Dualism, allosteric modulation, and biased signaling of opioid receptors: Future therapeutic potential.

Opioids are still the drugs of choice for the treatment of acute post-surgical pain and chronic cancer pain. Overprescribing of these drugs has given rise to an "opioid crisis" in some countries. In this context, attention has been drawn to the therapeutic potential of various ligands that act as allosteric modulators of orthosteric binding sites and modulate the drug's activity, affinity, potency, and even efficacy.

Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders.

BACKGROUND/OBJECTIVES: Exome sequencing may identify pathogenic variants unrelated with the purpose of the analysis. We investigated the frequency of secondary and incidental findings (SF/IF) in cancer susceptibility genes (CSG), their clinical actionability and the psychological impact in individuals with an SF/IF (cases) compared with individuals tested due to their cancer history (controls). METHODS: This study analysed 533 exomes ordered for non-cancer conditions. Medical records were reviewed for clinical actionability of SF/IF. Psychological impact was analysed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale and compared between cases and controls with a propensity score weighting method. RESULTS: The frequency of SF/IF in CSG was 2.1% (95% CI 1.1% to 3.8%): three BRCA2, three PMS2, two SDHB, and one each in BRCA1, MLH1 and RAD51C. Among the relatives, 18 were carriers. Twenty enrolled for surveillance, and a neoplasm was diagnosed in 20%: three paragangliomas and one breast cancer. Cases presented higher MICRA mean scores than controls (21.3 vs 16.2 in MICRA total score, 6.3 vs 4.2 in the distress subscale, and 8.3 vs 6.6 in the uncertainty subscale; all p<0.001). CONCLUSION: SF/IF in CSG were identified in 2.1% of patients. Despite a numerically higher psychological impact, the identification of SF/IF allowed early detection and cancer prevention in families without cancer history.

3D scaffolds of caprolactone/chitosan/polyvinyl alcohol/hydroxyapatite stabilized by physical bonds seeded with swine dental pulp stem cell for bone tissue engineering.

Bone Regeneration represents a clinical need, related to bone defects such as congenital anomalies, trauma with bone loss, and/or some pathologies such as cysts or tumors This is why a polymeric biomaterial that mimics the osteogenic composition and structure represents a high potential to face this problem. The method of obtaining these materials was first to prepare a stabilized hydrogel by means of physical bonds and then to make use of the lyophilization technique to obtain the 3D porous scaffolds with temperature conditions of -58 °C and pressure of 1 Pa for 16 h. The physicochemical and bioactive properties of the scaffolds were studied. FTIR and TGA results confirm the presence of the initial components in the 3d matrix of the scaffold. The scaffolds exhibited a morphology with pore size and interconnectivity that promote good cell viability. Together, the cell viability and proliferation test, Alamar BlueTM and the differentiation test: alizarin staining, showed the ability of physically stabilized scaffolds to proliferate and differentiate swine dental pulp stem cell (DPSCs) followed by mineralization. Therefore, the Cs-PCL-PVA-HA scaffold stabilized by physical bonds has characteristics that suggest great utility for future complementary in vitro tests and in vivo studies on bone defects. Likewise, this biomaterial was enhanced with the addition of HA, providing a scaffold with osteoconductive properties necessary for good regeneration of bone tissue. Graphical abstract.

Hyptis mociniana: phytochemical fingerprint and photochemoprotective effect against UV-B radiation-induced erythema and skin carcinogenesis.

