Optimization of Nutrition after Brain Injury: Mechanistic and Therapeutic Considerations.

Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed.

Multi-scale structural alterations of the thalamus and basal ganglia in focal epilepsy using 7T MRI.

Focal epilepsy is characterized by repeated spontaneous seizures that originate from cortical epileptogenic zone networks (EZN). Analysis of intracerebral recordings showed that subcortical structures, and in particular the thalamus, play an important role in seizure dynamics as well, supporting their structural alterations reported in the neuroimaging literature. Nonetheless, between-patient differences in EZN localization (e.g., temporal vs. non-temporal lobe epilepsy) as well as extension (i.e., number of epileptogenic regions) might impact the magnitude as well as spatial distribution of subcortical structural changes. Here we used 7 Tesla MRI T1 data to provide an unprecedented description of subcortical morphological (volume, tissue deformation, and shape) and longitudinal relaxation (T1 ) changes in focal epilepsy patients and evaluate the impact of the EZN and other patient-specific clinical features. Our results showed variable levels of atrophy across thalamic nuclei that appeared most prominent in the temporal lobe epilepsy group and the side ipsilateral to the EZN, while shortening of T1 was especially observed for the lateral thalamus. Multivariate analyses across thalamic nuclei and basal ganglia showed that volume acted as the dominant discriminator between patients and controls, while (posterolateral) thalamic T1 measures looked promising to further differentiate patients based on EZN localization. In particular, the observed differences in T1 changes between thalamic nuclei indicated differential involvement based on EZN localization. Finally, EZN extension was found to best explain the observed variability between patients. To conclude, this work revealed multi-scale subcortical alterations in focal epilepsy as well as their dependence on several clinical characteristics.

Awareness of social care needs in people with epilepsy and intellectual disability.

BACKGROUND: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. PURPOSE: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. METHOD: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher's exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. RESULTS: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. CONCLUSIONS: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways.

Optimized addition of nitric oxide compounds in semen extender improves post-thaw seminal attributes of Murrah buffaloes.

Semen dilution and cryopreservation alter the homogeneity of seminal plasma, resulting in a non-physiological redox milieu and consequently poor sperm functionality. Considering the concentration-specific bimodal action of nitric oxide (NO) in the regulation of sperm functions, cryopreservation media supplemented with optimized concentrations can improve the semen attributes. The present study aimed to evaluate the effect of adding an optimized concentration of sodium nitroprusside (SNP) and N-nitro-L-arginine methyl ester (L-NAME) in an extender on in vitro semen quality. An aliquot of semen samples (n = 32) from Murrah buffalo bulls (n = 8) was divided into control (C) and treatment (T-I: SNP in extender at 1 µmol/L; T-II: L-NAME in extender at 10 µmol/L). Fresh semen quality parameters showed no significant difference at 0 h except for the structural integrity in the T-II group. Post-thaw semen quality parameters and sperm kinematics using computer-aided sperm analysis (CASA) revealed significantly higher (p < 0.05) cryoresistance in the treatment groups. Viability, acrosome integrity, and membrane integrity were significantly higher (p < 0.05) in both treatment groups; however, the results were pervasive in T-II. Lower abnormal spermatozoa were observed in both T-I and T-II. SNP supplementation led to a significant rise (p < 0.05) in NO, whereas L-NAME reduced the NO concentration in post-thawed samples, which was directly correlated with different sperm functionality and associated biomarkers viz. total antioxidant capacity (TAC) and thiobarbituric acid reactive substance (TBARS). It was concluded that the cryopreservation media supplemented with SNP and L-NAME at 1 µmol/L and 10 µmol/L, respectively, lower the cryo-damage and improve post-thaw seminal attributes.

Resiliencies of soil phosphorus fractions after natural summer fire are governed by microbial activity and cation availability in a semi-arid Inceptisol.

