Specific Learning Disabilities and Emotional-Behavioral Difficulties: Phenotypes and Role of the Cognitive Profile.

Specific Learning Disabilities (SLD) are often associated with emotional-behavioral problems. Many studies highlighted a greater psychopathological risk in SLD, describing both internalizing and externalizing problems. The aims of this study were to investigate the emotional-behavioral phenotype through the Child Behavior Checklist (CBCL), and evaluate the mediating role of background and cognitive characteristics on the relationship between CBCL profile and learning impairment in children and adolescents with SLD. One hundred and twenty-one SLD subjects (7-18 years) were recruited. Cognitive and academic skills were assessed, and parents completed the questionnaire CBCL 6-18. The results showed that about half of the subjects manifested emotional-behavioral problems with a prevalence of internalizing symptoms, such as anxiety and depression, over externalizing ones. Older children showed greater internalizing problems than younger ones. Males have greater externalizing problems compared to females. A mediation model analysis revealed that learning impairment is directly predicted by age and familiarity for neurodevelopmental disorders and indirectly via the mediation of the WISC-IV/WAIS-IV Working Memory Index (WMI) by the CBCL Rule-Breaking Behavior scale. This study stresses the need to combine the learning and neuropsychological assessment with a psychopathological evaluation of children and adolescents with SLD and provides new interpretative insights on the complex interaction between cognitive, learning, and emotional-behavioral phenotypes.

Hydroxychloroquine increased cholesterol transfer to high-density lipoprotein in systemic lupus erythematosus: A possible mechanism for the reversal of atherosclerosis in the disease.

INTRODUCTION: The beneficial effect of hydroxychloroquine (HCQ) in decreasing LDL levels on Systemic Lupus Erythematosus (SLE) is well defined. The influence of this drug on HDL levels is still under debate and information about its effect on cholesterol reverse transport is lacking. OBJECTIVE: To evaluate the effects of HCQ on HDL levels and the transfer of lipids to this lipoprotein in SLE. METHODS: Nineteen SLE patients using only HCQ (SLE WITH HCQ), 19 SLE patients without any therapy (SLE WITHOUT THERAPY), and 19 healthy controls (CONTROL) were included. All three groups were premenopausal women age- and gender-matched. Serum lipids and apolipoproteins were determined by commercial kits. An in vitro transfer of four lipids (14C-Phospolipid, 3H-Cholesteryl ester, 3H-Triglyceride, and 14C-Unesterified cholesterol) from a radioactively labeled nanoemulsion donor to HDL was performed in all participants. RESULTS: Groups had comparable mean age, weight, height, BMI(body mass index), and waist circumference (p > .05). Mean HDL levels were higher in SLE WITH HCQ group compared to SLE WITHOUT THERAPY(58.37 ± 14.04 vs 49.79 ± 8.0 mg/dL; p < .05) but lower than CONTROL (58.37 ± 14.04 vs 68.58 ± 9.99 mg/dL; p < .05). Total cholesterol (TC) and LDL levels were also significantly lower in SLE WITH HCQ compared SLE WITHOUT THERAPY(148.16 ± 16.43 vs 167.11 ± 30.18 mg/dL; p < .05, 75.05 ± 22.52 vs 96.05 ± 25.63 mg/dL; p < .05) and CONTROL (148.16 ± 16.43 vs 174.11 ± 23.70 mg/dL; p < .05, 75.05 ± 22.52 vs 88.53 ± 20.24 mg/dL; p < .05). The in vitro lipid transfer to HDL study revealed a significant difference among the three groups (p = .002) with a higher transfer of unesterified cholesterol(UC) in SLE WITH HCQ compared to SLE WITHOUT THERAPY(5.40 ± 1.05% vs. 4.44 ± 1.05%; p < .05). The latter was significantly decreased compared to CONTROL (5.40 ± 1.05% vs. 5.99 ± 1.71%; p < .05).The percentages of transfer of triacylglycerol (4.93 ± 0.69% vs. 4.50 ± 0.69% vs. 5.14 ± 1.01%; p = .054), esterified cholesterol (5.24 ± 0.70% vs. 4.96 ± 0.89% vs. 5.69 ± 1.27%; p = .079), and phospholipid (15.67 ± 1.03% vs. 15.34 ± 1.44% vs. 16.47 ± 1.89%; p = .066) were similar among groups. CONCLUSION: The present study is the first to demonstrate that HCQ promoted a higher transfer of unesterified cholesterol which may account for the increased HDL levels in lupus patients under HCQ. This desirable effect may underlie the reported reduced atherosclerosis in SLE.