Skin cancer is a public health problem due to its high incidence. Ultraviolet radiation (UVR) is the main etiological agent of this disease. Photochemoprotection involves the use of substances to avoid damage caused by UV exposure. The aim of this work was to determine the phytochemical fingerprint and photochemoprotective effect against UVB radiation-induced skin damage such as erythema and carcinogenesis of H. mociniana methanolic extract (MEHm). The chemical composition of the MEHm was analysed by LC/ESI-MS/MS. Three quercetin derivatives, two pectinolides, and two caffeic acid derivatives were identified in the methanolic extract. MEHm has antioxidant effect and it is not cytotoxic in HaCaT cells. Phytochemicals from H. mociniana have a photochemopreventive effect because they absorb UV light and protect HaCaT cells from UVR-induced cell death. Also, in SKH-1 mice -acute exposure-, it decreased erythema formation, modulating the inflammatory response, reduced the skin damage according to histological analysis and diminished p53 expression. Finally, MEHm protects from photocarcinogenesis by reducing the incidence and multiplicity of skin carcinomas in SKH-1 mice exposed chronically to UVB radiation.

[Implementation of the Lean Six Sigma in the improvement of the medication dispensing circuit]. / Implementación Lean Six Sigma en la mejora del circuito de dispensación de medicación.

OBJECTIVE: Lean Six Sigma (LSS) methodology is used to increase productivity and to improve performance, by eliminating processes that do not add value to the customer, as well as reducing variability. In recent years, its application in healthcare sector is increasing in order to improve the efficiency of processes. The aim of this study was to evaluate the results obtained in terms of efficiency in the medication dispensing circuit, after application of LSS methodology. MATERIAL AND METHODS: A multidisciplinary team was created in order to analyse and improve the medication dispensing circuit. The main tools used in LSS methodology were the DMAIC cycle (Define, Measure, Analyse, Improve and Control), SIPOC diagram (Suppliers, Inputs, Process, Outputs, and Customers), a root-cause analysis; a survey to determine the "Customer's voice" about the circuit; and the cost of each task in terms of staff time. Two Pilot Nursing Units (Thoracic Surgery and Cardiology) were selected to introduce the improvement actions. The main analysed variables were: urgent medication orders per day, and percentage of medication orders made online. RESULTS: After the application of LSS methodology, a significant reduction was found in urgent medicament orders per day in both nursing units, and a significant improvement in the electronic processing of urgent orders. The performance of medication dispensing circuit was increased from 60% (1.76 sigma) during initial data analysis, to 93% (3 sigma) in Thoracic Surgery, and from 71% (2.11 sigma) to 81% (2.4 sigma) in Cardiology. Six months after the implementation of improvements, the performance values were increased to 94% (3.1 sigma) and 93% (3 sigma), respectively. Estimated cost savings related to staff were 798.2 € (266 € per month) after implementation, ascending to 2, 228.5 € (371.4 € per month) after 6months. CONCLUSION: The use of LSS methodology has improved the performance of medication dispensing circuits, reducing costs in terms of staff time, and obtaining satisfactory results.

[Trained eye vs. gold standard]. / Ojo clínico vs. gold standard.

OBJECTIVE: To determine the degree of correlation between the clinical diagnosis prior to the minor surgery process and its concordance with the results of histopathology report, as well as to determine the surgical data of little clinical importance compared to that which is really necessary and cost-effective. MATERIAL AND METHOD: A descriptive, observational, retrospective and transversal study was conducted of the Minor Surgery Activities of a clinic in the Ciudad Real Health Centre I. RESULTS: A total of 124 surgical specimens were sent for clinical diagnostic comparison, of which, the main clinical diagnoses were: intradermal melanocytic nevi (34.67%), seborrheic keratosis (11.30%), and epidermoid or sebaceous cysts (10.48%). A correlation of 68% was obtained. The protocols of the work centre have been followed to carry out this study in relation to the confidentiality of the data. CONCLUSIONS: These results were analysed and compared with other similar works performed in the field of minor surgery in Primary Care, being able to affirm that there is a good correlation between the initial clinical diagnosis and the histopathology results.

Flavonol glycosides in Dyssodia tagetiflora and its temporal variation, chemoprotective and ameliorating activities.

