Sex-Specific Effects of Cholesteryl Ester Transfer Protein (CETP) on the Perivascular Adipose Tissue.

Cholesteryl ester transfer protein (CETP) increases the atherosclerosis risk by lowering HDL-cholesterol levels. It also exhibits tissue-specific effects independent of HDL. However, sexual dimorphism of CETP effects remains largely unexplored. Here, we hypothesized that CETP impacts the perivascular adipose tissue (PVAT) phenotype and function in a sex-specific manner. PVAT function, gene and protein expression, and morphology were examined in male and female transgenic mice expressing human or simian CETP and their non-transgenic counterparts (NTg). PVAT exerted its anticontractile effect in aortas from NTg males, NTg females, and CETP females, but not in CETP males. CETP male PVAT had reduced NO levels, decreased eNOS and phospho-eNOS levels, oxidative stress, increased NOX1 and 2, and decreased SOD2 and 3 expressions. In contrast, CETP-expressing female PVAT displayed increased NO and phospho-eNOS levels with unchanged NOX expression. NOX inhibition and the antioxidant tempol restored PVAT anticontractile function in CETP males. Ex vivo estrogen treatment also restored PVAT function in CETP males. Moreover, CETP males, but not female PVAT, show increased inflammatory markers. PVAT lipid content increased in CETP males but decreased in CETP females, while PVAT cholesterol content increased in CETP females. CETP male PVAT exhibited elevated leptin and reduced Prdm16 (brown adipocyte marker) expression. These findings highlight CETP sex-specific impact on PVAT. In males, CETP impaired PVAT anticontractile function, accompanied by oxidative stress, inflammation, and whitening. Conversely, in females, CETP expression increased NO levels, induced an anti-inflammatory phenotype, and preserved the anticontractile function. This study reveals sex-specific vascular dysfunction mediated by CETP.

Insights into Leptocybe invasa resistance in Eucalyptus: phenotyping, genotyping and in silico approaches.

The gall wasp, Leptocybe invasa, poses a significant global threat to Eucalyptus cultivation, by causing substantial economic losses. The objective of this study was to differentiate between resistant and susceptible genotypes by morphological characteristics using image analysis based on the damage caused by the gall wasp. In addition, consensus sequences derived from transposable elements (TEs) and the genome of Eucalyptus spp. Were identified by in silico analysis. Furthermore, another objective was to discriminate Eucalyptus genotypes in response to Leptocybe invasa by conducting molecular analyses involving transposable elements and inter simple sequence markers. For image analysis, the GroundEye ® system was used to collect images of 60 leaves from six genotypes, three of which were resistant and three susceptible. Eucalyptus spp. sequences were obtained from the GenBank database by in silico analysis and pairwise alignments with TE sequences were conducted using BLASTN. Multiple sequence alignment was performed with Clustal Omega, followed by the identification of conserved regions in Jalview. A motif signature was generated using Weblogo. For molecular characterization using ISSR markers and TEs, samples of young leaves were obtained from a total of 80 Eucalyptus seedlings, of which 50 were classified as resistant and 30 as susceptible to L. invasa. It was possible to distinguish gall wasp susceptible and resistant genotypes by image analysis. In silico analysis enabled the identification of conserved regions in the Eucalyptus spp. genome, which were associated with proteins involved in secondary metabolite production, e.g., terpenes, which play a role in the response to L. invasa. The discrimination capacity of TEs and ISSR primers was demonstrated and bands were generated that could be used to identify resistant genotypes. However, increasing the number of markers required to discriminate genotypes in both cases is suggested.

Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions.

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Histomorphological evaluation of acellularized bovine pericardium in breast implant coverage.

Bovine pericardium (BP) has been used as a biomaterial for several decades in many medical applications particularly due to its mechanical properties and the high collagen content. In the acellular form it favors faster tissue repair, providing a three-dimensional support for cellular and vascular events observed during tissue repair and due, to a low elastin content, may favor its use as a breast implant cover, resulting in a low possibility of contracture of the biomaterial, preventing the appearance of irregularities during the reconstruction process. Thus, the aim of this study was to evaluate, histomorphologically, the behavior of acellularized bovine pericardium (ABP) as a mammary implant cover in rats. For this purpose, 16 animals were divided into two groups, with eight animals at each biological point: 7 and 15 days after surgery. Of the 16 animals, 32 specimens were obtained: 16 in the experimental group (EG) and 16 in the control group (CG). Throughout this study, none of the studied groups had postoperative complications. Results: The histomorphological results showed, in the two biological points, both in the EG and in the CG, chronic inflammatory infiltrate, leukocyte fibrin exudate, formation of granulation tissue and deposition of collagen fibers, more evident in the EG, regressive along the biological points. At 15 days, the implanted ABP showed initial biointegration with the fibrous capsule and surrounding tissues of the recipient bed. Conclusion: These results indicate that the due to the observed favorable tissue response ABP may be of potential use as a breast implant cover.

