviews what is known or can be inferred about compliance with psychiatric medications in the pediatric population. The review includes discussions of assessment techniques, risk and protective factors, the relevant research literature, and research-based practical techniques to improve compliance. A Medline search surveying the years from 1966 to August 2000 yielded only seven peer-reviewed papers reporting on compliance with pediatric psychopharmacology. All seven studies looked at stimulant compliance among children with attention deficit hyperactivity disorder. Reported levels of compliance range from 56% to 75%. These rates, although low, are likely to be overestimates of actual compliance. We review two related areas of research for which there are small but significant bodies of knowledge: pharmacological compliance studies among adult psychiatric populations and pediatric medical populations. This literature supports the idea that medication compliance is a significant obstacle to the effective treatment of patients. Because compliance rates are lower for children as compared to adults and psychiatric patients as compared to medical patients, we suspect that children with psychiatric illness may be at great risk for poor medication compliance. Fortunately, the research literature demonstrates several simple techniques that clinicians can use to improve medication compliance among their patients. The treatment alliance; education; and medication duration, dosing, palatability, and cost can all be tailored to improve medication compliance.

Fast temporal interactions in human auditory cortex.

The temporal resolution of the human primary auditory cortex (AC) was studied using middle-latency evoked fields. Paired sounds with either the same or different spectral characteristics were presented with gaps between the sounds of 1, 4, 8 and 14 ms. Spatio-temporal modelling showed (1) that the response to the second sound was recognizable with gaps of 1 ms and rapidly increased in amplitude with increasing gap durations, (2) an enhanced N40m amplitude at gaps > 4 ms, (3) delayed N19m-P30m latencies when the stimuli were different. The median psychoacoustical thresholds were 1.6 ms for the same stimuli and 2.5 ms for different stimuli, confirming the electrophysiological evidence for rapid pattern-specific temporal processing in human primary auditory cortex.

On the synchronizing mechanisms of tetanically induced hippocampal oscillations.

gamma (30-100 Hz) and beta (10-30 Hz) oscillations follow tetanic stimulation in the CA1 region of the rat hippocampal slice. Pyramidal neurons undergo a slow depolarization after the tetanus and generate synchronous action potentials. The slow depolarization was previously attributed to metabotropic glutamate receptor (mGluR) activation. However, we found that this event was mediated by GABA(A) receptors, being blocked by bicuculline (50 microM) and accompanied by a dramatic drop in input resistance. Experiments with NMDA and non-NMDA glutamate receptor antagonists revealed that fast synaptic excitation was not necessary for oscillations. IPSPs were strongly depressed during the oscillations. Instead, synchronization was caused by field effects, as shown by: (1) Action potentials of pyramidal neurons proximal (<200 micrometer) to the stimulation site were often preceded by negative deflections of the intracellular potential that masked a net transmembrane depolarization caused by the population spike. (2) Pyramidal neurons located on the surface of the slice, where field effects are weak, fired repetitively but were not synchronized to the network activity. (3) A moderate decrease (50 mOsm) in artificial CSF (ACSF) osmolality did not affect the slow depolarization but increased oscillation amplitude and duration and recruited previously silent neurons into oscillations. (4) 50 mOsm increase in ACSF osmolality dramatically reduced, or abolished, post-tetanic oscillations. Phasic IPSPs, not detectable in proximal neurons, were present, late in the oscillation, in cells located 200-400 micrometer from the stimulation site and possibly contributed to slowing the rhythm during the gamma to beta transition.

Historical clues to the diagnosis of the dysfunctional child and other psychiatric disorders in children.

This article focuses on selected historical clues that can help the busy pediatrician identify children who are at risk for or already suffering from psychosocial dysfunction. Certain historical elements have been chosen because they reveal either common areas of childhood dysfunction or potentially dire outcomes. The major function realms of a child's life are covered, such as family, school, peer relationships, activities, and emotions, as well as related topics such as injury, poverty, substance abuse, and risk-taking behavior. Questions designed to elicit the relevant historical clues are suggested. Used as a set, these questions are intended to bring to light sufficient psychosocial history for pediatricians to identify most dysfunctional children.

Early identification of emotional and behavioral problems in a primary care setting.