Dyssodia tagetiflora is known as 'Tzaracata' and 'flor de muerto'. Recently, D. tagetiflora has been reported to have antioxidant activities in its polar extracts as well as insecticidal activities. Hyperoside (1), avicularin (2) and avicularin acetate (3) have been isolated previously. However, the temporary variation in glycoside flavonoids biosynthesis, as well as antibacterial and chemoprotective activities, have not been reported. The amount of 1, 2 and 3 in the different collections was characterized by HPLC-MS. Two new C-glycosides were characterized, quercetin-4'-methyl ether 6-C glucoside (A1) and quercetin-4'-methyl ether 8-C glucoside (A2), as well as [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxochromen-3-yl]3,4,5-trihydroxyoxane-2,6-dicarboxylate (A3). This is the first report of the presence of C-C flavonoid glycosides compounds in the genus Dyssodia. Hyperoside was the majority compound at all collections. The methanolic extracts of August 2016 and October 2017 were active against Micrococcus luteus and Bacillus subtillis. The methanolic extract has chemoprotective effects because, when applied topically in SKH-1 mice, it decreases the severity of epidermal damage induced by acute exposure to ultraviolet radiation. In addition, cutaneous photocarcinogenesis was decreased in mice treated with the extract. The methanolic extract of D. tagetiflora has chemoprotective properties by decreasing the damage caused by acute and chronic exposure to UV in mice.

Development of Routine Dental Care for Liver Transplant Outpatients.

BACKGROUND: Liver transplantation has become commonplace for patients with end-stage liver disease. The liver is a bodily organ of great importance, and its dysfunction can cause significant complications throughout the body. Patients with hepatic disease should be able to acquire knowledge of the physiology of the liver via the dental profession, and it is also necessary to modify some aspects of dental treatment even in healthy patients. Problems such as excessive bleeding and hepatotoxicity caused by some of the drugs used in dental treatment can lead to a decrease in systemic health. Otherwise, patients with liver disease will have poorer oral health than the general population. Thus, it is important to have well-established routine dental care in this patient group and offer management of oral health in view of the effects of liver disease. METHODS: The objective of this work was to undertake a bibliographic review of the dental approaches to patients with liver disease and liver transplant recipients and to propose a dental care routine for such patients in an outpatient setting. RESULTS: A search was carried out on the main scientific databases (PubMed, Medline, and SciELO) for publications related to this subject and, particularly those published after 2010. The articles selected describe poor oral hygiene among patients, independent of the etiology of their liver disease. These patients also had a high index of xerostomia, caries, periodontal disease, apical lesions, and fungical infections. To control bleeding during and after surgery, hemostatic measures must be understood and adopted. CONCLUSION: There are no data about routine dental care among liver disease/transplantation patients. Thus, our findings will hopefully encourage other services to structure their approaches and consider enhancing their dental care protocols for patients with liver-related complications.

Lippia graveolens photochemopreventive effect against UVB radiation-induced skin carcinogenesis.

Lippia graveolens HBK (Mexican oregano) is a species that is regularly used as a condiment in Mexican cuisine. In traditional medicine, it is used for the treatment of respiratory and digestive illnesses, headaches, rheumatism and inflammation-related disorders. The main chemical components reported in this species include the following: terpenoids, iridoids and flavonoids. The aim of this study was to determine the potential photochemopreventive effect of the methanolic extract of Lippia graveolens (MELG) against ultraviolet B (UVB)-induced skin cancer in SKH-1 mice. The phenolic content, radical scavenger activity, penetration and genotoxicity of the MELG were also evaluated. The MELG exhibited scavenging activity against 1,1-diphenyl-2-picrylhydrazyl, superoxide and hydroxyl radicals, and it did not exhibit genotoxic activity in the micronucleus test. In addition, the MELG absorbed UVB (280nm) electromagnetic radiation. The main components detected in the plant extract were naringenin and galangin, and pinocembrin was also isolated and identified through spectroscopic analysis. The MELG demonstrated a photoprotective effect against UVB-induced cell death in Escherichia coli. In chronic challenge experiments, the MELG protected against UVB-induced skin cancer in SKH-1 mice. The MELG penetrated the skin of mice. Topical administration of the MELG protected against chronic UVB-induced damage in mouse SKH-1 skin. Our results suggest that the MELG has photochemopreventive activity and may potentially prevent photo-tumorigenesis.