The unintended impact of natural summer fire on soil is complicated and rather less studied than its above-ground impact. Recognising the impact of a fire on silvopastoral soils and their resilience can aid in improving the management of silvopastoral systems. We studied the immediate (after 1 week (W)) and short-term (after 3 months (M)) recovery of different soil biological and chemical properties after the natural fire, with specific emphasis on phosphorus (P) dynamics. Soil samples were collected from four different layers (0-15, 15-30, 30-45, and 45-60 cm) of Morus alba, Leucaena leucocephala, and Ficus infectoria based silvopastoral systems. In the 0-15 cm soil layer, soil organic carbon (SOC) declined by ∼37, 42, and 30% after the fire in Morus-, Leucaena-, and Ficus-based systems, respectively within 1W of fire. However, after 3M of fire, Morus and Leucaena regained ∼6 and 11.5% SOC as compared to their status after 1W in the 0-15 cm soil layer. After 1W of the fire, soil nitrogen (N), sulfur (S), and potassium availability declined significantly at 0-15 cm soil layer in all systems. Iron and manganese availability improved significantly after 1W of the fire. Saloid bound P and aluminium bound P declined significantly immediately after the fire, increasing availability in all systems. However, calcium bound P did not change significantly after the fire. Dehydrogenase and alkaline phosphatase activity declined significantly after the fire, however, phenol oxidase and peroxidase activity were unaltered. Resiliencies of these soil properties were significantly impacted by soil depth and time. Path analysis indicated microbial activity and cationic micronutrients majorly governed the resilience of soil P fractions and P availability. Pasture yield was not significantly improved after the fire, so natural summer fire must be prevented to avoid loss of SOC, N, and S.

Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer's dementia.

BACKGROUND: Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer's disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration. METHODS: Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype. RESULTS: Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes. CONCLUSION: These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.

Honokiol Affects Stem Cell Viability by Suppressing Oncogenic YAP1 Function to Inhibit Colon Tumorigenesis.

Honokiol (HNK) is a biphenolic compound that has been used in traditional medicine for treating various ailments, including cancers. In this study, we determined the effect of HNK on colon cancer cells in culture and in a colitis-associated cancer model. HNK treatment inhibited proliferation and colony formation while inducing apoptosis. In addition, HNK suppressed colonosphere formation. Molecular docking suggests that HNK interacts with reserve stem cell marker protein DCLK1, with a binding energy of -7.0 Kcal/mol. In vitro kinase assays demonstrated that HNK suppressed the DCLK1 kinase activity. HNK also suppressed the expression of additional cancer stem cell marker proteins LGR5 and CD44. The Hippo signaling pathway is active in intestinal stem cells. In the canonical pathway, YAP1 is phosphorylated at Ser127 by upstream Mst1/2 and Lats1/2. This results in the sequestration of YAP1 in the cytoplasm, thereby not allowing YAP1 to translocate to the nucleus and interact with TEAD1-4 transcription factors to induce gene expression. However, HNK suppressed Ser127 phosphorylation in YAP1, but the protein remains sequestered in the cytoplasm. We further determined that this occurs by YAP1 interacting with PUMA. To determine if this also occurs in vivo, we performed studies in an AOM/DSS induced colitis-associated cancer model. HNK administered by oral gavage at a dose of 5mg/kg bw for 24 weeks demonstrated a significant reduction in the expression of YAP1 and TEAD1 and in the stem marker proteins. Together, these data suggest that HNK prevents colon tumorigenesis in part by inducing PUMA-YAP1 interaction and cytoplasmic sequestration, thereby suppressing the oncogenic YAP1 activity.

Hidden labour: the skilful work of clinical audit data collection and its implications for secondary use of data via integrated health IT.