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein.

The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28, showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.

Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV-1 Nucleocapsid Protein.

Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested in vitro 18 NC inhibitors (NCIs) bearing a double functionalization. In these NCIs, one part of the molecule is deputed to interact noncovalently with the NC hydrophobic pocket, while the second portion is designed to interact with the N-terminal domain of NC. This binding hypothesis was verified by molecular dynamics simulations, while the linkage between these two pharmacophores was found to enhance antiretroviral activity both on the wild-type virus and on HIV-1 strains with resistance to currently licensed drugs. The two most interesting compounds 6 and 13 showed no cytotoxicity, thus becoming valuable leads for further investigations.

Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug-Resistant HIV-1 Strains.

HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of the HIV-1 life cycle are efficient in blocking viral replication but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets. In this respect, pharmacological inhibition of the highly conserved and multifunctional nucleocapsid protein (NC) of HIV-1 is considered a promising alternative to current drugs, particularly to overcome DR. Here, using a multidisciplinary approach combining in silico screening, fluorescence-based molecular assays, and cellular antiviral assays, we identified nordihydroguaiaretic acid (6), as a novel natural product inhibitor of NC. By using NMR, mass spectrometry, fluorescence spectroscopy, and molecular modeling, 6 was found to act through a dual mechanism of action never highlighted before for NC inhibitors (NCIs). First, the molecule recognizes and binds NC noncovalently, which results in the inhibition of the nucleic acid chaperone properties of NC. In a second step, chemical oxidation of 6 induces a potent chemical inactivation of the protein. Overall, 6 inhibits NC and the replication of wild-type and drug-resistant HIV-1 strains in the low micromolar range with moderate cytotoxicity that makes it a profitable tool compound as well as a good starting point for the development of pharmacologically relevant NCIs.

Relação entre o desenvolvimento do melanoma cutâneo e o estresse oxidativo / Relationship between the development of cutaneous melanoma and oxidative stress

O carcinoma cutâneo é a neoplasia maligna mais frequente na população brasileira, correspondendo a cerca de 25% de todas as lesões malignas registradas no País. Embora represente apenas cerca de 5% dos casos de câncer de pele, o melanoma provoca a maioria das mortes por malignidades cutâneas, pelo seu alto potencial de enviar metástases a órgãos distantes. Os fatores de risco para o desenvolvimento do câncer de pele tanto podem ser genéticos quanto ambientais. O prognóstico desse tipo de câncer pode ser considerado bom se detectado nos estágios iniciais.

The skin carcinoma is the most common malignancy in the Brazilianpopulation, accounting for about 25% of all malignant lesions recorded in Brazil. While representing only about 5% of cases skin cancer, melanoma causes the most deaths from cutaneous malignancies, for its high potential to send metastases to distant organs. Risk factors for the development of skin cancer can be both genetic and environmental. The prognosis of this type of cancer can be considered good if detected in the early stages.

Insights into the interaction of high potency inhibitor IRC-083864 with phosphatase CDC25.

