Musical and psychomotor interventions for cognitive, sensorimotor, and cerebral decline in patients with Mild Cognitive Impairment (COPE): a study protocol for a multicentric randomized controlled study.

BACKGROUND: Regular cognitive training can boost or maintain cognitive and brain functions known to decline with age. Most studies administered such cognitive training on a computer and in a lab setting. However, everyday life activities, like musical practice or physical exercise that are complex and variable, might be more successful at inducing transfer effects to different cognitive domains and maintaining motivation. "Body-mind exercises", like Tai Chi or psychomotor exercise, may also positively affect cognitive functioning in the elderly. We will compare the influence of active music practice and psychomotor training over 6 months in Mild Cognitive Impairment patients from university hospital memory clinics on cognitive and sensorimotor performance and brain plasticity. The acronym of the study is COPE (Countervail cOgnitive imPairmEnt), illustrating the aim of the study: learning to better "cope" with cognitive decline. METHODS: We aim to conduct a randomized controlled multicenter intervention study on 32 Mild Cognitive Impairment (MCI) patients (60-80 years), divided over 2 experimental groups: 1) Music practice; 2) Psychomotor treatment. Controls will consist of a passive test-retest group of 16 age, gender and education level matched healthy volunteers. The training regimens take place twice a week for 45 min over 6 months in small groups, provided by professionals, and patients should exercise daily at home. Data collection takes place at baseline (before the interventions), 3, and 6 months after training onset, on cognitive and sensorimotor capacities, subjective well-being, daily living activities, and via functional and structural neuroimaging. Considering the current constraints of the COVID-19 pandemic, recruitment and data collection takes place in 3 waves. DISCUSSION: We will investigate whether musical practice contrasted to psychomotor exercise in small groups can improve cognitive, sensorimotor and brain functioning in MCI patients, and therefore provoke specific benefits for their daily life functioning and well-being. TRIAL REGISTRATION: The full protocol was approved by the Commission cantonale d'éthique de la recherche sur l'être humain de Genève (CCER, no. 2020-00510) on 04.05.2020, and an amendment by the CCER and the Commission cantonale d'éthique de la recherche sur l'être humain de Vaud (CER-VD) on 03.08.2021. The protocol was registered at clinicaltrials.gov (20.09.2020, no. NCT04546451).

Positive psychological well-being: A novel concept for improving symptoms, quality of life, and health behaviors in irritable bowel syndrome.

BACKGROUND: Though a growing body of research suggests that greater positive psychological well-being in irritable bowel syndrome (IBS) may be protective, existing brain-gut behavior therapies primarily target negative psychological factors. Little is known about how positive psychological factors in IBS relate to IBS symptoms, health-related quality of life (HRQoL), or adherence to key health behaviors, such as physical activity and diet modification. Accordingly, per the ORBIT model of behavioral treatment development for chronic diseases, we explored potential connections between psychological constructs and IBS symptoms, health behavior engagement (physical activity and dietary modification), and HRQoL in a qualitative study to inform the development of a novel brain-gut behavior therapy. METHODS: Participants with IBS completed self-report assessments and semi-structured phone interviews about relationships between positive and negative psychological constructs, IBS symptoms, health behavior engagement, and HRQoL. KEY RESULTS: Participants (n = 23; 57% female) ranged in age from 25 to 79 (mean age = 54). IBS subtypes were similarly represented (IBS-diarrhea [n = 8], IBS-constipation [n = 7], and IBS-mixed [n = 8]). Participants described opposing relationships between positive and negative psychological constructs, IBS symptoms, health behavior engagement, and HRQoL, respectively, such that experiencing positive constructs largely mitigated IBS symptoms, boosted health behavior participation, and improved HRQoL, and negative constructs exacerbated symptoms, reduced health behavior participation, and worsened HRQoL. CONCLUSIONS AND INFERENCES: Participants with IBS linked greater positive psychological well-being to moderated IBS symptoms and better HRQoL and health behavior participation. An intervention to cultivate greater well-being may be a novel way to mitigate IBS symptoms, boost health behavior participation, and improve HRQoL in IBS.