Biological behavior of magnesium-substituted hydroxyapatite during bone repair / Comportamento biológico de hidroxiapatita substituída com magnésio durante o reparo ósseo

Abstract The aim of this study was to analyze the biological behavior and osteogenic potential of magnesium (Mg) substituted hydroxyapatite (HA) microspheres, implanted in a critical bone defect, considering that this ion is of great clinical interest, since it is closely associated with homeostasis and bone mineralization. For the purpose of this study, 30 rats were used to compose three experimental groups: GI - bone defect filled with HA microspheres; GII - bone defect filled with HA microspheres replaced with Mg; GIII - empty bone defect; evaluated at biological points of 15 and 45 days. The histological results, at 15 days, showed, in all the groups, a discrete chronic inflammatory infiltrate; biomaterials intact and surrounded by connective tissue; and bone neoformation restricted to the borders. At 45 days, in the GI and GII groups, an inflammatory response of discrete granulomatous chronic type was observed, and in the GIII there was a scarce presence of mononuclear inflammatory cells; in GI and GII, the microspheres were seen to be either intact or fragmented, surrounded by fibrous connective tissue rich in blood vessels; and discrete bone neoformation near the edges and surrounding some microspheres. In GIII, the mineralization was limited to the borders and the remaining area was filled by fibrous connective tissue. It was concluded that the biomaterials were biocompatible and osteoconductive, and the percentage of Mg used as replacement ion in the HA did not favor a greater bone neoformation in relation to the HA without the metal.

Resumo O objetivo deste estudo foi analisar o comportamento biológico de microesferas de hidroxiapatita (HA) substituída com magnésio (Mg) durante o reparo de defeito ósseo crítico, tendo em vista que este íon é de grande interesse clínico, pois está intimamente associado à homeostasia e à mineralização óssea. Para tanto, utilizou-se 30 ratos para compor três grupos experimentais: GI - defeito ósseo preenchido com microesferas de HA; GII - defeito ósseo preenchido com microesferas de HA substituída com Mg; GIII (controle) - defeito ósseo vazio; avaliados nos pontos biológicos de 15 e 45 dias. Os resultados histológicos evidenciaram, aos 15 dias, discreto infiltrado inflamatório crônico e neoformação óssea restrita às bordas, em todos os grupos. Nos grupos GI e GII, os biomateriais mantiveram-se íntegros e circundados por tecido conjuntivo frouxo. Aos 45 dias, notou-se resposta inflamatória do tipo crônica granulomatosa discreta nos grupos GI e GII, e no GIII presença escassa de células inflamatórias mononucleares. As microesferas implantadas no GI e GII mantiveram-se, em sua maioria, íntegras e envolvidas por tecido conjuntivo fibroso. Notou-se discreta neoformação óssea próxima às bordas e circunjacente a algumas microesferas. No GIII, a mineralização limitou-se às bordas e a área remanescente foi preenchida por tecido conjuntivo fibroso. Conclui-se que os biomateriais foram biocompatíveis, bioativos, osteocondutores e apresentaram biodegradação lenta, indicando seu grande potencial para em aplicações clínica como biomaterial de preenchimento.

Biological behavior of magnesium-substituted hydroxyapatite during bone repair.

The aim of this study was to analyze the biological behavior and osteogenic potential of magnesium (Mg) substituted hydroxyapatite (HA) microspheres, implanted in a critical bone defect, considering that this ion is of great clinical interest, since it is closely associated with homeostasis and bone mineralization. For the purpose of this study, 30 rats were used to compose three experimental groups: GI - bone defect filled with HA microspheres; GII - bone defect filled with HA microspheres replaced with Mg; GIII - empty bone defect; evaluated at biological points of 15 and 45 days. The histological results, at 15 days, showed, in all the groups, a discrete chronic inflammatory infiltrate; biomaterials intact and surrounded by connective tissue; and bone neoformation restricted to the borders. At 45 days, in the GI and GII groups, an inflammatory response of discrete granulomatous chronic type was observed, and in the GIII there was a scarce presence of mononuclear inflammatory cells; in GI and GII, the microspheres were seen to be either intact or fragmented, surrounded by fibrous connective tissue rich in blood vessels; and discrete bone neoformation near the edges and surrounding some microspheres. In GIII, the mineralization was limited to the borders and the remaining area was filled by fibrous connective tissue. It was concluded that the biomaterials were biocompatible and osteoconductive, and the percentage of Mg used as replacement ion in the HA did not favor a greater bone neoformation in relation to the HA without the metal.

