Current and Future Therapeutic Options for Irritable Bowel Syndrome with Diarrhea and Functional Diarrhea.

Irritable bowel syndrome with diarrhea and functional diarrhea are disorders of gut-brain interaction presenting with chronic diarrhea; they have significant impact on quality of life. The two conditions may exist as a continuum and their treatment may overlap. Response to first-line therapy with antispasmodics and anti-diarrheal agents is variable, leaving several patients with suboptimal symptom control and need for alternative therapeutic options. Our aim was to discuss current pharmacologic options and explore alternative therapeutic approaches and future perspectives for symptom management in irritable bowel syndrome with diarrhea and functional diarrhea. We conducted a search of PubMed, Cochrane, clinicaltrial.gov, major meeting abstracts for publications on current, alternative, and emerging drugs for irritable bowel syndrome with diarrhea and functional diarrhea. Currently approved therapeutic options for patients with first-line refractory irritable bowel syndrome with diarrhea and functional diarrhea include serotonin-3 receptor antagonists, eluxadoline and rifaximin. Despite their proven efficacy, cost and availability worldwide impact their utilization. One-third of patients with disorders of gut-brain interaction with diarrhea have bile acid diarrhea and may benefit from drugs targeting bile acid synthesis and excretion. Further understanding of underlying pathophysiology of irritable bowel syndrome with diarrhea and functional diarrhea related to bile acid metabolism, gastrointestinal transit, and microbiome has led to evaluation of novel therapeutic approaches, including fecal microbiota transplantation and enterobacterial "crapsules". These opportunities to treat disorders of gut-brain interaction with diarrhea should be followed with formal studies utilizing large samples of well-characterized patients at baseline and validated response outcomes as endpoints for regulatory approval.

Municipal solid waste management with recyclable potential in developing countries: Current scenario and future perspectives.

Municipal solid waste (MSW) is a complex challenge to be solved worldwide, intensified in developing countries since in addition to economic and environmental aspects there is also the social aspect represented by the collector individual. From an integrative bibliographic review this study longitudinally analyses the socio-productive inclusion of collectors in the municipal solid waste management (MSWM) at an international level. Aiming: (a) to identify relevant articles describing/studies on MSWM with social inclusion of scavengers around the world; (b) to analyse these articles in order to present its main characteristics; (c) to describe municipal solid waste management with recyclable potential (MSWRP) with socio-productive inclusion of collectors; (d) the study provides a more detailed summary of MSWRP management in some developing countries: Brazil, China, India, Indonesia, Mexico, Nigeria and Pakistan; and (e) to provide a framework indicating the future practices and perspectives of MSWRP. As result, this study presents the paradigms and future questions for an effective improvement of WSWM, such as: Professional Training of Scavengers, Cultural Issues, Empowerment of Scavenger, Recycling Cooperatives and Cooperativism, Policy Issues and Recycling Chain, Management Systems and Process Improvement, Quality of Services Provided, Circular Economy and Informal Sector, Health Quality and Safety at Work, Barriers and Solutions for the Inclusion of the Informal Sector, Environmental, Economic and Social Benefits.

Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis.

Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC50 and CC50, respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 µg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 µg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum-infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment.

Investigation of the cytotoxic activity of two novel digitoxigenin analogues on H460 lung cancer cells.

Cardiac glycosides (CGs) are natural compounds traditionally used for the treatment of heart disorders, and recently new therapeutic possibilities were proposed. Their antitumor reports and clinical trials have notably enhanced, including those targeted for lung cancer, the most lethal type that lacks of new treatment agents, instigating the research of these molecules. The CGs studied here, named C10 {3ß-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin} and C18 (3ß-(aminoacetyl)amino-3-deoxydigitoxigenin), are semisynthetic derivatives prepared from digitoxigenin scaffold. Both compounds demonstrated high cytotoxicity for different cancer cell lines, especially H460 lung cancer cells, and their cytotoxic effects were deeply investigated using different methodological approaches. C10 induced cell death at lower concentrations and during shorter periods of treatment than C18, and increased the number of small and irregular nuclei, which are characteristics of apoptosis. This type of cell death was confirmed by caspase-3/7 assay. Both compounds reduced H460 cells proliferative potential by long-term action, and C10 showed the strongest potential. Moreover, these compounds induced a significant decrease of the area and viability of H460 spheroids providing preclinical favorable profiles to develop new chemotherapeutic agents.

