Daikenchuto increases blood flow in the superior mesenteric artery in humans: A comparison study between four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction magnetic resonance imaging and Doppler ultrasound.

Respiratory-gated four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction (4D PC-VIPR) is magnetic resonance (MR) imaging technique that enables analysis of vascular morphology and hemodynamics in a single examination using cardiac phase resolved 3D phase-contrast magnetic resonance imaging. The present study aimed to assess the usefulness of 4D PC-VIPR for the superior mesenteric artery (SMA) flowmetry before and after flow increase was induced by the herbal medicine Daikenchuto (TJ-100) by comparing it with Doppler ultrasound (DUS) as a current standard. Twenty healthy volunteers were enrolled in this prospective single-arm study. The peak cross-sectionally averaged velocity was measured by 4D PC-VIPR, peak velocity was measured by DUS, and flow volume (FV) of SMA and aorta were measured by 4D PC-VIPR and DUS 25 min before and after the peroral administration of TJ-100. The peak cross-sectionally averaged velocity, peak velocity, and FV of SMA measured by 4D PC-VIPR and DUS significantly increased after administration of TJ-100 (4D PC-VIPR: the peak cross-sectionally averaged velocity; p = 0.004, FV; p = 0.035, DUS: the peak velocity; p = 0.003, FV; p = 0.010). Furthermore, 4D PC-VIPR can analyze multiple blood vessels simultaneously. The ratio of the SMA FV to the aorta, before and after oral administration on the 4D PC-VIPR test also increased (p = 0.015). The rate of change assessed by 4D PC-VIPR and DUS were significantly correlated (the peak cross-sectionally averaged velocity and peak velocity: r = 0.650; p = 0.005, FV: r = 0.659; p = 0.004). Retrospective 4D PC-VIPR was a useful modality for morphological and hemodynamic analysis of SMA.

Bioactivation of α,ß-Unsaturated Carboxylic Acids Through Acyl Glucuronidation.

After oral administration to monkeys of [14C]GDC-0810, an α,ß-unsaturated carboxylic acid, unchanged parent and its acyl glucuronide metabolite, M6, were the major circulating drug-related components. In addition, greater than 50% of circulating radioactivity in plasma was found to be nonextractable 12 hours post-dose, suggesting possible covalent binding to plasma proteins. In the same study, one of the minor metabolites was a cysteine conjugate of M6 (M11) that was detected in plasma and excreta (urine and bile). The potential mechanism for the covalent binding to proteins was further investigated using in vitro methods. In incubations with glutathione (GSH) or cysteine (5 mM), GSH and cysteine conjugates of M6 were identified, respectively. The cysteine reaction was efficient with a half-life of 58.6 minutes (k react = 0.04 1/M per second). Loss of 176 Da (glucuronic acid) followed by 129 Da (glutamate) in mass fragmentation analysis of the GSH adduct of M6 (M13) suggested the glucuronic acid moiety was not modified. The conjugation of N-glucuronide M4 with cysteine in buffer was >1000-fold slower than with M6. Incubations of GDC-0810, M4, or M6 with monkey or human liver microsomes in the presence of NADPH and GSH did not produce any oxidative GSH adducts, and the respective substrates were qualitatively recovered. In silico analysis quantified the inherent reactivity differences between the glucuronide and its acid precursor. Collectively, these results show that acyl glucuronidation of α,ß-unsaturated carboxylic acids can activate the compound toward reactivity with GSH, cysteine, or other biologically occurring thiols and should be considered during the course of drug discovery. SIGNIFICANCE STATEMENT: Acyl glucuronidation of the α,ß-unsaturated carboxylic acid in GDC-0810 activates the conjugated alkene toward nucleophilic addition by glutathione or other reactive thiols. This is the first example that a bioactivation mechanism could lead to protein covalent binding to α,ß-unsaturated carboxylic acid compounds.

A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer.

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

Understanding inter-organizational trust among integrated care service provider networks: A perspective on organizational asymmetries.