Favorable Long-term Outcome in Patients Submitted to Liver Transplantation After Downstaging of Hepatocellular Carcinoma According to a Brazilian Selection Protocol.

BACKGROUND: In October 2008, the Brazilian Ministry of Health authorized listing of downstaged hepatocellular carcinoma (HCC) for liver transplantation, according to a standardized protocol. The aim of this study was to compare the outcome of patients submitted to liver transplantation after downstaging of HCC with the results other standard indications in Brazil. METHODS: We conducted a retrospective analysis of 2,667 adult 1st elective deceased-donor liver transplantations registered at the database of the Transplant Notification Center of the São Paulo State Health Secretariat. These cases are classified into 3 groups: "cirrhosis," including 1,709 patients transplanted because of end-stage liver disease; "Milan-HCC," including 873 HCC patients initially meeting the Milan criteria; and "downstaging" group, including 85 HCC patients submitted to tumor downstaging to the Milan criteria before liver transplantation. RESULTS: One-, 3-, 5-, and 6-year patients survivals were, respectively, 82.7%, 72.0%, 66.1%, and 66.1%, in the "downstaging" group and 76.7%, 68.4%, 63.9%, and 63.5% in the "Milan-HCC" group (P = .483). At the same time intervals, patient survivals were 67.8%, 62.9%, 60.9%, and 60.2% in the "cirrhosis" group. These probabilities were significantly lower than those of both "downstaging" (P = .047) and "Milan-HCC" (P = .001) groups. CONCLUSIONS: Patients submitted to liver transplantation after downstaging of HCC, according to a Brazilian selection protocol, present long-term outcomes similar to HCC patients initially within the Milan criteria and better survival than recipients with end-stage liver disease.

Clinical evaluation of hepatic transection on pediatric liver transplantation.

OBJECTIVES: Liver transplantation is an effective technique in the treatment of end-stage liver disease. The aim of this study was to evaluate the impact of hepatic transection, an advanced surgical technique able to tailor size to generate two grafts to from a single donor. MATERIALS AND METHODS: A retrospective study between January 2000 and September 2013, reviewing 91 pediatric patients who underwent 96 liver transplants from deceased donors. Patients were distributed into two groups: whole organ (WO, n = 39) and transected liver grafts (TLG, n = 57). The following were evaluated: etiology, anthrophometric parameters (age, weight, height, z score weight/age, and height/age), model for end-stage liver disease (MELD) or pediatric end-stage liver disease (PELD), previous surgeries, transfusion of blood components, 1-year survival rate, preoperative laboratory testing, from the second and seventh postoperative days, lactate during surgery, postoperative complications, duration of surgery, duration of cold and warm ischemia, types of biliary reconstruction, and laboratory testing of the donor. RESULTS: The anthropometric values showed significant differences (P < .05) between the groups. The average age was 124.7 months in the WO group and 33.6 months in the TLG group (P < .0001), while the weight was 28.0 kg and 7.4 kg, respectively (P < .0001). The analysis of z score weight/age showed that the TLG had greater acute and chronic malnutrition, probably due to the etiology of liver disease, present from birth in patients as young. Red blood transfusion was higher in the TLG group (P < .0006) due to the cut surface of the graft, emphasizing the use and improvement of hemostatic techniques. CONCLUSION: Despite differences between the groups, clinical and surgical complications were similar, showing that liver transection injury didn't change the results of transplantation. There was no impact on liver function, graft, or 1-year patient survival after liver transection. Second postoperative lactate is a predictive factor of death. Transection liver transplantation is an effective method as an alternative to pediatric liver transplantation.

