Complicações decorrentes de cirurgia bariátrica em pacientes atendidos em um hospital no sul de Santa Catarina / Complications due to bariatric surgery in patients attended in a hospital in southern Santa Catarina

A obesidade tem relação com maior risco para doenças cardiovasculares, diabetes e alguns cânceres. O tratamento é clínico ou cirúrgico, sendo a escolha baseada na gravidade do problema e na presença de complicações associadas. O objetivo do estudo foi descrever o perfil dos pacientes submetidos à cirurgia bariátrica, identificar a incidência de complicações decorrentes do procedimento e relacionalas às características dos pacientes. Foi realizado estudo de coorte retrospectiva, utilizando como amostra pacientes submetidos à gastroplastia para obesidade mórbida no ano de 2014 em um hospital no sul de Santa Catarina. A obtenção dos dados foi feita a partir de prontuários eletrônicos. Foram avaliadas características clínicas do paciente, técnica cirúrgica realizada e se houve ocorrência de complicação pós-operatória descrita. Foram verificados os prontuários de 99 pacientes. As comorbidades mais prevalentes foram hipertensão arterial sistêmica (49,5%) e dislipidemia (32,3%). Foram verificadas 22 descrições de complicações em 16 pacientes (16,2%), sendo colelitíase sintomática a complicação mais incidente (12,1%). O Índice de Massa Corpórea (IMC) pré-operatório esteve relacionado com desfecho de complicações de forma significante (p = 0,01). Não houve registro de óbito decorrente da cirurgia. A incidência de complicação encontrada foi discrepante em relação às da literatura, entretanto a incidência da colelitíase sintomática foi próxima a de outros estudos. A característica do paciente mais relacionada à ocorrência de complicação foi elevado IMC, corroborando outros autores. Entre as limitações do estudo estão o acompanhamento variável em consultas de rotina e a descrição incompleta de eventos nos prontuários eletrônicos.

Obesity is associated with a higher risk for cardiovascular disease, diabetes and some cancers. The treatment is clinical or surgical, being the choice based on the severity of the problem and the presence of associated complications. The objective of the study was to describe the profile of patients undergoing bariatric surgery, to identify the incidence of complications resulting from the procedure and to relate them to the characteristics of the patients. A retrospective cohort study was carried out, using as sample patients submitted to gastroplasty for morbid obesity in 2014 in a hospital in southern Santa Catarina. The data were obtained from electronic medical records. Clinical characteristics of the patient, surgical technique performed and described postoperative complication were evaluated. The medical records of 99 patients were verified. The most prevalent comorbidities were systemic arterial hypertension (49.5%) and dyslipidemia (32.3%). 22 descriptions of complications were found in 16 patients (16.2%), with symptomatic cholelithiasis being the most incident complication (12.1%). Preoperative Body Mass Index (BMI) was related to a significant outcome of complications (p = 0.01). There was no death record due to surgery. The incidence of complications found was inconsistent with the literature, however, the incidence of symptomatic cholelithiasis was similar to other studies. The characteristic of the patient most related to the occurrence of complication was higher BMI, corroborating other authors. Among the limitations of the study are variable follow-up in routine visits and incomplete description of events in electronic medical records.

Perfil clínico-epidemiológico dos pacientes atendidos pelo Serviço de Genética Médica do Ambulatório Materno Infantil da Universidade do Sul de Santa Catarina / Clinical profile of patients followed at the Medical Genetics Department of the Maternal and Child Ambulatory of the Santa Catarina Southern University

As doenças genéticas e anomalias congênitas representam a segunda causa de mortalidade infantil no Brasil, afetando 3% a 7% da população mundial. Reconhecendo isto, este estudo teve como objetivo traçar o perfil clínico-epidemiológico dos pacientes atendidos no serviço de genética médica no Ambulatório Materno Infantil (AMI) da Universidade do Sul de Santa Catarina (UNISUL), no período compreendido entre maio de 2013 e março de 2014. Trata-se de um estudo transversal, realizado por meio de revisão padronizada dos prontuários dos pacientes. A população analisada foi composta pelos indivíduos que procuraram o especialista em genética médica do AMI, na cidade de Tubarão-SC, no período da pesquisa. No estudo foram avaliados 161 prontuários. Por meio da distribuição do diagnóstico clínico dos pacientes, foram averiguadas quais são as principais doenças genéticas incidentes na região, quais os exames mais utilizados pelos médicos para diagnosticá-las e quais situações devem ser alvo de intervenções específicas, tanto terapêuticas quanto profiláticas. No trabalho foi descrito também o desfecho dos pacientes ao final do atendimento e a presença/ausência de uma história familiar positiva para as respectivas doenças diagnosticadas. Em última instância, este estudo servirá de subsídio para construção de uma linha de cuidado integral para pacientes com doenças genéticas e anomalias congênitas na região.