Adolescence is a time when many psychiatric disorders first manifest themselves. The challenge to pediatricians is to recognize early signs of behavioral problems in their adolescent patients. This review suggests several practical approaches to the detection, assessment, and treatment of emotional problems in adolescents within the time limits of a typical pediatric exam. The approaches presented range from general health supervision of all adolescents to more intensive evaluation of at-risk adolescents.

Anorexia nervosa in a 7-year-old girl.

We report on a 7-year-old girl with anorexia nervosa and consider factors contributing to this early emergency. Cognitive differences in younger children can alter their understanding of this illness, so we chronicled this girl's treatment because it diverged from practices used with older patients. Accordingly, effective interventions in very young anorexics might require modifications of treatments used in postpubertal populations.

Resting energy expenditure. Evolution during antibiotic treatment for pulmonary exacerbation in cystic fibrosis.

STUDY OBJECTIVES: To compare the changes in resting energy expenditure (REE) to concomitant changes in clinical status and pulmonary function in cystic fibrosis (CF) patients during treatment for acute pulmonary exacerbation. To determine if weight loss during exacerbation in CF is related to decreased calorie intake or increased energy needs. DESIGN: Measurements of REE, pulmonary function tests, oxygen saturation, respiratory rate, maximal inspiratory pressure (MIP), white blood cell count, chest x-ray films and attribution of clinical score (ACS) on admission, mid-hospitalization, and discharge. Anthropometric measurements on admission, assessment of dietary intake and nitrogen balance upon admission and prior to discharge. SUBJECTS: Thirteen CF patients admitted for treatment of acute pulmonary exacerbation with a mean age of 11.0 +/- 7.9 (SD) years. RESULTS: From admission to discharge, REE decreased from 44.5 +/- 9.0 to 33.8 +/- 8.5 kilocalorie (kcal)/kg/d (p < 0.003). Similarly, the ACS improved from 7.5 +/- 2.0 to 4.0 +/- 2.2 (p < 0.0001); the absolute neutrophil count decreased from 10,685 +/- 6,226/microliters to 6,363 +/- 168/microliters (p < 0.005); respiratory rate decreased from 32.6 +/- 6.2 to 25.0 +/- 3.7 breaths per minute (p < 0.01); and MIP increased from 77.5 +/- 20.0 to 90.0 +/- 20.4 cm H2O (p < 0.01). In parallel, less significant improvements occurred in pulmonary function tests, oxygen saturation and chest x-ray film scores. Calorie intake was 1,893 +/- 635 and 2,054 +/- 707 kcal/d on admission and discharge, respectively (p = NS); during hospitalization, weight increased from 23.6 +/- 10.1 to 25.7 +/- 10.1 kg (p < 0.005). While carbohydrate and fat content of the diet remained essentially unchanged, a significant increase in protein intake (3.15 +/- 0.92 to 3.5 +/- 0.81 g/kg/d [p < 0.05]) and in nitrogen balance (1.8 +/- 2.5 to 5.6 +/- 2.9 g of nitrogen per day [p < 0.05]) were observed. CONCLUSIONS: In acute CF, pulmonary exacerbation, changes in REE parallel those of clinical improvements and are more sensitive than pulmonary function tests and chest x-ray films as an objective clinical correlate. Increased metabolic requirements but not decreased dietary intake are the cause of weight loss in CF patients.

Antibodies to human papillomavirus and to other genital infectious agents and invasive cervical cancer risk.

Human papillomaviruses (HPVs) play an important part in the development of cervical cancer, but the role of other infectious agents, such as herpes simplex virus (HSV), is not clear. We assayed serum samples collected from 219 women with cervical cancer and from 387 controls for antibody to infectious agents. HPV 16-E7 and/or HPV 18-E7 antibodies were significantly related to cervical cancer risk (RR 1.9, 95% CI 1.2-3.2). Antibodies to HSV types 1 and 2, Chlamydia trachomatis, and to multiple infectious agents were associated with cervical cancer when seroprevalence rates in all cases and controls were compared, but when HPV-seropositive cases and controls were compared these associations were weaker and non-significant. This finding suggests that past infections with sexually transmitted infections other than HPV may be surrogate markers of exposure to HPV, and of no separate aetiological significance.

Vitamin E measurement in patients receiving intravenous lipid emulsions.