Anti-inflammatory activity of Piper umbellatum Linn. leaf extracts

Background@#Earlier studies reported the anti-inflammatory activity in several species of Piper, and Piper umbellatum Linn. leaves containing some phytochemicals that are potent anti-inflammatory agents. However, there was no thorough investigation on the anti-inflammatory activity of the locally grown P. umbellatum in the Philippines. @*Objective@#The study aimed to determine the anti-inflammatory activity of Piper umbellatum leaves using in vitro and in vivo assays. @*Methodology@#Crude extracts were obtained from P. umbellatum leaves using polar and non-polar solvents. The anti-inflammatory activities of all crude extracts were determined using the carrageenan-induced paw edema test in mice and phytochemical analysis. The crude extract with the highest activity was partially purified using column chromatography. The fractions with similar TLC profile were pooled and tested for antiinflammatory activity. COX-1 and COX-2 enzyme inhibitory activity were determined in pooled fractions that showed initial activity in animal model. @*Results@#Among the crude extracts of P.umbellatum, the crude ethyl acetate extract exhibited a significant dose-dependent inhibition on paw edema test with doses of 500 mg/kg bw, 1,000 mg/kg bw and 1,500 mg/kg bw (p<0.05). Among the 20 pooled fractions (PF) collected from the ethyl acetate extract, PF58, PF60 and PF64 had the highest COX-2 enzyme inhibitions of 83.12 %, 84.78% and 77.47%, respectively (p<0.05). PF60 also exhibited the highest anti-inflammatory activity on paw edema with inhibitions of 62.45% at low dose (250 mg/kg bw) and 76.10 % at high dose (1,000 mg/kg bw) in mice. @*Conclusion@#The ethyl acetate extract of P. umbellatum leaves and its fraction-PF60 exhibited a significant anti-inflammatory activity in in vitro and in vivo assays and contained high amounts of total phenolic and total flavonoid.

Efficacy and safety of sunflower oil for mild to moderate plaque-type psoriasis: A double-blind, randomized controlled trial

@#<p style="text-align: justify;"><strong>Background:</strong> Psoriasis is a chronic, complex, inflammatory disease that needs safe and effective treatment options to decrease its disease burden.</p><p style="text-align: justify;"><strong>Objectives:</strong> To determine the efficacy and safety of sunflower oil in mild to moderate plaque-type psoriasis at the outpatient department of a tertiary hospital.</p><p style="text-align: justify;"><strong>Methods:</strong> This was an 8-week, single-center, randomized, double-blind controlled trial that compared the efficacy and safety of sunflower oil + placebo cream (Group SO), betamethasone valerate cream + placebo oil (Group BC), sunflower oil + betamethasone valerate cream (Group SOBC) in mild to moderate plaque-type psoriasis. Psoriasis Area Severity Index (PASI) was used to measure the extent of psoriasis by assessing the erythema, induration, scaling, and body surface area involvement. The difference from baseline PASI was recorded. The Dermatology Life Quality Index (DLQI) questionnaire was used to measure the impact of psoriasis on the patient's quality of life.</p><p style="text-align: justify;"><strong>Results:</strong> Fifty-one patients were randomized and blinded to three treatment arms; evaluated at baseline, week 4 and 8. The proportion of patients who achieved PASI ?50 at week 4 was 29% in Group SO, 38% in Group BC, and 60% in Group SO-BC. By week 8, Groups SO and BC achieved 80% while Group SO-BC achieved 93%. There was significant decline of PASI at week 4 and week 8 compared to baseline. The mean percentage change of PASI was highest at Group SO-BC followed by Group BC and lastly Group SO at week 4 and week 8. The mean reduction in score for scaling was significantly higher in Group SO-BC. Mean reduction in induration and erythema was not statistically significant across the three groups. There was 40-50% improvement in DLQI scores in all groups. There were no adverse events.</p><p style="text-align: justify;"><strong>Conclusion:</strong> This study showed that sunflower oil is effective and safe in mild to moderate plaque-type psoriasis.</p>

Sample-independent approach to normalize two-dimensional data for orthogonality evaluation using whole separation space scaling.

Orthogonality is a key parameter that is used to evaluate the separation power of chromatography-based two-dimensional systems. It is necessary to scale the separation data before the assessment of the orthogonality. Current scaling approaches are sample-dependent, and the extent of the retention space that is converted into a normalized retention space is set according to the retention times of the first and last analytes contained in a unique sample to elute. The presence or absence of a highly retained analyte in a sample can thus significantly influence the amount of information (in terms of the total amount of separation space) contained in the normalized retention space considered for the calculation of the orthogonality. We propose a Whole Separation Space Scaling (WOSEL) approach that accounts for the whole separation space delineated by the analytical method, and not the sample. This approach enables an orthogonality-based evaluation of the efficiency of the analytical system that is independent of the sample selected. The WOSEL method was compared to two currently used orthogonality approaches through the evaluation of in silico-generated chromatograms and real separations of human biofluids and petroleum samples. WOSEL exhibits sample-to-sample stability values of 3.8% on real samples, compared to 7.0% and 10.1% for the two other methods, respectively. Using real analyses, we also demonstrate that some previously developed approaches can provide misleading conclusions on the overall orthogonality of a two-dimensional chromatographic system.