CDC25 phosphatases play a crucial role in cell cycle regulation. They have been found to be over-expressed in various human tumours and to be valuable targets for cancer treatment. Here, we report the first model of binding of the most potent CDC25 inhibitor to date, the bis-quinone IRC-083864, into CDC25B obtained by combining molecular modeling and NMR studies. Our study provides new insights into key interactions of the catalytic site inhibitor and CDC25B in the absence of any available experimental structure of CDC25 with a bound catalytic site inhibitor. The docking model reveals that IRC-083864 occupies both the active site and the inhibitor binding pocket of the CDC25B catalytic domain. NMR saturation transfer difference and WaterLOGSY data indicate the binding zones of the inhibitor and support the docking model. Probing interactions of analogues of the two quinone units of IRC-083864 with CDC25B demonstrate that IRC-083864 competes with each monomer. Proteins 2017; 85:593-601. © 2016 Wiley Periodicals, Inc.

Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family.

Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.

Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroyxindole class LDH inhibitors as anticancer agents.

Inhibitors of human lactate dehydrogenase A (LDH-A) are promising therapeutic agents against cancer. The development of LDH-A inhibitors that possess cellular activities has so far proved to be particularly challenging, since the enzyme's active site is narrow and highly polar. In the recent past, we were able to develop a glucose-conjugated N-hydroxyindole-based LDH-A inhibitor designed to exploit the sugar avidity expressed by cancer cells (the Warburg effect). Herein we describe a structural modulation of the sugar moiety of this class of inhibitors, with the insertion of α-D-mannose, ß-D-gulose, or ß-N-acetyl-D-glucosamine portions in their structures. Their stereospecific chemical synthesis, which involves a substrate-dependent stereospecific glycosylation step, and their biological activity in reducing lactate production and proliferation in cancer cells are reported. Interestingly, the α-D-mannose conjugate displayed the best properties in the cellular assays, demonstrating an efficient antiglycolytic and antiproliferative activity in cancer cells.

The effects of healing touch on pain, nausea, and anxiety following bariatric surgery: a pilot study.

CONTEXT: Given the growth in the number of bariatric surgeries, it is important for healthcare practitioners to maximize symptom management for these patients, including the option of complementary therapies such as Healing Touch. OBJECTIVE: A quasi-experimental study was conducted to determine the feasibility of a Healing Touch intervention for reducing pain, nausea, and anxiety in patients undergoing laparoscopic bariatric surgery. DESIGN: Following surgery, a nurse administered the Healing Touch intervention once daily. Study participants reported levels of pain, nausea, and anxiety immediately before and after the Healing Touch intervention using separate numeric rating scales. RESULTS: Significant decreases in pain, nausea, and anxiety were observed immediately following the intervention on post-operative days one and two, and in pain and anxiety on post-operative day three compared with pre-intervention levels. These findings indicate that the Healing Touch intervention is feasible and acceptable to patients undergoing bariatric surgery, and significantly improved pain, nausea, and anxiety in these patients.

Effect of fat on serum 25-hydroxyvitamin D levels after a single oral dose of vitamin D in young healthy adults: a double-blind randomized placebo-controlled study.

PURPOSE: This double-blind placebo-controlled trial evaluated serum 25-hydroxyvitamin D [25(OH)D] levels after the oral intake of a single dose of cholecalciferol during one of the three meals, containing different amounts of fat or placebo. METHODS AND RESULTS: Sixty-four healthy medical residents or students of a university hospital in Porto Alegre, latitude 30° S, Brazil, were divided into four groups. Three groups received a single 50,000 IU oral dose of cholecalciferol during a meal containing 0 g (Group 1), 15 g (Group 2) or 30 g (Group 3) of fat, and one group received placebo (Group 4), according to randomization. Serum 25(OH)D, parathyroid hormone, total calcium, albumin, magnesium, and creatinine levels, and urinary calcium, magnesium, and creatinine levels were measured at baseline and after 14 days. Baseline mean serum 25(OH)D levels were low in all groups. Vitamin D given during breakfast increased the mean change of serum 25(OH)D levels, when compared to placebo. Furthermore, the intake of fat with vitamin D increased the mean change of serum 25(OH)D levels. CONCLUSION: A single oral dose of vitamin D given with food increased mean serum 25(OH)D levels, after 2 weeks, and the mean increase was larger, when the meal had at least 15 g of fat. These findings can have important implications to oral vitamin D supplementation.