Elucidation of the mechanism of anti-herpes action of two novel semisynthetic cardenolide derivatives.

Human herpesviruses are among the most prevalent pathogens worldwide and have become an important public health issue. Recurrent infections and the emergence of resistant viral strains reinforce the need of searching new drugs to treat herpes virus infections. Cardiac glycosides are used clinically to treat cardiovascular disturbances, such as congestive heart failure and atrial arrhythmias. In recent years, they have sparked new interest in their potential anti-herpes action. It has been previously reported by our research group that two new semisynthetic cardenolides, namely C10 (3ß-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin) and C11 (3ß-(hydroxyacetyl)amino-3-deoxydigitoxigenin), exhibited potential anti-HSV-1 and anti-HSV-2 with selectivity index values > 1,000, comparable with those of acyclovir. This work reports the mechanism investigation of anti-herpes action of these derivatives. The results demonstrated that C10 and C11 interfere with the intermediate and final steps of HSV replication, but not with the early stages, since they completely abolished the expression of the UL42 (ß) and gD (γ) proteins and partially reduced that of ICP27 (α). Additionally, they were not virucidal and had no prophylactic effects. Both compounds inhibited HSV replication at nanomolar concentrations, but cardenolide C10 was more active than C11 and can be considered as an anti-herpes drug candidate including against acyclovir-resistant HSV-1 strains.

Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation.

Influenza virus infections represent a major public health issue by causing annual epidemics and occasional pandemics that affect thousands of people worldwide. Vaccination is the main prophylaxis to prevent these epidemics/pandemics, although the effectiveness of licensed vaccines is rather limited due to the constant mutations of influenza virus antigenic characteristics. The available anti-influenza drugs are still restricted and there is an increasing viral resistance to these compounds, thus highlighting the need for research and development of new antiviral drugs. In this work, two semisynthetic derivatives of digitoxigenin, namely C10 (3ß-((N-(2-hydroxyethyl)aminoacetyl)amino-3-deoxydigitoxigenin) and C11 (3ß-(hydroxyacetyl)amino-3-deoxydigitoxigenin), showed anti-influenza A virus activity by affecting the expression of viral proteins at the early and late stages of replication cycle, and altering the transcription and synthesis of new viral proteins, thereby inhibiting the formation of new virions. Such antiviral action occurred due to the interference in the assembly of viral polymerase, resulting in an impaired polymerase activity and, therefore, reducing viral replication. Confirming the in vitro results, a clinically relevant ex vivo model of influenza virus infection of human tumor-free lung tissues corroborated the potential of these compounds, especially C10, to completely abrogate influenza A virus replication at the highest concentration tested (2.0 µM). Taken together, these promising results demonstrated that C10 and C11 can be considered as potential new anti-influenza drug candidates.

The effect of extended glaze firing on the flexural fatigue strength of hard-machined ceramics.

STATEMENT OF PROBLEM: It is unclear whether an extended glaze firing could improve the long-term mechanical performance of densely sintered CAD-CAM ceramics. PURPOSE: The purpose of this in vitro study was to analyze the effect of an extended glaze firing on the flexural fatigue strength (FFS) of densely sintered milled (hard-machined) leucite-based (LEU) and lithium disilicate-based (DIS) ceramics. MATERIAL AND METHODS: Disks were machined from ceramic blocks and divided into 6 groups (n=20) according to the material, LEU or DIS, and to the applied glaze firing: manufacturer-recommended glaze (G group), extended glaze (EG group), and control/no firing (C group). The surface roughness of the disks was measured before and after firing by using a contact profilometer, and data were compared by paired sample tests. Specimens were submitted to fatigue by using the staircase test design in water (piston-on-3 balls; 500 000 cycles, 20 Hz, and sinusoidal loading). Mean (±SD) FFS values were then calculated and analyzed by using 1-way analysis of variance and post hoc Tukey test (α=.05). RESULTS: Surface roughness did not change after the firing (P>.05). The highest FFS value in both ceramics was obtained after EG firing (LEU-EG=80.52 ±6.3 MPa; DIS-EG=147.25 ±10.5 MPa), which was statistically superior to G firing (LEU-G=73 ±6.8 MPa, P=.003; DIS-G=134.34 ±15.6 MPa; P=.023) and C group (LEU-C=61.94 ±6.3 MPa; P<.001; DIS-C=134.13 ±17.3 MPa; P=.023). CONCLUSIONS: EG firing optimized the biaxial flexural fatigue strength of hard-machined leucite and lithium disilicate ceramics compared with conventional glaze firing.