Grade IV fibrosis interferes in biliary drainage after Kasai procedure.

OBJECTIVES: Biliary atresia (BA) is the most common cause of liver transplantation in children. The earlier the treatment is done, the better the prognosis. The aim is to evaluate the impact of late diagnosis in children with BA, including the histopathological findings and success rate of biliary drainage in patients submitted to hepatic portoenterostomy (HPE). MATERIALS AND METHODS: A retrospective study of cases of BA in the Department of Pediatric Surgery, Federal University of São Paulo (UNIFESP) between 1998-2011. We found 63 cases of BA; of these, 42 underwent HPE and 21 were referred for liver transplantation. Clinic and pathologic data were evaluated. RESULTS: The HPE was performed with a mean age of 86.5 days, with 16.6% having the operation at 60 days or earlier; 59.2% between 61 and 90 days; and 23.8% after 90 days. Successful biliary drainage occurred in 31% of surgeries, Mean days when HPE drained was 69.1 days, and 94.3 days when the surgery did not drain (P = .05). All patients who were successfully drained, did not have grade IV fibrosis on histology. In cases in which surgery was performed after 60 days that had not drained, 25% had grade IV fibrosis on biopsy (P = .0469). CONCLUSION: The age of HPE relates to better prognosis of the disease. It was found that the rate of grade IV fibrosis is higher in no drainage patients. All patients with grade IV fibrosis had no biliary drainage.

MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Compounds derived from endophytes: a review of phytochemistry and pharmacology.

OBJECTIVE: Endophytes, microorganisms that reside in the tissues of living plants, are a promising source of novel compounds with biological activity, or an alternative source of compounds originally isolated from higher plants. The intent of this review is to provide insights into their occurrence in nature, the products that they make, and how some of these organisms are beginning to show some potential for human use. METHODS: Information for analysis of endophytic microorganisms was obtained from libraries and Internet scientific databases such as Scirus, Google Scholar, CAB-Abstracts, MedlinePlus, PubMed, SciFinder, Scopus and Web of Science. RESULTS: Many of the compounds reported here were isolated exclusively from endophytes in culture, while other compounds had been previously reported as chemical constituents of higher plants. A survey of the literature shows endophytic microorganisms are mainly known for their alkaloids with cytotoxic, chemopreventive, anti-metastatic and antitumor properties used in the treatment of several types of cancer. The studies of these alkaloids highlight the existence of various potential leads for the development of novel anti-cancer agents. Modern pharmacology studies demonstrated that their crude extracts and active compounds possess wide pharmacological actions, especially for anti-microbial drug discovery, with neuroprotective, antioxidant, nematicidal, antiplasmodium, anti-inflammatory activities. AIM OF THE REVIEW: This review summarizes the up-to-date and comprehensive information on compounds from endophytes fungi from 1995 to 2011 that relates to 313 compounds isolated from endophytic microorganisms, together with the botany, phytochemistry, pharmacology and toxicology, and discusses possible trends and the scope for future research of endophytes.

The expression of thyroid hormone transporters in the human fetal cerebral cortex during early development and in N-Tera-2 neurodifferentiation.