Synthesis of linear and cyclic guazatine derivatives endowed with antibacterial activity.

Antibiotic resistance has reached alarming levels in many clinically-relevant human pathogens, and there is an increasing clinical need for new antibiotics active on drug-resistant Gram-negative pathogens who rapidly evolve towards pandrug resistance phenotypes. Here, we report on two related classes of guanidinic compounds endowed with antibacterial activity. The two best compounds (9a and 13d) exhibited the most potent antibacterial activity with MIC values ranging 0.12-8 µg/ml with most tested pathogens, including both Gram-positive and Gram-negative bacteria. Interestingly, MIC values were not affected (1-8 µg/ml) when measured using recent clinical isolates with various antibiotic resistance determinants. The results reported herein identify guazatine derivatives as an interesting starting point for the optimization of a potentially novel class of antibacterial agents.

Functional and structural characterization of 2-amino-4-phenylthiazole inhibitors of the HIV-1 nucleocapsid protein with antiviral activity.

The nucleocapsid protein (NC) is a highly conserved protein in diverse HIV-1 subtypes that plays a central role in virus replication, mainly by interacting with conserved nucleic acid sequences. NC is considered a highly profitable drug target to inhibit multiple steps in the HIV-1 life cycle with just one compound, a unique property not shown by any of the other antiretroviral classes. However, most of NC inhibitors developed so far act through an unspecific and potentially toxic mechanism (zinc ejection) and are mainly being investigated as topical microbicides. In an effort to provide specific NC inhibitors that compete for the binding of nucleic acids to NC, here we combined molecular modeling, organic synthesis, biophysical studies, NMR spectroscopy, and antiviral assays to design, synthesize, and characterize an efficient NC inhibitor endowed with antiviral activity in vitro, a desirable property for the development of efficient antiretroviral lead compounds.

Dislipidemias e risco cardiovascular em pacientes HIV-positivo utilizando terapia antirretroviral na região oeste de Santa Catarina / Dyslipidemia and cadiovascular risk In HIV positive pacients on antiretroviral therapy in the western region of Santa Catarina

A terapia antirretroviral é a chave no tratamento de indivíduos portadores do vírus da imunodeficiência humana, cuja eficácia crescente tem possibilitado um aumento na expectativa de vida dos usuários. Apesar desta notável realização, a terapia não está livre de efeitos colaterais. Entre os conhecidos, as dislipidemias representam um papel marcante devido a sua alta prevalência e efeitos negativos na qualidade de vida. Objetivo: caracterizaro perfil lipídico e o risco cardiovascular dos pacientes portadores do vírus da imunodeficiência humana que fazem uso da terapia antirretroviral na região oeste de Santa Catarina. Métodos: estudo transversal quantitativo, utilizando dados dos prontuários de pacientes cadastrados no hospital-dia até janeiro de2010. Análise estatística com: T-student, qui-quadrado e one-way ANOVA . Resultados: dos 113 pacientes estudados, 64,6% apresentaram dislipidemias,principalmente baixo nível de lipoproteína de alta densidade (24,8%). Comparando o perfil lipídico anterior e posterior ao uso da terapia, houve redução do número de dislipidemias, porém estas sofreram um agravamento (p < 0,05). A associação de inibidores da transcriptase reversa análogos de nucleosídeos(ITRN) com inibidores de protease (IP) foi a mais relacionada com o desenvolvimento de dislipidemias (RR = 1,54) e o RCV foi predominantemente baixo.Conclusão: assim como esperado, a HAART, principalmente através do uso de ITRN com IP, foi responsável por agravar o perfil lipídico de seus usuários que já apresentavam dislipidemia. Porém, neste estudo não houve aumento no número absoluto de pacientes dislipidêmicos e no geral o risco cardiovascular foi baixo.