Ten controversies in gastroparesis and a look to the future.

BACKGROUND: Gastroparesis is a complex, challenging gastrointestinal disorder presenting with upper gastrointestinal symptoms, especially nausea and vomiting, with significant impact on patients' quality of life. After ruling out mechanical obstruction, it is essential to identify delay in gastric emptying for definitive diagnosis. The most common causes are idiopathic (no identified etiology), diabetes mellitus, and postsurgical status. Management of gastroparesis focuses on dietary modifications and treatment directed to symptom relief. Unfortunately, approximately one-third of patients are refractory to pharmacological therapy, and the effectiveness of the few nonpharmacological options has been questioned. PURPOSE: Extensive review of the literature identifies several uncertainties or controversies regarding the differential diagnosis based on the spectrum of symptoms, the lack of availability of reliable diagnostic test, and questions regarding effective therapeutic options. In this review, we discuss ten controversies regarding gastroparesis: clinical presentation, diagnosis, overlap syndromes, pathophysiology, etiology, as well as pharmacological and nonpharmacological therapeutic options. In addition, we briefly review studies exploring pathological, inflammatory, and molecular disturbances affecting the intrinsic neuromuscular elements that may be involved in the pathophysiology of gastroparesis and may constitute possible therapeutic targets in the future. Finally, we tabulate future research opportunities to resolve these controversies in the management of patients with gastroparesis.

An affordable gradient mixer for chromatography with aqueous and organic solvents.

A gradient mixer for preparative column chromatography has been developed, using a microcontroller, a three-way solenoid valve, and a one-channel pump of any chosen design, controlled by a microcontroller and with specifications for the gradient entered through a touchscreen. The gradient mixer is economical and can be produced with the design files provided.

Individual Responses of Captive Amazon Parrots to Routine Handling Can Reflect Their Temperament.

Individual responses to physical restraint and temperament have been assessed in birds of several species; however, there is a paucity of research which investigates both aspects, especially in captive parrots. This lack of studies raises doubts about which temperament traits, if any, are evidenced during handling and if the intensity of responses to restraint is affected by behavioral training programs, a common practice used in ex situ conservation programs. To understand more about the subject, this study aimed to identify the main temperament dimensions of parrots and investigate their relationship with response to physical restraint for blood collection. A secondary aim was to evaluate whether parrots exhibited higher responsiveness to physical restraint after training to improve flight capacity and increase aversion to humans. The main dimensions identified were activity, neophilia, vigilance, and fearfulness. The more fearful parrots in temperament evaluations were more responsive to physical restraint, showing more vocalizations and struggle attempts than the less fearful ones. After training, the parrots showed higher responsiveness to physical restraint. We suggest that physical restraint for routine handling, such as blood collection, could be a feasible option for centers of rehabilitation to use to obtain data on individual behavioral differences in fear responses.

Cesarean rates according to the Robson classification: analysis in a municipal maternity in São Paulo.

OBJECTIVE: To investigate the distribution of parturients at Hospital Municipal da Vila Santa Catarina Dr. Gilson de Cássia Marques de Carvalho according to the Robson classification, identify the cesarean rate in each Robson Group, and understand which group contributes more to the prevalence of Cesarean sections. METHODS: This is a retrospective observational cross-sectional study conducted through the analysis of medical records of parturients admitted to Hospital Municipal da Vila Santa Catarina Dr. Gilson de Cássia Marques de Carvalho from October 2016 to August 2019. RESULTS: A total of 9,794 births were recorded, and 31% were by Cesarean section. The most prevalent Robson Groups were Group 3 (25.7%-2,519), 1 (22.8%-2,234), and 5 (20.5%-2,006). The relative contribution of Cesarean sections was greatest in Groups 5 (39%), 2 (18%), and 1 (12.5%). CONCLUSION: This study demonstrated the Robson classification is useful to lead to a more critical view, identifying the groups that deserve more attention, since they are the major contributors to cesarean rates; hence, the management protocols could be modified aim to reduce cesarean rates.