BACKGROUND: Secondary use of data via integrated health information technology is fundamental to many healthcare policies and processes worldwide. However, repurposing data can be problematic and little research has been undertaken into the everyday practicalities of inter-system data sharing that helps explain why this is so, especially within (as opposed to between) organisations. In response, this article reports one of the most detailed empirical examinations undertaken to date of the work involved in repurposing healthcare data for National Clinical Audits. METHODS: Fifty-four semi-structured, qualitative interviews were carried out with staff in five English National Health Service hospitals about their audit work, including 20 staff involved substantively with audit data collection. In addition, ethnographic observations took place on wards, in 'back offices' and meetings (102 h). Findings were analysed thematically and synthesised in narratives. RESULTS: Although data were available within hospital applications for secondary use in some audit fields, which could, in theory, have been auto-populated, in practice staff regularly negotiated multiple, unintegrated systems to generate audit records. This work was complex and skilful, and involved cross-checking and double data entry, often using paper forms, to assure data quality and inform quality improvements. CONCLUSIONS: If technology is to facilitate the secondary use of healthcare data, the skilled but largely hidden labour of those who collect and recontextualise those data must be recognised. Their detailed understandings of what it takes to produce high quality data in specific contexts should inform the further development of integrated systems within organisations.

Neurobiology and Spirituality in Addiction Recovery.

This commentary explores the neurobiology of spirituality and asks whether it is possible or desirable to apply genetic engineering to increase human spiritual and religious experience - (gene-spirituality) to deal better with the ever-increasing catastrophes that face humanity? Neurological connections between spirituality and reward genes, reward deficiencies (RDS) (hypodopaminergia), the mirror neuron system, and the default mode network are examined. Some interventions from addiction medicine that may be useful to enhance the neuro-spirituality connectome identified as a cornerstone of the Purpose and Meaning of Life as Reward (PMLR) are identified as reasonable targets for interventions to treat RDS and balance DMN activity.

Online interventions aimed at reducing psychological distress in cancer patients: evidence update and suggestions for future directions.

PURPOSE OF REVIEW: A great proportion of people affected by cancer experience psychological distress. To reduce pressure on limited health-management resources available, evidence-based eHealth or online interventions can fill an important gap by making psychosocial care more easily accessible. However, evidence of their effectiveness is mixed. This present review provides an update on the effectiveness of online interventions in reducing psychological distress in patients with cancer by including studies published from January 2018 to September 2019. RECENT FINDINGS: Thirty-three publications describing online interventions were included in the review, including web-based, blended care, telehealth, mHealth, and other online interventions. There was great heterogeneity across studies. The evidence of online interventions' effectiveness in reducing distress was mixed; there was partial support for reduction in psychological distress and depression, but limited evidence for reducing anxiety. Some important limitations should be taken into account when interpreting the results. SUMMARY: Online interventions for people affected by cancer, in general, are well received and seem to be a necessary component of comprehensive cancer care. However, these interventions should be more rigorously tested to provide more conclusive evidence about their effectiveness.

New role for crinamine as a potent, safe and selective inhibitor of human monoamine oxidase B: In vitro and in silico pharmacology and modeling.

ETHNOPHARMACOLOGICAL RELEVANCE: The development of selective inhibitors of monoamine oxidase B (MAO-B) has been essential in treating Parkinson's disease. However, the apparent hepatotoxicity and drug-drug interactions of current inhibitors accentuate the need for the development of novel pharmacotherapies. Crossyne guttata (L.) D. & U. Müll-Doblies is used frequently by Rastafarian bush doctors to treat alcoholism, a disorder which is also accentuated by MAO. OBJECTIVE: The study sought to isolate, identify and characterise the biologically active constituents of C. guttata based on their ability to inhibit the MAO enzymes. MATERIALS AND METHODS: Column chromatography was used to isolate the biologically active alkaloids of C. guttata. The ability of the alkaloids to inhibit the biotransformation of 4-aminoantipyrine by the MAO enzymes was evaluated in vitro. In silico docking was conducted using AutoDock Vina server while the pharmacokinetic properties of the compounds were evaluated using SwissADME. RESULTS: Chromatographic separation of an ethanolic fraction of C. guttata yielded the alkaloids crinamine 1 and epibuphanisine 2. 1 and 2 along with structurally related alkaloids haemanthamine 3 and haemanthidine 4 were evaluated for their ability to inhibit the action of isozymes of MAO in vitro. Alkaloids effected submicromolar IC50 values against MAO-B, the most potent of which being crinamine 1 (0.014 µM) > haemanthidine 4 (0.017 µM) > epibuphanisine 2 (0.039 µM) > haemanthamine 3 (0.112 µM). Binding energies of the alkaloids correlated well with their inhibitory potential with crinamine displaying the best binding efficacy and binding energy score with MAO-B. DISCUSSION AND CONCLUSION: Crinamine and epibuphanisine exhibited potent and selective inhibitory activity towards MAO-B. After comprehensive in silico investigations encompassing robust molecular docking analysis, the drug-like attributes and safety of the alkaloids suggest the crinamine is a potentially safe drug for human application.