Primary surgical management of anterior pelvic organ prolapse: a systematic review, network meta-analysis and cost-effectiveness analysis.

BACKGROUND: Anterior compartment prolapse is the most common pelvic organ prolapse (POP) with a range of surgical treatment options available. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of surgical treatments for the repair of anterior POP. METHODS: We conducted a systematic review of randomised controlled trials comparing surgical treatments for women with POP. Network meta-analysis was possible for anterior POP, same-site recurrence outcome. A Markov model was used to compare the cost-utility of surgical treatments for the primary repair of anterior POP from a UK National Health Service perspective. MAIN RESULTS: We identified 27 eligible trials for the network meta-analysis involving eight surgical treatments tested on 3194 women. Synthetic mesh was the most effective in preventing recurrence at the same site. There was no evidence to suggest a difference between synthetic non-absorbable mesh, synthetic partially absorbable mesh, and biological mesh. The cost-utility analysis, which incorporated effectiveness, complications and cost data, found non-mesh repair to have the highest probability of being cost-effective. The conclusions were robust to model inputs including effectiveness, costs and utility values. CONCLUSIONS: Anterior colporrhaphy augmented with mesh appeared to be cost-ineffective in women requiring primary repair of anterior POP. There is a need for further research on long-term effectiveness and the safety of mesh products to establish their relative cost-effectiveness with a greater certainty. TWEETABLE ABSTRACT: New study finds mesh cost-ineffective in women with anterior pelvic organ prolapse.

Management of mesh complications following surgery for stress urinary incontinence or pelvic organ prolapse: a systematic review.

BACKGROUND: Mesh surgery for stress urinary incontinence or pelvic organ prolapse can result in complications such as mesh exposure, mesh extrusion, voiding dysfunction, dyspareunia, and pain. There is limited knowledge or guidance on the effective management for mesh-related complications. OBJECTIVE: To determine the best management of mesh complications; a systematic review was conducted as part of the national clinical guideline 'Urinary incontinence (update) and pelvic organ prolapse in women: management'. SEARCH STRATEGY: Search strategies were developed for each indication for referral. SELECTION CRITERIA: Relevant interventions included complete or partial mesh removal, mesh division, and non-surgical treatments such as vaginal estrogen. DATA COLLECTION AND ANALYSIS: Characteristics and outcome data were extracted, and as a result of the heterogeneous nature of the data a narrative synthesis was conducted. MAIN RESULTS: Twenty-four studies were included; five provided comparative data and four studies stated the indication for referral. Reported outcomes (including pain, dyspareunia, satisfaction, quality of life, incontinence, mesh exposure, and recurrence) and the reported incidences of these varied widely. CONCLUSIONS: The current evidence base is limited in quantity and quality and does not permit firm recommendations to be made on the most effective management for mesh-related complications. Robust data are needed so that mesh complications can be managed effectively in the future. TWEETABLE ABSTRACT: Systematic review demonstrates that the outcomes following mesh revision surgery are highly variable.

A second species of Araucariocladus Silveira amp; Mermudes, with notes on the variation in antennomere numbers in this genus (Coleoptera: Lampyridae).

Here, we describe Araucariocladus amfractus sp. nov., and compare it to the previously monotypic type-species, A. hiems. The new species can be distinguished from A. hiems by the following combination: colour pattern overall dark-brown; pedicel three times shorter than antennomere III and slightly wider than long; distance between antennal sockets as wide as 3/5 clypeal width; labial palpomere III with sides divergent towards apex, apical margin longer than dorsal and shorter than ventral margin; pronotum 1.5x wider than long, anterior margin somewhat sinuose, with a shallow angle anteriad, posterior margin almost straight. A. amfractus sp. nov. is, prima facie, endemic to the Itatiaia Massif, part of the Mantiqueira Mountain Range, Southeastern Brazil. We provide illustrations of the diagnostic features, and an occurrence map for the Araucariocladus species. Finally, we report a previously unrecognized intra-specific variation in the antennomere numbers of A. hiems, a feature also present in Araucariocladus amfractus sp. nov., and adjust the generic diagnosis to include species with 17 or 18 antennomeres. [Zoobank LSID: urn:lsid:zoobank.org:act:C335B064-FBD4-4256-983D-B17DF06BAA0D].