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212.

Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.

Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia.

Gram-negative pneumonia is a dangerous illness, and bacterial dissemination to the bloodstream during the infection is strongly associated with death. Antibiotic resistance among the causative pathogens has resulted in diminishing treatment options against this infection. Hepcidin is the master regulator of extracellular iron availability in vertebrates, but its role in the context of host defense is undefined. We hypothesized that hepcidin-mediated depletion of extracellular iron during Gram-negative pneumonia protects the host by limiting dissemination of bacteria to the bloodstream. During experimental pneumonia, hepcidin was induced in the liver in an IL-6-dependent manner and mediated a rapid decline in plasma iron. In contrast, hepcidin-deficient mice developed a paradoxical increase in plasma iron during infection associated with profound susceptibility to bacteremia. Incubation of bacteria with iron-supplemented plasma enhanced bacterial growth in vitro, and systemic administration of iron to WT mice similarly promoted increased susceptibility to bloodstream infection. Finally, treatment with a hepcidin analogue restored hypoferremia in hepcidin-deficient hosts, mediated bacterial control, and improved outcomes. These data show hepcidin induction during pneumonia to be essential to preventing bacterial dissemination by limiting extracellular iron availability. Hepcidin agonists may represent an effective therapy for Gram-negative infections in patients with impaired hepcidin production or signaling.

Utilizing Levine's conservation model in the care of patient with lithium toxicity: Caring beyond the symptoms

@#<p style="text-align: justify;">Health  professionals  are  trained  to  recognize  and  address  cues  which  endanger  the  client's survival. In critical situations, we focus on ensuring the airway, breathing and circulation (ABC) in order to sustain life. Oftentimes, we feel great in performing dramatic interventions and save our patients from the brink of death. But is this enough? Does our role end here? Is this only how we define good nursing care?<br />This is the case of DL, a 39 year old female who, upon admission to the pay ward in Philippine General  Hospital,  presented  with  respiratory  distress,  as  evidenced  by  dyspnea  and  oxygen desaturation, necessitating intubation. Health history revealed the client as a diagnosed case of Bipolar  I  Disorder  for  21  years.  The  goal  of  providing  holistic  care  to  a  patient  with  a  mood-affective disorder presenting with a medical emergency, like DL, poses a crucial challenge - the challenge in going beyond what meets the eye and focusing on human responses and not just the disease process. This case was then selected to serve as a reminder and a learning opportunity that we should not be limited to symptom management, but more importantly, to recognize the totality of the human being, which is the true essence of nursing care. </p>

Implementation of an intersectoral program to eliminate human and canine rabies: the Bohol Rabies Prevention and Elimination Project.

BACKGROUND: The province of Bohol, located in the Visayas islands region in the Philippines has a human population of 1.13 million and was the 4th highest region for human rabies deaths in the country, averaging 10 per year, prior to the initiation of the Bohol Rabies Prevention and Elimination Project (BRPEP). AIMS: The BRPEP was initiated in 2007 with the goal of building a sustainable program that would prevent human rabies by eliminating rabies at its source, in dogs, by 2010. This goal was in line with the Philippine National Rabies Program whose objective is to eliminate rabies by 2020. METHODS: The intersectoral BRPEP was launched in 2007 and integrated the expertise and resources from the sectors of agriculture, public health and safety, education, environment, legal affairs, interior and local government. The program included: increasing local community involvement; implementing dog population control; conducting mass dog vaccination; improving dog bite management; instituting veterinary quarantine; and improving diagnostic capability, surveillance and monitoring. Funding was secured from the national government, provincial, municipal and village units, dog owners, NGOs, the regional office of the WHO, the UBS Optimus Foundation, and the Global Alliance for Rabies Control. The BRPEP was managed by the Bohol Rabies Prevention and Eradication Council (BRPEC) under the jurisdiction of the Governor of Bohol. Parallel organizations were created at the municipal level and village level. Community volunteers facilitated the institution of the program. Dog population surveys were conducted to plan for sufficient resources to vaccinate the required 70% of the dogs living in the province. Two island-wide mass vaccination campaigns were conducted followed by "catch up" vaccination campaigns. Registration of dogs was implemented including a small fee that was rolled back into the program to maintain sustainability. Children were educated by introducing rabies prevention modules into all elementary schools in Bohol. Existing public health legislation at the national, provincial, and municipal level strengthened the enforcement of activities. A Knowledge, Attitude and Practices (KAP) survey was conducted in 2009 to evaluate the educational knowledge of the population. Increased surveillance was instituted to ensure that dogs traveling into and out of the province were vaccinated against rabies. Human and animal cases of rabies were reported to provincial and national authorities. KEY RESULTS: Within the first 18 months of the BRPEP, human rabies deaths had decreased annually from 0.77 to 0.37 to zero per 100,000 population from 2007-2009. Between October 2008 and November 2010 no human and animal cases were detected. Increased surveillance on the island detected one suspected human rabies case in November 2010 and one confirmed case of canine rabies in April 2011. Two mass vaccination campaigns conducted in 2007 and 2008 successfully registered and vaccinated 44% and 70% of the dogs on the island. The additional surveillance activities enabled a mobilization of mop up vaccination activities in the region where the human and canine case was located. Due to the increased effective and continuous surveillance activities, rabies was stopped before it could spread to other areas on the island. The program costs totaled USD 450,000. Registration fees collected to maintain the program amounted to USD 105,740 and were re-allocated back into the community to sustain the program.