Genetic diseases and congenital anomalies represent the second cause of child mortality in Brazil, affecting from 3% to 7% of the World's population. Aware of that, this study aimed to estimate the clinical and epidemiologic profile of patients followed at the medical genetics department at the maternal and child ambulatory of the Santa Catarina Southern University (UNISUL) from May 2013 to March 2014. It was a cross-sectional study, performed by medical records review. The population was compound by individuals who looked for a geneticist in this ambulatory located in Tubarão-SC. During the research period, 161 medical records have been reviewed. Through the distribution of clinical diagnostic, the mean genetic diseases of the region, the most asked exams and what situations need specific interventions were the variables elucidated. It has also been described the outcomes of the patients and the presence or absence of family history for the diagnosed diseases. After all, this study will contribute to build an integral care line to patients who live with genetic diseases and congenital anomalies in the region.

Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression.

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases.

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.

Vreteno, a gonad-specific protein, is essential for germline development and primary piRNA biogenesis in Drosophila.

In Drosophila, Piwi proteins associate with Piwi-interacting RNAs (piRNAs) and protect the germline genome by silencing mobile genetic elements. This defense system acts in germline and gonadal somatic tissue to preserve germline development. Genetic control for these silencing pathways varies greatly between tissues of the gonad. Here, we identified Vreteno (Vret), a novel gonad-specific protein essential for germline development. Vret is required for piRNA-based transposon regulation in both germline and somatic gonadal tissues. We show that Vret, which contains Tudor domains, associates physically with Piwi and Aubergine (Aub), stabilizing these proteins via a gonad-specific mechanism that is absent in other fly tissues. In the absence of vret, Piwi-bound piRNAs are lost without changes in piRNA precursor transcript production, supporting a role for Vret in primary piRNA biogenesis. In the germline, piRNAs can engage in an Aub- and Argonaute 3 (AGO3)-dependent amplification in the absence of Vret, suggesting that Vret function can distinguish between primary piRNAs loaded into Piwi-Aub complexes and piRNAs engaged in the amplification cycle. We propose that Vret plays an essential role in transposon regulation at an early stage of primary piRNA processing.

CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor.

The metabotropic glutamate receptor 5 (mGlu5) is a glutamate-activated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinson's disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [(3)H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED(50) equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30- to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.

Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers.

Small molecule mGluR1 enhancers, which are 9H-xanthene-9-carboxylic acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides, have been previously reported. Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides with improved pharmacokinetic properties have been designed and synthesized as useful pharmacological tools for the study of the physiological roles mediated by mGlu1 receptors. The synthesis and the structure-activity relationship of this class of positive allosteric modulators of mGlu1 receptors will be discussed in detail.

Metabolite identification via LC-SPE-NMR-MS of the in vitro biooxidation products of a lead mGlu5 allosteric antagonist and impact on the improvement of metabolic stability in the series.

Detailed information on the metabolic fate of lead compounds can be a powerful tool for an informed approach to the stabilization of metabolically labile compounds in the lead optimization phase. The combination of high performance liquid chromatography (HPLC) with nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) has been used to give comprehensive structural data on metabolites of novel drugs in development. Recently, increased automation and the embedding of on-line solid-phase extraction (SPE) into a integrated LC-SPE-NMR-MS system have improved enormously the detection limits of this approach. The new technology platform allows the analysis of complex mixtures from microsome incubations, combining low material requirements with relatively high throughput. Such characteristics make it possible to thoroughly characterize metabolites of selected compounds at earlier phases along the path to lead identification and clinical candidate selection, thus providing outstanding guidance in the process of eliminating undesired metabolism and detecting active or potentially toxic metabolites. Such an approach was applied at the lead identification stage of a backup program on metabotropic glutamate receptor 5 (mGlu5) allosteric inhibition. The major metabolites of a lead 5-aminothiazole-4-carboxylic acid amide 1 were synthesized and screened, revealing significant in vitro activity and possible involvement in the overall pharmacodynamic behavior of 1. The information collected on the metabolism of the highly active compound 1 was pivotal to the synthesis of related compounds with improved microsomal stability.

Synthesis and biological evaluation of fenobam analogs as mGlu5 receptor antagonists.

Optimization of affinity and microsomal stability led to identification of the potent, metabolically stable fenobam analog 4l. Robust in vivo efficacy of 4l was demonstrated in four different models of anxiety. Additionally, a ligand based pharmacophore alignment of fenobam and MPEP is proposed.

Rational design, synthesis, and structure-activity relationship of benzoxazolones: new potent mglu5 receptor antagonists based on the fenobam structure.

A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-throughput screening campaign with the structure of the known anxiolytic fenobam. Representative compounds from this class show favorable pharmacokinetic properties and are active in an in vivo model of anxiety.