Antiretroviral therapy is the key to treat individuals with human immunodeficiency virus, whose efficiency has enabled an increase in life expectancy. Despite this remarkable achievement, antiretroviral therapy is not free of side effects. Among them dyslipidemia represents a striking role dueto its high prevalence and negative effects on quality of life. Objective: to characterize the lipid profile and cardiovascular risk in patients with humanimmunodeficiency virus who undergo therapy in western Santa Catarina. Methods: cross-sectional quantitative, using medical records of patients enrolledat Hospital Dia until January 2010. Statistical analysis with: T-Student, Chi-square and one-way ANOVA . Results: study population was 113 patients from whom 64.6% had dyslipidemia, the most frequent being the low level of high density lipoprotein (24.8%). Comparing the lipid profile before and after the use of therapy, there was a reduction in the number of dyslipidemias, but these have suffered a worsening (p < 0.05). The combination of Reverse Transcriptase Inhibitors (RTI s) with protease inhibitors (PI) was more related to the development of dyslipidemia (RR = 1.54) and was predominantly low cardiovascular risk. Conclusion: as expected, antiretroviral therapy, primarily through the use of RTIs-PI, was responsible for aggravating the lipid profile of their users that have already had dyslipidemia. However, in this study there was no increase in the absolute number of patients with dyslipidemia andover all cardiovascular risk was low.

Epidemiological profile of patients with cutaneous melanoma in a region of southern Brazil.

Cutaneous melanoma (CM) is responsible for 75% of deaths from malignant skin cancer. The incidence of CM in the southern region of Brazil, particularly in the western region of Santa Catarina, is possibly higher than estimated. In this study, the clinical and epidemiological profile of patients with CM treated in the western region of Santa Catarina was examined. A cross-sectional study was performed with patients diagnosed with CM from January 2002 to December 2009, from 78 counties of the western region of the state of Santa Catarina. Data were collected using a protocol adapted from the Brazilian Melanoma Group and 503 patients were evaluated. The incidence and prevalence of CM found in this region are much higher than those found elsewhere in the country. This fact is most likely due to the phenotypic characteristics of the population and the high incidence of UV radiation in this region due to its location in southern Brazil, as is the case in the countries of Oceania.

Novel circovirus in European catfish (Silurus glanis).

Circular single-stranded DNA viral genomes had been identified worldwide in different species and in environmental samples. Among them, viruses belonging to the genus Circovirus of the family Circoviridae are present in birds and pigs, and recently, they were detected in barbels. The present study reports the identification of a new circovirus in fish. PCR amplification and sequencing were used to identify the novel circular DNA virus in European catfish (Silurus glanis). Full genome characterization and phylogenetic analysis showed that the virus belonged to the family Circoviridae and that it was distantly related to the previously described barbel circovirus.

A proposed multidisciplinary approach for identifying feeding abnormalities in children with cerebral palsy.

Children with neurodevelopmental disabilities, such as cerebral palsy, frequently have associated oral motor dysfunction, which leads to feeding difficulties, risk of aspiration, prolonged feeding times, and malnutrition with its attendant physical compromise. The authors propose a comprehensive multidisciplinary assessment, including neurological and dysphagia examination and ear, nose, and throat examination, to evaluate clinical indicators and severity of feeding impairment in children affected by neurodevelopmental disorders. A representative sample of 40 children with cerebral palsy (spastic, dyskinetic, or mixed), intellectual disability, and feeding problems was included in the study. A specific multidisciplinary evaluation and standardized mealtime observation in patients with cerebral palsy appear feasible and appropriate to recognize proactive indicators of dysphagia and to establish personalized programs of gastric and rehabilitative interventions.