Dose-dependent Effect of Statin Therapy on Circulating CXCL12 Levels in Patients with Hyperlipidemia.

BACKGROUND: HMG-CoA reductase inhibitors (statins) have pleiotropic effects that are independent of cholesterol-lowering, including a dose-dependent effect on angiogenesis. Angiogenesis plays a critical role both in vascularization of the chronically ischemic myocardium and in stabilization of atherosclerotic plaques. Chemokines, a family of structurally-related cytokine molecules, exert diverse biological functions including control of angiogenesis. The effect of statin therapy on angiogenic and angiostatic chemokines has not been evaluated extensively. We sought to test the hypothesis that, in subjects with hyperlipidemia, statin therapy influences plasma levels of angiogenic and angiostatic chemokines in a dose-dependent manner. METHODS: We prospectively collected demographic, angiographic and laboratory data from subjects with a history of hyperlipidemia who were either untreated or on statin therapy. A peripheral blood sample was obtained for measurement of plasma angiogenic and angiostatic chemokines. Multivariable analysis using logistic regression was performed adjusting for the following variables: age, gender, prior myocardial infarction, and chronic administration of aspirin, clopidogrel, insulin, oral hypoglycemic agents, beta-blockers and calcium channel blockers. RESULTS: 168 patients on statin therapy (48 on low-dose, defined as <10mg atorvastatin-equivalent, and 120 on high-dose, defined as ≥10mg atorvastatin-equivalent dose) and 11 subjects from the same database who had a history of hyperlipidemia but who were not on statins were enrolled. There were no significant differences in baseline demographics, co-morbidities, lipid panels, other medications, or angiographic data between the groups. The angiogenic chemokines CXCL1 and CXCL12 levels were significantly different across the groups. Median levels of CXCL1 were highest in subjects not on statin therapy. Compared to subjects either not on statin therapy or on low-dose statins, those taking high-dose statins had lower median values of CXCL12 (2316 [2255-11071], vs 2362 [2016-10622], vs 2189 [1968-2705] pg/mL, p=0.042). On multivariate analysis, CXCL12 remained the only factor that was strongly and inversely associated with statin dose at the 95% level (p=0.011). CONCLUSIONS: Compared to no therapy or low-dose statin therapy, treatment with high-doses of HMG-CoA reductase inhibitors is associated with decreased circulating CXCL12 levels in subjects with hyperlipidemia, and CXCL12 is strongly and inversely associated with statin dose. Additional studies are needed to confirm this finding in other cohorts and to determine if high-dose statins affect angiogenesis in patients.

Phoneme discrimination and mismatch negativity in English and Japanese speakers.

Neural templates for phonemes in one's native language are formed early in life; these can be modified but are difficult to form de novo. These can be examined with mismatch negativity (MMN). Three phonemic contrasts were presented to adult native English compared with Japanese speakers who acquired English later in life: vowels native to both languages (/i//iy/), consonant-vowel contrasts (/da//wa/) phonemic in both languages, and consonant-vowel contrasts phonemic in English but not in Japanese (/ra//la/). For vowels, no MMN differences were found. For /da//wa/, MMN amplitude was significantly reduced in Japanese speakers. For /ra//la/, only 50% of the Japanese group showed an identifiable MMN. This suggests that phonemic templates are formed early in life, and non-native consonant contrasts are difficult to learn later.

[Diagnosis of Mycobacterium ulcerans infections in French Guiana]. / Diagnostic de l'infection à Mycobacterium ulcerans en Guyane française.