Knowledge of gynecologists in the public health system care of women victims of violence.

OBJECTIVE: This study aimed to evaluate the knowledge of the obstetricians and gynecologists in the care of women victims of violence in the public health system and the existence of institutional mechanisms to support them. METHODS: A cross-sectional and observational study was conducted with an electronic questionnaire by physicians who provided care in the obstetrics and gynecology emergency unit of the public health system. This study aimed to identify the care for victims of violence who received the institutional mechanisms of support, the difficulties encountered in determining the appropriate care, and estimates of the prevalence of violence against women. RESULTS: Notably, 92 physicians responded to the questionnaire. Of these, 85% had already provided care in one or more cases of violence, and 60% believed that <20% of the women received adequate care in these cases, mainly due to the short-time frame of the consultation, lack of team preparation, and lack of institutional resources. A total of 61% of the participants believed that they were not prepared to provide adequate care in those cases. CONCLUSIONS: Most of the physicians interviewed, although reported to have sufficient knowledge to adequately treat victims of violence, did not provide such care due to lack of institutional support.

New dual dye for vitreoretinal surgery with increased transparency.

OBJECTIVES: To develop a new dye formulation for vitreoretinal surgery, which shows increased transparency for better intraoperative handling with better parameters important for use. METHODS AND ANALYSIS: A new blue dye, DDG, was synthesised and tested for toxicity and staining. Diglycerol as new density-increasing additive was identified, and its toxicity and lack of influence of the staining with trypan blue (TB) on a collagen membrane as model for the epiretinal membrane was determined. Transparency of the dye solution was evaluated. RESULTS: DDG is as alternative to Brilliant Blue G (BBG), with good staining properties for interna limitans models, and a good safety profile. Diglycerol is a new non-toxic additive replacing PEG3350, with reduced viscosity and no reduction in staining, allowing the reduction of TB to achieve the same staining level of the collagen membrane by 40%, with greater transparency of the dye solution and reduced viscosity. Both factors should facilitate a safe removal during surgery. CONCLUSION: A new dye preparation with improved performance in comparison to marketed combinations of BBG and TB was developed. Its reduced TB concentration and viscosity with maintained density allow better tolerance and handling.

Nanoencapsulation of buriti oil (Mauritia flexuosa L.f.) in porcine gelatin enhances the antioxidant potential and improves the effect on the antibiotic activity modulation.

The present study evaluated the cytotoxicity, antioxidant potential, and antimicrobial effect on the antibiotic activity modulation of gelatin nanoparticles containing buriti oil (OPG). The cytotoxicity analysis was performed on Chinese Hamster Ovary Cells (CHO) using a MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test. The antioxidant potential of buriti oil and OPG was determined by total antioxidant capacity, reducing power, and the ABTS (2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid) test. The modulating antimicrobial activity was evaluated by determining the minimum inhibitory concentration (MIC) concentration against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, gentamicin and norflaxacillin. The nanoformulation of OPG did not show a cytotoxic effect on CHO cells and had a higher antioxidant potential than free buriti oil (p<0.05). The combination of antibiotics with free buriti oil and OPG was more efficient in inhibiting E. coli and P. aeruginosa than isolated norfloxacillin and gentamicin (p<0.05). Regarding the inhibition of S. aureus, OPG in combination with norfloxacillin reduced MIC by 50%. Nanoencapsulation was a viable alternative to enhance functionality and adding commercial value to buriti oil.

Temperament in Captivity, Environmental Enrichment, Flight Ability, and Response to Humans in an Endangered Parrot Species.

Temperament assessment is useful in reintroduction programs. Reactivity to humans and flight ability are also important behavioral aspects for captive parrots candidates to reintroduction. The study aimed: a) to evaluate if behavioral responses to environmental enrichment differ as a function of temperament in captive Vinaceous-breasted Amazon parrots (Amazona vinacea) and b) to evaluate if the behavioral responses to environmental enrichment are related to flight ability and animal's reaction to human when offered food. A temperament assessment was performed and behavioral evaluations of parrots (n = 13) using an ethogram were carried out, in two phases: unenriched and enriched. Flight skill and food reward tests were also performed. Two temperament dimensions were described ("vigilance" and "risk-taking"). Parrots categorized as "vigilant" spent less time feeding on the feeder and interacting with environment. Animals with compromised flight ability spent more time preening, had lower frequency of vocalizations, tended to have fewer negative social interactions, and interacted less with the enrichment than individuals with better flight ability. Flight performance and temperament of captive parrots should be considered while planning and executing environmental enrichment techniques.