OBJECTIVE: To explore the factors that influence trust among the integrated healthcare service provider network in the context of seeking combined health and care services in the UK. DATA SOURCES/STUDY SETTING: Primary data were collected from three regional integrated care service provider networks from March 2016 to October 2017. STUDY DESIGN: Explorative qualitative study and inductive methods from emerging findings. DATA COLLECTION/EXTRACTION METHODS: We conducted qualitative semi-structured interviews in three care networks and collected organizational documents from local integration boards from 2016 to 2017. Thematic analysis was performed in three large care networks with hospital staff, local councils, integration boards, and community and voluntary organizations under the NHS England Better Care Fund. PRINCIPAL FINDINGS: Our findings reveal that trust among integrated care service provider networks is influenced by the following factors on various asymmetries: 1) recognition and knowledge asymmetries among care service partners of each other's skills, expertise and capabilities; 2) capacity and financial imbalances within the network; and 3) organizational differences in management, culture and attitudes toward change. CONCLUSION: There is a need to improve competence recognition and capacity imbalances and to foster open minds toward change within networks to build trust to overcome divisions and facilitate integrated services among health and care organizations.

Vitamin D deficiency and fatigue: an unusual presentation.

Fatigue is a vague but common complaint that is poorly characterized by physicians as well as patients. While fatigue may result from a number of different etiologies, at the present time, a comprehensive approach to each patient with fatigue does not include routine measurement of serum vitamin D levels. A 61-year-old man was evaluated for excessive daytime fatigue. No features characteristic for depression, sleep apnea, or narcolepsy were present. A comprehensive work-up, including thyroid function tests and testosterone levels, did not reveal any abnormalities. However, serum 25-hydroxyvitamin D level was low, at 18.4 ng/mL. Vitamin D supplementation was initiated. At follow-up in 3 and 12 months, the patient reported complete resolution of daytime fatigue, corresponding to an increase in his vitamin D levels. Possible mechanisms for clinical improvement include effects of vitamin D on components of inflammatory cascades, including tumor necrosis factor-alpha and prostaglandin D2, which result in decrease in central nervous system homeostatic sleep pressure. While more research is needed to determine if patients presenting with fatigue should be routinely screened for vitamin D deficiency, clinicians should consider obtaining vitamin D levels in patients with unexplained fatigue, nonspecific musculoskeletal pain, and risk factors for vitamin D deficiency.

Developing an educational dvd on the use of hand massage in the care of people with dementia: An innovation.

The world's population is ageing and while the vast majority of older people live independently, a significant number will develop dementia. Communication and interpersonal skills are essential in developing relationships. People with dementia may have complex health needs and may have limited language capacity and therefore the use of presence and touch and more specifically hand massage gains greater significance for their wellbeing. This paper describes the process of developing an educational dvd on the use of hand massage in the care of people with dementia which is easily accessible via the web. A description of the design and project management including post production editing is provided. A number of outcomes are identified including: dvd launch, development of local and national interest, facilitation of workshops and the securing of funding for research. The educational dvd is a resource for learning for health care professionals and members of the public. The initiative offers a way of using technology to support individuals, nurses, carers and families living with dementia. This project demonstrates collaboration and connection between practice, education and technology and highlights the importance of the cyclical nature of theory and practice in responding to health care needs of a community.

Understanding central mechanisms of acupuncture analgesia using dynamic quantitative sensory testing: a review.

We discuss the emerging translational tools for the study of acupuncture analgesia with a focus on psychophysical methods. The gap between animal mechanistic studies and human clinical trials of acupuncture analgesia calls for effective translational tools that bridge neurophysiological data with meaningful clinical outcomes. Temporal summation (TS) and conditioned pain modulation (CPM) are two promising tools yet to be widely utilized. These psychophysical measures capture the state of the ascending facilitation and the descending inhibition of nociceptive transmission, respectively. We review the basic concepts and current methodologies underlying these measures in clinical pain research, and illustrate their application to research on acupuncture analgesia. Finally, we highlight the strengths and limitations of these research methods and make recommendations on future directions. The appropriate addition of TS and CPM to our current research armamentarium will facilitate our efforts to elucidate the central analgesic mechanisms of acupuncture in clinical populations.

Volitional reduction of anterior cingulate cortex activity produces decreased cue craving in smoking cessation: a preliminary real-time fMRI study.