Impact of type 1 diabetes mellitus and celiac disease on nutrition and quality of life.

OBJECTIVE: Type 1 diabetes mellitus (T1DM) and celiac disease (CD) are autoimmune diseases and have similar genetic patterns. T1DM treatment is based on diet, physical activity and insulin therapy, whereas CD depends on dietary changes with restriction of wheat, rye and barley. The aim of the study was to evaluate the quality of life (QoL) of individuals with the association of T1DM and CD, to characterize their nutritional status and to compare it with those with only one disease and healthier controls. SUBJECTS/METHODS: Sixty patients controlled by sex, age and body mass index (BMI) were stratified by previous diagnosis in: T1DM and CD (DMCD group); T1DM (DM group); CD (CD group); or healthy participants (HC). The SF-36 questionnaire was applied to assess psychological well being and results were compared with glycemic control and presence of complications related to diabetes, adhesion to gluten-free diet (GFD). Nutritional status and body mass composition were determined by BMI, waist circumference, bioimpedance, general laboratory tests and whole-body densitometry. RESULTS: The time of diagnosis of T1DM was similar between DMCD and DM groups; however, the duration of CD was significantly higher in the CD group compared with DMCD. The SF-36 analysis revealed statistically significant differences between DM and HC groups in two domains: general health (P=0.042) and energy/vitality (P=0.012). QoL was also correlated with compliance to a GFD, and scores were similar in both groups: DMCD and CD. Forty percent of individuals in the CD group had visceral fat area above 100 cm2, as opposed to 20% in the other groups. CONCLUSIONS: Individuals of DMCD group had similar scores to DM, CD and HC on QoL, as well as on their nutritional status and bone metabolism. Thereby, we should conclude that the association of T1DM and CD did not deteriorate their health status.

Biological behavior of magnesium-substituted hydroxyapatite during bone repair

Abstract The aim of this study was to analyze the biological behavior and osteogenic potential of magnesium (Mg) substituted hydroxyapatite (HA) microspheres, implanted in a critical bone defect, considering that this ion is of great clinical interest, since it is closely associated with homeostasis and bone mineralization. For the purpose of this study, 30 rats were used to compose three experimental groups: GI - bone defect filled with HA microspheres; GII - bone defect filled with HA microspheres replaced with Mg; GIII - empty bone defect; evaluated at biological points of 15 and 45 days. The histological results, at 15 days, showed, in all the groups, a discrete chronic inflammatory infiltrate; biomaterials intact and surrounded by connective tissue; and bone neoformation restricted to the borders. At 45 days, in the GI and GII groups, an inflammatory response of discrete granulomatous chronic type was observed, and in the GIII there was a scarce presence of mononuclear inflammatory cells; in GI and GII, the microspheres were seen to be either intact or fragmented, surrounded by fibrous connective tissue rich in blood vessels; and discrete bone neoformation near the edges and surrounding some microspheres. In GIII, the mineralization was limited to the borders and the remaining area was filled by fibrous connective tissue. It was concluded that the biomaterials were biocompatible and osteoconductive, and the percentage of Mg used as replacement ion in the HA did not favor a greater bone neoformation in relation to the HA without the metal.

Resumo O objetivo deste estudo foi analisar o comportamento biológico de microesferas de hidroxiapatita (HA) substituída com magnésio (Mg) durante o reparo de defeito ósseo crítico, tendo em vista que este íon é de grande interesse clínico, pois está intimamente associado à homeostasia e à mineralização óssea. Para tanto, utilizou-se 30 ratos para compor três grupos experimentais: GI - defeito ósseo preenchido com microesferas de HA; GII - defeito ósseo preenchido com microesferas de HA substituída com Mg; GIII (controle) - defeito ósseo vazio; avaliados nos pontos biológicos de 15 e 45 dias. Os resultados histológicos evidenciaram, aos 15 dias, discreto infiltrado inflamatório crônico e neoformação óssea restrita às bordas, em todos os grupos. Nos grupos GI e GII, os biomateriais mantiveram-se íntegros e circundados por tecido conjuntivo frouxo. Aos 45 dias, notou-se resposta inflamatória do tipo crônica granulomatosa discreta nos grupos GI e GII, e no GIII presença escassa de células inflamatórias mononucleares. As microesferas implantadas no GI e GII mantiveram-se, em sua maioria, íntegras e envolvidas por tecido conjuntivo fibroso. Notou-se discreta neoformação óssea próxima às bordas e circunjacente a algumas microesferas. No GIII, a mineralização limitou-se às bordas e a área remanescente foi preenchida por tecido conjuntivo fibroso. Conclui-se que os biomateriais foram biocompatíveis, bioativos, osteocondutores e apresentaram biodegradação lenta, indicando seu grande potencial para em aplicações clínica como biomaterial de preenchimento.