Glycopyrrolate/eFlow CS: The First Nebulized Long-Acting Muscarinic Antagonist Approved to Treat Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS) nebulizer, approved for maintenance treatment of chronic obstructive pulmonary disease (COPD). DATA SOURCES: A PubMed search was conducted (January 2000 to July 2018) using the following terms/phrases: nebulized glycopyrrolate, inhalation devices in COPD, long-acting muscarinic antagonists COPD, and COPD survey. Retrieved articles were reviewed to identify additional references. STUDY SELECTION AND DATA EXTRACTION: Primary and review articles on GLY/eFlow CS and other treatment options for patients with COPD were selected. DATA SYNTHESIS: Guidelines recommend the use of LAMAs, alone or in combination with long-acting ß2-agonists, as maintenance therapy for the majority of patients with COPD. With the range of different devices and bronchodilators now available, treatment can be tailored based on individual needs. The eFlow CS nebulizer delivers GLY rapidly over a 2- to 3-minute period and provides bronchodilation within 30 minutes, lasting 12 hours. Phase 2 dose-finding and phase 3 studies demonstrated sustained statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with GLY/eFlow CS. Relevance to Patient Care and Clinical Practice: GLY/eFlow CS provides a novel, portable, efficient, and rapid drug delivery system. CONCLUSIONS: The recently approved GLY/eFlow CS drug-device combination provides a viable treatment option for patients with COPD, particularly those with conditions that may impair proper use of traditional handheld inhalers.

Problem behaviours and psychotropic medication use in intellectual disability: a multinational cross-sectional survey.

BACKGROUND: Problem behaviours (PBs) are a common cause for clinician contact in people with disorders of intellectual development and may be a common cause for the prescription of psychotropic medication. We aimed to use a large, multinational sample to define the prevalence of PBs, the associations with psychotropic medication use, and to assess for any potential 'diagnostic overshadowing' by the label of PBs in a population of people with disorders of intellectual development. METHOD: A multinational, multi-setting, cross-sectional service evaluation and baseline audit was completed. Data were collected from UK hospitals, UK community settings, Sri Lanka and Hong Kong. A semi-structured questionnaire was completed by treating clinicians, capturing demographic details, prevalence rates of intellectual disability and psychotropic medication use, alongside psychiatric co-morbidity. RESULTS: A sample size of 358 was obtained, with 65% of included participants treated in an inpatient setting. Psychotropic use was prevalent (90%) in our sample, particularly antipsychotics (74%). The prevalence of PB was high (83%). There was no statistically significant association between psychotropic prescription and recorded psychiatric co-morbidity, suggesting prevalent 'off-label' use for PBs, or poor recording of psychiatric co-morbidity. There was some evidence of possible diagnostic overshadowing due to the PB classification. A higher dose of psychotropic medication was associated with aggression toward others (P = 0.03). CONCLUSIONS: We found evidence of prevalent potential 'off-label' use for psychotropic medication, which may be due to PBs. We also found evidence of potential diagnostic-overshadowing, where symptoms of psychiatric co-morbidity may have been attributed to PBs. Our findings provide renewed importance, across borders and health systems, for clinicians to consider a holistic approach to treating PBs, and attempting to best understand the precipitants and predisposing factors before psychotropic prescribing.

Association of prenatal folate status with early childhood wheeze and atopic dermatitis.