Treatment of oral chronic graft-versus-host disease: a retrospective cohort study.

OBJECTIVE: The aim of this study was to evaluate patients with complete response of oral chronic graft-versus-host disease to immunosuppressive treatment. METHODS: A total of 29 patients submitted to allogeneic hematopoietic stem cell transplantation, with oral chronic graft-versus-host disease, were enrolled in this retrospective study, from September 2012 to February 2018. Patients were treated with combined topical dexamethasone solution and topical tacrolimus ointment, combined topical dexamethasone and topical tacrolimus, systemic immunosuppressive medication, and topical dexamethasone only. RESULTS: The mean time of complete response of lichenoid lesions, erythema, and ulcers using dexamethasone and systemic immunosuppressive medication was of 105, 42 and 42 days, respectively (p=0.013).When we associated dexamethasone, tacrolimus and systemic immunosuppressive medication, the mean time of complete response of lichenoid lesions, erythema and ulcers was of 91,84 and 77 days (p=0.011). When dexamethasone was used alone, the mean time of complete response of lichenoid lesions, erythema and ulcers was 182, 140, 21 days, respectively (p=0.042). CONCLUSION: Our study shows that lichenoid lesions require more time to heal. Notably, lichenoid lesions tend to respond better to dexamethasone combined with tacrolimus and systemic immunosuppressive medication, whereas erythema and ulcers respond better to dexamethasone combined with systemic immunosuppressive medication and dexamethasone only, respectively.

Feldspathic and Lithium Disilicate Onlays with a 2-Year Follow-Up: Split-Mouth Randomized Clinical Trial.

The present study was a prospective, controlled, randomized, clinical short-term trial aiming to evaluate the clinical performance of adhesively luted, lithium disilicate and feldspathic glass-ceramics onlays over a period up to 2 years. A total of 11 patients (7 female, 4 male; age range: 18-60 years, mean age: 39 years) were selected for this study. Each patient received a maximum of two restorations per group in a split-mouth-design. LD: Eleven onlays, performed with lithium disilicate-based ceramic (IPS e.max CAD, Ivoclar Vivadent, Schaan, Liechtenstein), and FP: Eleven onlays, performed with feldspathic ceramic (Vita Mark II, Vita Zanhfabrik, Bad Säckingen). Recalls were performed at 2 weeks (baseline = R1), 1 year (R2) and 2 years (R3) after the cementation by three calibrated blinded independent investigators using mirrors, magnifying eyeglasses, probes and bitewing radiographs. The postoperative sensitivity, secondary caries, marginal integrity, marginal discoloration, color match, surface roughness, tooth integrity, and restoration integrity were evaluated. The Friedman test was used to determine if there was a statistically significant difference in time-to-time comparison of the parameters in the ceramics restorations. A total of 95.4% of the restorations were clinically acceptable at the 2-year recall, without a difference for any evaluation parameter for both ceramic materials. Based on the 2-year data, the CAD-CAM onlays manufactured with feldspathic and lithium-disilicate based ceramics showed similar clinical performance.

Extracellular DNA: Insight of a Signal Molecule in Crop Protection.

Agricultural systems face several challenges in terms of meeting everyday-growing quantities and qualities of food requirements. However, the ecological and social trade-offs for increasing agricultural production are high, therefore, more sustainable agricultural practices are desired. Researchers are currently working on diverse sustainable techniques based mostly on natural mechanisms that plants have developed along with their evolution. Here, we discuss the potential agricultural application of extracellular DNA (eDNA), its multiple functioning mechanisms in plant metabolism, the importance of hormetic curves establishment, and as a challenge: the technical limitations of the industrial scale for this technology. We highlight the more viable natural mechanisms in which eDNA affects plant metabolism, acting as a damage/microbe-associated molecular pattern (DAMP, MAMP) or as a general plant biostimulant. Finally, we suggest a whole sustainable system, where DNA is extracted from organic sources by a simple methodology to fulfill the molecular characteristics needed to be applied in crop production systems, allowing the reduction in, or perhaps the total removal of, chemical pesticides, fertilizers, and insecticides application.