THE SITUATION: Buruli's ulcer is a severe necrotic cutaneous infection due to Mycobacterium ulcerans. It is a major public health problem in developing countries. FROM A CLINICAL POINT OF VIEW: The early stage of the infection corresponds to a painless cutaneous nodule, whereas the late stage corresponds to ulceration with detachment of the edges. There is currently no other treatment than surgical excision combined with heat therapy. FROM A DIAGNOSTIC POINT OF VIEW: Three methods can be used: direct examination of swabs stained according to Ziehl-Neelsen's method, culture in specific medium at 32 degrees C and the polymerization chain reaction assay (PCR). The latter is the technique of choice.

In vivo anti-inflammatory activity of Alchornea cordifolia (Schumach. & Thonn.) Müll. Arg. (Euphorbiaceae).

Alchornea cordifolia (Schumach. & Thonn.) Müll. Arg. (Euphorbiaceae) is a widely distributed plant in Africa. It is used in the traditional medicine of many African countries for the treatment of bacterial, fungal, parasitic and inflammatory disorders. Aqueous decoction and methanol leaf extracts were tested for their ability to reduce Croton oil-induced oedema in the mouse ear, after topical application. The methanol leaf extract dose-dependently inhibited the Croton oil-induced ear oedema in mice (ID(50)<500 microg/cm(2)). A bio-assay guided liquid-liquid fractionation of this methanol extract gave four active fractions: water insoluble (F1), hexane (F2), ethyl acetate (F3) and water (F4). The hexane fraction showed a very high activity (42% inhibition at 0.7 microg/cm(2)) as compared to the control. The other fractions were less active (F1: 56% at 506.2 microg/cm(2); F3: 57% at 289.3 microg/cm(2); F4: 32% for 203.8 microg/cm(2)) while indomethacin gave 49% of inhibition at 90 microg/cm(2). The activity of F1 and F3 may be at least in part explained by the presence of anti-inflammatory flavonoids (hyperoside and quercitrin, quercitrin being identified in the plant for the first time) while the activity was not correlated to the tannin contents. None of these compounds were detected in the most active F2 fraction. These results support the reported traditional use of this plant against topical inflammatory disorders.

Anti-mitotic properties of indirubin-3'-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest.

The bis-indole indirubin is the active ingredient of the Traditional Chinese Medicine recipe Danggui Longhui Wan used against chronic myelocytic leukemia. We have previously shown that indirubins are potent inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3. We here investigated the anti-mitotic properties of this class of compounds using the cell permeable indirubin-3'-monoxime and the HBL-100 cell line. Indirubin-3'-monoxime reversibly arrests asynchronous HBL-100 cells in G2. This arrest is not accompanied by any significant change in expression of the major cell cycle regulators. However indirubin-3'-monoxime inhibits the phosphorylation of consensus CDK phosphorylation sites as well as of nucleolin at a specific CDK1/cyclin B phosphorylation site, suggesting a direct action on the mitotic CDK1/cyclin B. When indirubin-3'-monoxime is added to HBL-100 cells synchronized in M phase by nocodazole, cells undergo an endoreplication leading to an 8n DNA content. As soon as indirubin-3'-monoxime is washed away, these polyploid cells become aneuploid and later die from necrosis. This mechanism of endoreplication followed by cell death may contribute to the anti-tumour properties of indirubins.

Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases.

Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Here we identify indirubin and its analogues as potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell cycle. These results have implications for therapeutic optimization of indigoids.

Application of the novel nucleic acid dyes YOYO-1, YO-PRO-1, and PicoGreen for flow cytometric analysis of marine prokaryotes.

Novel blue light-excited fluorescent dyes for nucleic acids (YOYO-1, YO-PRO-1, and PicoGreen) were tested on cultures of Escherichia coli and of a variety of marine prokaryotes. Results of flow cytometric DNA analyses were compared with those obtained with the UV-excited dyes bis-benzimide Hoechst 33342 or 4', 6-diamidino-2-phenylindole (DAPI). YOYO-1, YO-PRO-1, and PicoGreen can be used only on aldehyde-fixed cells and need to be supplemented with cofactors such as potassium, citrate, or EDTA. They are highly sensitive to ionic strength. Consequently, seawater culture samples cannot be stained directly with these dyes and require at least a 10-fold dilution with distilled water to obtain reliable fluorescence signals. After treatment with RNase, coefficients of variation for the G1 peak of the DNA distributions of the different strains tested with YOYO-1 or PicoGreen indicated in general an improvement over Hoechst 33342 staining. These novel dyes can be used to enumerate prokaryotic cells by flow cytometry, as demonstrated with E. coli. However, their sensitivity to ionic strength makes them unsuitable for cell cycle analysis in natural samples.