BACKGROUND: Prenatal folic acid supplementation is recommended to prevent birth defects. Some foods are fortified in the USA to ensure sufficient intake among reproductive-aged women. However, high prenatal folate exposure may be a risk factor for childhood atopic diseases. We investigated associations between prenatal folate and early childhood wheeze and atopic dermatitis in a US cohort. METHODS: We studied 858 mother-child dyads, enrolled prenatally. Folate was measured in 2nd and 3rd trimester maternal plasma. Parents reported current wheeze (previous 12 months) and healthcare provider diagnosis of atopic dermatitis at 3 years. We examined associations using logistic regression, modeling folate continuously and dichotomously (< or ≥20 ng/mL), a level often considered supraphysiologic. RESULTS: Over half of women were African American and on Medicaid. Median (interquartile range) folate levels were 22.6 (15.9-30.0) and 23.1 (16.1-30.0) ng/mL for 2nd and 3rd trimesters, respectively. Current wheeze and atopic dermatitis were reported for 20.4% and 26.8% of children, respectively. Second trimester folate as a continuous exposure was not significantly associated with outcomes. Decreased odds of current wheeze were observed in children born to mothers who had 2nd trimester folate ≥20 ng/mL (adjusted odds ratios = 0.67, 95% confidence interval = 0.46, 0.97) compared to children with maternal levels <20 ng/mL. Third trimester folate was not associated with outcomes. CONCLUSIONS: High plasma folate in mid-pregnancy was associated with decreased odds of current wheeze at age 3. Our findings do not support harmful effects of high prenatal folate levels on childhood atopic diseases in this setting.

Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass.

Background Roux-en-Y gastric bypass increases circulating bile acid concentrations, known mediators of postprandial suppression of markers of bone resorption. Long-term data, however, indicate that Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients. Methods Thirty-six obese individuals, median age 44 (26-64) with median body mass index at baseline of 42.5 (40.4-46) were studied before and 15 months after Roux-en-Y gastric bypass. After an overnight fast, patients received a 400 kcal mixed meal. Blood samples were collected premeal then at 30-min periods for 120 min. Pre and postmeal samples were analysed for total bile acids, parathyroid hormone and C-terminal telopeptide. Results Body weight loss post Roux-en-Y gastric bypass was associated with a median 4.9-fold increase in peak postprandial total bile acid concentration, and a median 2.4-fold increase in cumulative food evoked bile acid response. Median fasting parathyroid hormone, postprandial reduction in parathyroid hormone and total parathyroid hormone release over 120 min remained unchanged after surgery. After surgery, median fasting C-terminal telopeptide increased 2.3-fold, peak postprandial concentrations increased 3.8-fold and total release was increased 1.9-fold. Conclusions Fasting and postprandial total bile acids and C-terminal telopeptide are increased above reference range after Roux-en-Y gastric bypass. These changes occur in spite of improved vitamin D status with supplementation. These results suggest that post-Roux-en-Y gastric bypass increases in total bile acids do not effectively oppose an ongoing resorptive signal operative along the gut-bone axis. Serial measurement of C-terminal telopeptide may be of value as a risk marker for long-term skeletal pathology in patients post Roux-en-Y gastric bypass.

Development and validation of the Learning Disabilities Needs Assessment Tool (LDNAT), a HoNOS-based needs assessment tool for use with people with intellectual disability.