Two methods for the determination of plasma vitamin E--high-pressure liquid chromatography and spectrophotofluorometry--were compared on samples from four groups of pediatric patients: children and infants receiving lipid emulsion as part of their parenteral nutrition regimen, neonates receiving parenteral nutrition who were not receiving lipid emulsion at the time of blood sampling, and short admission surgery control subjects. In control subjects and patients not receiving lipid emulsions, both methods yielded similar results for vitamin E as alpha-tocopherol. In contrast, in patients receiving lipid emulsion, the fluorometric method yielded values ranging from 200% to 300% greater than did high-pressure liquid chromatography. The source of the discrepancy is most probably the presence of naturally occurring non-alpha-tocopherol isomers in the lipid products, which add to the fluorescent measurement but are resolved by high-pressure liquid chromatography. This study confirms clinically that fluorescent measurement of vitamin E is no longer the method of choice for monitoring tocopherol status in intensive care nurseries.

Effect of cigarettes on memory search and subjective ratings.

The effects of smoking a nicotine versus a nonnicotine cigarette on performance on Sternberg's memory search task and subjective ratings were examined. Testing sessions were undertaken both before and after a period of 24 hours' abstinence in occasional and regular smokers. Memory search rate was significantly faster after the nicotine cigarette than the nonnicotine cigarette. No significant difference in search rate was found between the results from occasional and regular smokers, and between the effect of a cigarette before and after the period of abstinence. The regular smokers inhaled more smoke from the nicotine and nonnicotine cigarettes than did the occasional smokers, but the amount of smoke inhaled from the test cigarettes did not change significantly from pre- to postabstinence. The nicotine cigarette produced stronger dizziness, tremor and palpitations than the nonnicotine cigarette, the more so after abstinence than before in the regular smokers. The results indicate that smoking a cigarette can produce subjective effects and performance improvements in regular and occasional smokers during the course of normal smoking, and that some subjective effects can be greater after abstinence.

Serum vitamin A and E concentrations in pediatric total parenteral nutrition patients.

There is uncertainty as to optimal doses of fat soluble vitamins required by pediatric total parenteral nutrition (TPN) patients. We compared serum vitamin A (A) and E (E) concentrations analyzed by HPLC in chronic (greater than 2 weeks) TPN patients aged 1 month to 12 years to values obtained in out-patient surgery patients of the same age. TPN patients received 1500 micrograms of retinol and 2.5 IU of E as alpha-tocopheryl acetate (2.5 ml LyphoMed Multi Vitamin Concentrate). These doses were 214% of the recommended dose of A and 36% for E. Oral intake was minimal in most patients. The results of our study revealed a mean serum A level for TPN patients (N = 29) of 26.0 +/- 15.0 (SD) micrograms/dl vs 25.0 +/- 10.0 (SD) micrograms/dl in controls (N = 52). Mean serum E was 0.63 +/- 0.24 (SD) mg/dl vs 0.89 +/- 0.31 (SD) mg/dl for TPN patients and controls, respectively. There was no consistent trend related to duration of TPN for 23 patients with serial values. Seven (24%) TPN patients had serum A greater than mean + 2 SD of control (p less than 0.01). No values were less than mean - 2 SD. Infants on TPN had a significantly lower mean serum A (22.3 +/- 10.9 micrograms/dl) than TPN patients greater than 1 year of age (34.1 +/- 16.0 micrograms/dl; p less than 0.001). Fifty-two percent of TPN patients vs 26% of control had serum A less than 20 micrograms/dl (p greater than 0.1). For E, one patient had a high value and two patients low values relative to control.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic ventilation scintigraphy: a comparison of parameter estimation gating models.

Two procedures for providing the synchronization of ventilation scintigraphic data to create dynamic displays of the pulmonary cycle are described and compared. These techniques are based on estimating instantaneous lung volume by pneumotachometry and by scintigraphy. Twenty-three patients were studied by these two techniques. The results indicate that the estimation of the times of end-inspiration and end-expiration are equivalent by the two techniques but the morphologies of the two estimated time-volume waveforms are not equivalent. Ventilation cinescintigraphy based on time division gating but not on isovolume division gating can be equivalently generated from list mode acquired data by employing either technique described.