Associations of neurological impairment with mutations in the thyroid hormone (TH) transporter, MCT8, and with maternal hypothyroxinaemia, suggest that THs are crucial for human fetal brain development. It has been postulated that TH transporters regulate the cellular supply of THs within the fetal brain during development. This study describes the expression of TH transporters in the human fetal cerebral cortex (7­20 weeks gestation) and during retinoic acid induced neurodifferentiation of the human N-Tera-2 (NT2) cell line, in triiodothyronine (T3) replete and T3-depleted media. Compared with adult cortex, mRNAs encoding OATP1A2, OATP1C1, OATP3A1 variant 2, OATP4A1, LAT2 and CD98 were reduced in fetal cortex at different gestational ages, whilst mRNAs encoding MCT8, MCT10, OATP3A1 variant 1 and LAT1 were similar. From the early first trimester, immunohistochemistry localised MCT8 and MCT10 to the microvasculature and to undifferentiated CNS cells. With neurodifferentiation, NT2 cells demonstrated declining T3 uptake, accompanied by reduced expressions of MCT8, LAT1, CD98 and OATP4A1. T3 depletion significantly reduced MCT10 and LAT2 mRNA expression at specific time points during neurodifferentiation but there were no effects upon T3 uptake, neurodifferentiation marker expression or neurite lengths and branching. MCT8 repression also did not affect NT2 neurodifferentiation. In conclusion, many TH transporters are expressed in the human fetal cerebral cortex from the first trimester, which could regulate cellular TH supply during early development. However, human NT2 neurodifferentiation is not dependent upon T3 or MCT8 and there were no compensatory changes to promote T3 uptake in a T3-depleted environment.

Impact of liver ex situ transection on pediatric liver transplantation.

UNLABELLED: Ex situ hepatic transection (ESHT) has allowed transplantation of younger and smaller patients than whole liver grafts. Liver transection is a technical challenge due to the prolonged back table time, possible graft lesions, and increased surgical bleeding from the cut surface. We compare the outcomes of whole versus transected liver grafts in pediatric liver transplantation. METHODS: We retrospectively studied 41 pediatric patients who underwent 42 consecutive liver transplants (1 retransplant) from cadaveric donors. The study included all patients <18 years old who were transplanted at our institution from December 2001 to September 2009. Patients were distributed into 2 groups: whole organ (WO; n = 20) and transected liver grafts (TLG; n = 21). The ESHT grafts included 17 splits and 5 reduced size livers. We evaluated the age, weight, blood component transfusions, 1-year survival, laboratory tests at 2nd and 7th days postoperatively, surgical complications, reoperations, rejection episodes, cold ischemia time, biliary reconstruction type, and donor laboratory tests. Data were analyzed using Fisher and Student's t-tests. RESULTS: The mean age was 115 months (range, 7 months to 17.6 years) in the WO group and 43.3 months (range, 5 months to 16.25 years) in the TLG group (P = .0003). Mean weight was 19.8 kg (range, 5.8-67) and 9.7 Kg (range, 5.2-57) in the WO and TLG groups, respectively (P = .0079). Red blood cell transfusion was higher in the TLG group (P = .0479). Laboratory tests showed no difference between the 2 groups considering hepatic lesions or function markers. One-year patient survivals were 90% and 85.8% among the WO and LTG, respectively (P = .588). The overall 1-year survival rate was 88.8%. CONCLUSION: ESHT allowed smaller and younger children to be transplanted. There was an increased necessity of red blood cell transfusions after hepatic transection. There was no impact on liver function or 1-year patient or graft survival after ESHT.

Extreme subcutaneous, intramuscular and inhaled insulin resistance treated by pancreas transplantation alone.

Diabetes mellitus with resistance to insulin administered subcutaneously or intramuscularly (DRIASM) is a rare syndrome and is usually treated with continuous intravenous insulin infusion. We present here two cases of DRIASM in 16 and 18 years female patients that were submitted to pancreas transplantation alone (PTA). Both were diagnosed with type 1 diabetes as young children and had labile glycemic control with recurrent episodes of diabetic ketoacidosis. They had prolonged periods of hospitalization and complications related to their central venous access. Exocrine and endocrine drainages were in the bladder and systemic, respectively. Both presented immediate graft function. In patient 1, enteric conversion was necessary due to reflux pancreatitis. Patient 2 developed mild postoperative hyperglycemia in spite of having normal pancreas allograft biopsy and that was attributed to her immunosuppressive regimen. Patient 1 died 9 months after PTA from septic shock related to pneumonia. In 8 months of follow-up, Patient 2 presented optimal glycemic control without the use of antidiabetic agents. In conclusion, PTA may be an alternative treatment for DRIASM patients.