BACKGROUND: In meeting the needs of individuals with intellectual disabilities (ID) who access health services, a brief, holistic assessment of need is useful. This study outlines the development and testing of the Learning Disabilities Needs Assessment Tool (LDNAT), a tool intended for this purpose. METHOD: An existing mental health (MH) tool was extended by a multidisciplinary group of ID practitioners. Additional scales were drafted to capture needs across six ID treatment domains that the group identified. LDNAT ratings were analysed for the following: item redundancy, relevance, construct validity and internal consistency (n = 1692); test-retest reliability (n = 27); and concurrent validity (n = 160). RESULTS: All LDNAT scales were deemed clinically relevant with little redundancy apparent. Principal component analysis indicated three components (developmental needs, challenging behaviour, MH and well-being). Internal consistency was good (Cronbach alpha 0.80). Individual item test-retest reliability was substantial-near perfect for 20 scales and slight-fair for three scales. Overall reliability was near perfect (intra-class correlation = 0.91). There were significant associations with five of six condition-specific measures, i.e. the Waisman Activities of Daily Living Scale (general ability/disability), Threshold Assessment Grid (risk), Behaviour Problems Inventory for Individuals with Intellectual Disabilities-Short Form (challenging behaviour) Social Communication Questionnaire (autism) and a bespoke physical health questionnaire. Additionally, the statistically significant correlations between these tools and the LDNAT components made sense clinically. There were no statistically significant correlations with the Psychiatric Assessment Schedules for Adults with Developmental Disabilities (a measure of MH symptoms in people with ID). CONCLUSIONS: The LDNAT had clinically utility when rating the needs of people with ID prior to condition-specific assessment(s). Analyses of internal and external validity were promising. Further evaluation of its sensitivity to changes in needs is now required.

Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy.

Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3'-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.

Optogenetic Activation of a Lateral Hypothalamic-Ventral Tegmental Drive-Reward Pathway.

Electrical stimulation of the lateral hypothalamus can motivate feeding or can serve as a reward in its own right. It remains unclear whether the same or independent but anatomically overlapping circuitries mediate the two effects. Electrical stimulation findings implicate medial forebrain bundle (MFB) fibers of passage in both effects, and optogenetic studies confirm a contribution from fibers originating in the lateral hypothalamic area and projecting to or through the ventral tegmental area. Here we report that optogenetic activation of ventral tegmental fibers from cells of origin in more anterior or posterior portions of the MFB failed to induce either reward or feeding. The feeding and reward induced by optogenetic activation of fibers from the lateral hypothalamic cells of origin were influenced similarly by variations in stimulation pulse width and pulse frequency, consistent with the hypothesis of a common substrate for the two effects. There were, however, several cases where feeding but not self-stimulation or self-stimulation but not feeding were induced, consistent with the hypothesis that distinct but anatomically overlapping systems mediate the two effects. Thus while optogenetic stimulation provides a more selective tool for characterizing the mechanisms of stimulation-induced feeding and reward, it does not yet resolve the question of common or independent substrates.

Clinical relevance of trace element measurement in patients on initiation of parenteral nutrition.

Background and Aims Serum zinc, copper and selenium are measured in patients prior to commencing on parenteral nutrition; however, their interpretation can be difficult due to acute phase reactions. We assessed (i) the relationship of raised C-reactive protein with trace elements and albumin (ii) benefits of measuring trace elements when C-reactive protein is raised in patients requiring short-term parenteral nutrition. Methods Samples were collected for zinc, copper, selenium and albumin at baseline and then every two weeks and correlated with C-reactive protein results in patients on parenteral nutrition. Results were categorized into four groups based on the C-reactive protein concentrations: (i) <20 mg/L, (ii) 20-39 mg/L, (iii) 40-79 mg/L and (iv) ≥80 mg/L. Results In 166 patients, zinc, selenium and albumin correlated (Spearman's) negatively with C-reactive protein; r = -0.26, P < 0.001 (95% CI -0.40 to -0.11), r = -0.44, P < 0.001 (-0.56 to -0.29) and r = -0.22 P = 0.005 (-0.36 to -0.07), respectively. Copper did not correlate with C-reactive protein (r = 0.09, P = 0.25 [-0.07 to 0.25]). Comparison of trace elements between the four groups showed no difference in zinc and copper (both P > 0.05), whereas selenium and albumin were lower in the group with C-reactive protein > 40 mg/L ( P < 0.05). Conclusion In patients on short-term parenteral nutrition, measurement of C-reactive protein is essential when interpreting zinc and selenium but not copper results. Routine measurement of trace elements prior to commencing parenteral nutrition has to be considered on an individual basis in patients with inflammation.