Numerous research groups are now using analysis of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) results and relaying back information about regional activity in their brains to participants in the scanner in 'real time'. In this study, we explored the feasibility of self-regulation of frontal cortical activation using real-time fMRI (rtfMRI) neurofeedback in nicotine-dependent cigarette smokers during exposure to smoking cues. Ten cigarette smokers were shown smoking-related visual cues in a 3 Tesla MRI scanner to induce their nicotine craving. Participants were instructed to modify their craving using rtfMRI feedback with two different approaches. In a 'reduce craving' paradigm, participants were instructed to 'reduce' their craving, and decrease the anterior cingulate cortex (ACC) activity. In a separate 'increase resistance' paradigm, participants were asked to increase their resistance to craving and to increase middle prefrontal cortex (mPFC) activity. We found that participants were able to significantly reduce the BOLD signal in the ACC during the 'reduce craving' task (P=0.028). There was a significant correlation between decreased ACC activation and reduced craving ratings during the 'reduce craving' session (P=0.011). In contrast, there was no modulation of the BOLD signal in mPFC during the 'increase resistance' session. These preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue-induced craving. Further research is needed to determine the optimal parameters of neurofeedback rtfMRI, and whether it might eventually become a therapeutic tool for nicotine dependence.

Intermittent "real-time" fMRI feedback is superior to continuous presentation for a motor imagery task: a pilot study.

BACKGROUND: Real-time functional MRI feedback (RTfMRIf) is a developing technique, with unanswered methodological questions. Given a delay of seconds between neural activity and the measurable hemodynamic response, one issue is the optimal method for presentation of neurofeedback to subjects. The primary objective of this preliminary study was to compare the methods of continuous and intermittent presentation of neural feedback on targeted brain activity. METHODS: Thirteen participants performed a motor imagery task and were instructed to increase activation in an individually defined region of left premotor cortex using RTfMRIf. The fMRI signal change was compared between real and false feedback for scans with either continuous or intermittent feedback presentation. RESULTS: More individuals were able to increase their fMRI signal with intermittent feedback, while some individuals had decreased signal with continuous feedback. The evaluation of feedback itself activated an extensive amount of brain regions, and false feedback resulted in brain activation outside of the individually defined region of interest. CONCLUSIONS: As implemented in this study, intermittent presentation of feedback is more effective than continuous presentation in promoting self-modulation of brain activity. Furthermore, it appears that the process of evaluating feedback involves many brain regions that can be isolated using intermittent presentation.

Anti-hyperglycemia properties of Tea (Camellia sinensis) bioactives using in vitro assay models and influence of extraction time.

Tea (Camellia sinensis) has well-known health benefits, which are attributed to its polyphenolic metabolites. This research explored the potential of regular tea consumption and influence of extraction time typically used in daily consumption of tea, as a therapeutic dietary support for potential management of early stage type 2 diabetes using in vitro assay models. Extraction times of 2 and 5 minutes were compared. The 5-minute extraction time had significantly higher total phenolic content compared with the 2-minute extraction time. Choice Darjeeling 5-minute extraction yielded the highest amount of total phenolics (299.6 ± 5.9 mg/g), followed by Tazo Black 5-minute extraction (240 ± 9.7 mg/g), whereas Bigelow Green 2-minute extraction had the lowest total phenolic content (53 ± 8.2 mg/g). 1,1-Diphenyl-2-picrylhydrazyl scavenging-linked antioxidant activity was high (81-91%) for all types evaluated, and for most samples it was influenced by the extraction time. Similarly, high in vitro α-glucosidase inhibition was observed in almost all the samples assayed, and for most samples the 5-minute extraction had significantly higher inhibition compared with the 2-minute extraction time. The most fermented teas showed highest α-amylase inhibition: Choice Darjeeling 5-minute extraction had the highest inhibition (84.1%), followed by Tazo Black 5-minute extraction (71.6%). Angiotensin converting enzyme inhibition was not observed in any sample. Overall, the 5-minute extraction time was found to have more relevance for potential benefits for managing hyperglycemia than the 2-minute procedure. This research suggests that tea offers an attractive potential strategy to regulate postprandial hyperglycemia toward an overall dietary support for type 2 diabetes management.

Inhibitory potential of tea polyphenolics and influence of extraction time against Helicobacter pylori and lack of inhibition of beneficial lactic acid bacteria.