Analysis of FKBP10, SERPINH1, and SERPINF1 genes in patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous disorder that causes fragility, deformity, and fractures in bones. A large number of genes that are associated with the disease have been identified in the last decade; this makes the genetic diagnosis of OI more difficult. To improve our knowledge of the genetic mutation profile in OI we used single-stranded conformation polymorphism screening and automated sequencing to investigate the SERPINH1, FKBP10, and SERPINF1 genes, which are related to recessive OI, in 23 unrelated Brazilian patients. Nine rare changes and four common polymorphisms were detected. Most changes were benign genetic variants. In general, changes in the SERPINH1 and SERPINF1 genes were synonymous polymorphisms or missense changes located in non-coding regions. A pathogenic change was found in the FKBP10 gene. The characterization of mutations related to OI in distinct populations can improve our knowledge of the genetic aspects of OI and help us develop molecular strategies for the diagnosis of the disease.

Canine cutaneous leishmaniasis by Leishmania (Viannia) braziliensis in an agricultural settlement, endemic area for leishmaniasis / Leishmaniose tegumentar canina por Leishmania (Viannia) braziliensis em um assentamento agrícola, área endêmica para leishmanioses

Cutaneous leishmaniasis has several species of Leishmania as agents, and a wide variety of wild and domestic animals as hosts and different species of phlebotomines as vectors. A case of cutaneous leishmaniasis in a dog coming from an agricultural settlement is described. This is the first report of parasitism in a dog by Le. (Viannia) braziliensis in Mato Grosso do Sul State. Attention is called to the importance of including this protozoonosis in the differential diagnosis of dermopathies in dogs as also the need to assess the importance of the domestic dog as a possible reservoir of Le. braziliensis.(AU)

As leishmanioses tegumentares são antropozoonoses metaxênicas de importância em saúde pública. Possuem como agentes etiológicos várias espécies de Leishmania, com ampla variedade de hospedeiros, como animais selvagens e domésticos, e diferentes espécies de flebotomíneos como vetores. Um caso de leishmaniose tegumentar em um cão procedente de um assentamento agrícola em Mato Grosso do Sul é descrito, sendo este o primeiro relato de parasitismo em cão doméstico nesse estado por Le. (Viannia) braziliensis. Alerta-se para a importância de se incluir essa protozoonose no diagnóstico diferencial de dermopatias em cães e para a necessidade de se avaliar o papel do cão doméstico como reservatório de Le. (Vi.) braziliensis.(AU)

Massive gastrointestinal bleeding after chemotherapy for gastric lymphoma.

INTRODUCTION: Gastrosplenic fistula (GSF) is a rare condition almost always associated with lymphoma, with gastric and splenic involvement. CASE REPORT: We report a 52 year old male with gastric lymphoma admitted to the emergency department with hematemesis. The first chemotherapy cycle had been completed four weeks before. Oesophagoduodenoscopy showed a pulsatile ulcerated lesion. Surgical hemostasis was performed. Four days after surgery, the patient initiated sudden and massive upper gastrointestinal bleeding with hemodynamic compromise. A gastrosplenic fistula was recognized during emergency laparotomy and an en bloc total gastrectomy and splenopancreatectomy resection was performed, with massive blood transfusion. Patient was discharged 13 days after the second surgery. DISCUSSION: Gastrosplenic fistula is a rare condition, previously described associated with gastric lymphoma at presentation or after treatment. A prompt recognition of the underlying pathology could avoid a second surgery. CONCLUSION: A systematic and interdisciplinary approach is the key for success in rare challenging emergencies. Infrequent etiologies must always be considered as they need specific therapeutic approaches that defy paradigms.