Arylmethoxypyridines as novel, potent and orally active mGlu5 receptor antagonists.

Optimisation of affinity, chemical stability, metabolic stability and solubility led from a chemically labile HTS hit 1 to mGlu5 receptor antagonists (24-26) with high affinity for the allosteric MPEP binding site, improved microsomal metabolic stability and anxiolytic-like activity in vivo as assessed by the Vogel conflict drinking test.

9H-Xanthene-9-carboxylic acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides as potent, orally available mGlu1 receptor enhancers.

Small molecule mGluR1 enhancers based on the lead compound (9H-xanthene-9-carbonyl)-carbamic acid butyl ester derived from random-screening hit diphenylacetyl-carbamic acid ethyl ester were designed and synthesized as useful pharmacological tools for the study of the physiological roles mediated by mGlu1 receptors. The synthesis and the structure-activity relationship of this new class of positive allosteric modulators of mGlu1 receptors will be discussed in detail.

Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity.

Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC(50) = 58 +/- 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC(50) = 84 +/- 13 nM. [(3)H]Fenobam bound to rat and human recombinant receptors with K(d) values of 54 +/- 6 and 31 +/- 4 nM, respectively. MPEP inhibited [(3)H]fenobam binding to human mGlu5 receptors with a K(i) value of 6.7 +/- 0.7 nM, indicating a common binding site shared by both allosteric antagonists. Fenobam exhibits anxiolytic activity in the stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, and conditioned emotional response with a minimum effective dose of 10 to 30 mg/kg p.o. Furthermore, fenobam is devoid of GABAergic activity, confirming previous reports that fenobam acts by a mechanism distinct from benzodiazepines. The non-GABAergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxiolytic agents.

Evidence for multiple cycles of strand invasion during repair of double-strand gaps in Drosophila.

DNA double-strand breaks (DSBs), a major source of genome instability, are often repaired through homologous recombination pathways. Models for these pathways have been proposed, but the precise mechanisms and the rules governing their use remain unclear. In Drosophila, the synthesis-dependent strand annealing (SDSA) model can explain most DSB repair. To investigate SDSA, we induced DSBs by excision of a P element from the male X chromosome, which produces a 14-kb gap relative to the sister chromatid. In wild-type males, repair synthesis tracts are usually long, resulting in frequent restoration of the P element. However, repair synthesis is often incomplete, resulting in internally deleted P elements. We examined the effects of mutations in spn-A, which encodes the Drosophila Rad51 ortholog. As expected, there is little or no repair synthesis in homozygous spn-A mutants after P excision. However, heterozygosity for spn-A mutations also resulted in dramatic reductions in the lengths of repair synthesis tracts. These findings support a model in which repair DNA synthesis is not highly processive. We discuss a model wherein repair of a double-strand gap requires multiple cycles of strand invasion, synthesis, and dissociation of the nascent strand. After dissociation, the nascent strand may anneal to a complementary single strand, reinvade a template to be extended by additional synthesis, or undergo end joining. This model can explain aborted SDSA repair events and the prevalence of internally deleted transposable elements in genomes.

An essential role of DmRad51/SpnA in DNA repair and meiotic checkpoint control.

Rad51 is a conserved protein essential for recombinational repair of double-stranded DNA breaks (DSBs) in somatic cells and during meiosis in germ cells. Yeast Rad51 mutants are viable but show meiosis defects. In the mouse, RAD51 deletions cause early embryonic death, suggesting that in higher eukaryotes Rad51 is required for viability. Here we report the identification of SpnA as the Drosophila Rad51 gene, whose sequence among the five known Drosophila Rad51-like genes is most closely related to the Rad51 homologs of human and yeast. DmRad51/spnA null mutants are viable but oogenesis is disrupted by the activation of a meiotic recombination checkpoint. We show that the meiotic phenotypes result from an inability to effectively repair DSBs. Our study further demonstrates that in Drosophila the Rad51-dependent homologous recombination pathway is not essential for DNA repair in the soma, unless exposed to DNA damaging agents. We therefore propose that under normal conditions a second, Rad51-independent, repair pathway prevents the lethal effects of DNA damage.

Alkyl diphenylacetyl, 9H-xanthene- and 9H-thioxanthene-carbonyl carbamates as positive allosteric modulators of mGlu1 receptors.

Starting from the random-screening hit 1a, a series of alkyl diphenylacetyl, 9H-xanthene- and 9H-thioxanthene-carbonyl carbamates 1 has been prepared. These derivatives turned out to be selective positive allosteric modulators of mGlu1 receptors. These compounds do not directly activate mGlu1 receptors but markedly potentiate agonist stimulated responses, increasing potency and maximum efficacy.