Tea polyphenolics such as catechins are known to have the potential to inhibit many bacterial pathogens. Helicobacter pylori has been identified as an etiologic agent in the development of gastric ulcer, peptic ulcer, gastritis, and many other stomach-related diseases. In this study, we investigated the effect of 9 tea extracts--3 different brands representing 4 different processed types (white, green, oolong, and black)--on the inhibition of H. pylori. Extraction times of 2 and 5 minutes were compared. Most 5-minute extracts showed H. pylori inhibition, whereas 2-minute extracts only of Choice darjeeling black and Tazo white showed inhibition. No recovery was observed after the addition of 0.5 and 5 mM proline, indicating that tea polyphenols do not inhibit H. pylori by inhibition of proline oxidation via proline dehydrogenase. Extracts that showed inhibition were further evaluated for their effect on beneficial lactic acid bacteria. None of the samples showed inhibition, suggesting that tea might be able to inhibit H. pylori without affecting the beneficial lactic acid bacteria. High-performance liquid chromatography indicated the presence of gallic acid, quercetin, caffeine, and tea catechins (including catechin, epicatechin, and epigallocatechin) in all the tea samples. Our study indicates that tea can be potentially used as a low-cost dietary support to combat H. pylori-linked gastric diseases without affecting the beneficial intestinal bacteria.

Cerebral activation patterns related to initiation and inhibition of hand movement.

Sequential ordering of purposeful movements includes distinct transitions between muscle contraction and relaxation. To explore cerebral activation patterns underlying such movement initiation and inhibition, we applied functional magnetic resonance imaging to test the effects of (1) ballistic movement (dominated by initiation), (2) movement with stepwise interruption (dominated by inhibition) and (3) smooth movements. Right-hand movements were performed by 21 healthy participants. In the basal ganglia, ballistic movements evoked putamen activation, indicating its specific contribution to initiation. Stepwise interrupted movement induced increased activation of the caudate nucleus, globus pallidus and subthalamic nucleus whereas, at the cortical level, supplementary motor area activation increased. This indicates a specific basal ganglia-thalamocortical circuit involved in motor inhibition.

Does a clinical pathway improve the quality of care for sickle cell anemia?

BACKGROUND: Clinical pathways are often implemented to improve care, yet their effect on quality of care and outcomes is often not evaluated. The Johns Hopkins Children's Center instituted a clinical pathway in early 1996 to improve the care for pediatric sickle cell vaso-occlusive crisis (VOC) and used a retrospective before-after study to describe how quality of care and outcomes changed after introduction of the pathway. RESULTS: Physicians used the pathway in 43% of eligible admissions, with use decreasing over time. Patients on the pathway were more likely to receive each of its required elements than those not on the pathway (odds ratios [OR] 1.15-2.49). After pathway implementation, even patients not on the pathway were more likely to receive incentive spirometry than those admitted before pathway availability (OR 1.40). Pathway use was associated with longer length of stay (LOS) and time to oral pain medication, while readmission rates did not change. DISCUSSION: Use of a clinical pathway improved quality of care by increasing compliance with specific care elements, with mixed results on outcomes. Pathways may improve care for all patients, including nonpathway-treated patients, by influencing underlying practice patterns. Quality improvement committees must regularly monitor outcomes after pathway implementation to evaluate the need for pathway reinforcement and refinement.

Environmental exposure to polychlorinated biphenyls among raccoons (Procyon lotor) at the paducah gaseous diffusion plant, Western Kentucky, USA.

An investigation involving raccoons (Procyon lotor) as a sentinel species at the Paducah Gaseous Diffusion Plant (PGDP) in Western Kentucky (USA) delineated the extent of exposure to polychlorinated biphenyls (PCBs) and PCB spatial distribution. Raccoon exposure to PCBs was demonstrated through analysis of subcutaneous fat, abdominal fat, liver, and brain tissues from raccoons collected at the PGDP but also was clearly evident in raccoons from a reference area situated along the Ohio River (USA). Raccoons with the highest tissue PCB concentrations appeared to be those inhabiting areas nearest the plant itself and most likely those that ventured into the plants interior. Male raccoons at the PGDP had similar concentrations of total PCBs in subcutaneous fat (1.86 +/- 0.64 microg/g) as males from the reference site (1.41 +/- 0.35 microg/g), but females had higher PCB body burdens than those at the reference site (9.90 +/- 6.13 microg/g vs 0.75 +/- 0.40 microg/g). Gross measurements of exposure to radiation-producing materials revealed that counts per minute exceeded background in 61% of PGDP raccoons compared with 27% at the reference site and five raccoons at the PGDP had beta counts that were more than twice the background. Differences among trapping success, growth rates, and serum chemistry parameters were noted but may have been related to habitat and other environmental and population density factors.