Mutational characterization of the P3H1/CRTAP/CypB complex in recessive osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone deformities and fractures. Most cases are caused by autosomal dominant mutations in the type I collagen genes COL1A1 and COL1A2; however, an increasing number of recessive mutations in other genes have been reported. The LEPRE1, CRTAP, and PPIB genes encode proteins that form the P3H1/CRTAP/CypB complex, which is responsible for posttranslational modifications of type I collagen. In general, mutations in these genes lead to severe and lethal phenotypes of recessive OI. Here, we describe sixteen genetic variations detected in LEPRE1, CRTAP, and PPIB from 25 Brazilian patients with OI. Samples were screened for mutations on single-strand conformation polymorphism gels and variants were determined by automated sequencing. Seven variants were detected in patients but were absent in control samples. LEPRE1 contained the highest number of variants, including the previously described West African allele (c.1080+1G>T) found in one patient with severe OI as well as a previously undescribed p.Trp675Leu change that is predicted to be disease causing. In CRTAP, one patient carried the c.558A>G homozygous mutation, predicted as disease causing through alteration of a splice site. Genetic variations detected in the PPIB gene are probably not pathogenic due to their localization or because of their synonymous effect. This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. In addition, the results strengthen the proposition that LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI.

Reference values for high-density lipoprotein particle size and volume by dynamic light scattering in a Brazilian population sample and their relationships with metabolic parameters.

BACKGROUND: Current data indicate that the size of high-density lipoprotein (HDL) may be considered an important marker for cardiovascular disease risk. We established reference values of mean HDL size and volume in an asymptomatic representative Brazilian population sample (n=590) and their associations with metabolic parameters by gender. METHODS: Size and volume were determined in HDL isolated from plasma by polyethyleneglycol precipitation of apoB-containing lipoproteins and measured using the dynamic light scattering (DLS) technique. RESULTS: Although the gender and age distributions agreed with other studies, the mean HDL size reference value was slightly lower than in some other populations. Both HDL size and volume were influenced by gender and varied according to age. HDL size was associated with age and HDL-C (total population); non- white ethnicity and CETP inversely (females); HDL-C and PLTP mass (males). On the other hand, HDL volume was determined only by HDL-C (total population and in both genders) and by PLTP mass (males). CONCLUSIONS: The reference values for mean HDL size and volume using the DLS technique were established in an asymptomatic and representative Brazilian population sample, as well as their related metabolic factors. HDL-C was a major determinant of HDL size and volume, which were differently modulated in females and in males.

Arterial tissue and plasma concentration of enzymatic-driven oxysterols are associated with severe peripheral atherosclerotic disease and systemic inflammatory activity.

INTRODUCTION: Cholesterol undergoes oxidation via both enzymatic stress- and free radical-mediated mechanisms, generating a wide range of oxysterols. In contrast to oxidative stress-driven metabolites, enzymatic stress-derived oxysterols are scarcely studied in their association with atherosclerotic disease in humans. METHODS: 24S-hydroxycholesterol (24S-HC), 25-hydroxycholesterol (25-HC), and 27-hydroxycholesterol (27-HC) were assessed in plasma and arteries with atherosclerotic plaques from 10 patients (54-84 years) with severe peripheral artery disease (PAD) as well as arteries free of atherosclerotic plaques from 13 individuals (45-78 years, controls). RESULTS: Plasma 25-HC was higher in PAD individuals than in controls (6.3[2] vs. 3.9[1.9] ng/mgCol; p = 0.004). 24S-HC and 27-HC levels were, respectively, five- and 20-fold higher in the arterial tissue of PAD individuals than in those of the controls (p = 0.016 and p = 0.001). Plasma C-reactive protein correlated with plasma 24-HC (r = 0.51; p = 0.010), 25-HC (r = 0.75; p < 0.001), 27-HC (r = 0.48; p = 0.015), and with tissue 24S-HC (r = 0.4; p = 0.041) and 27-HC (r = 0.46; p = 0.023). CONCLUSION: Arterial intima accumulation of 27-HC and 24S-HC is associated with advanced atherosclerotic disease and systemic inflammatory activity in individuals with severe PAD.

Preoperative somatostatin analogues versus direct transsphenoidal surgery for newly-diagnosed acromegaly patients: a systematic review and meta-analysis using the GRADE system.

UNLABELLED: Whether the preoperative use of somatostatin analogues (SA) improves surgical outcomes in acromegaly is still a matter of debate. OBJECTIVE: We conducted a systematic review of randomized, controlled trials that compared the short-term outcomes of preoperative use of SA (Pre-SA) with direct TSS (No-SA) for the treatment of newly diagnosed acromegaly. METHODS: Embase, Pubmed, Lilacs, and Central Cochrane were used as our data sources. The primary outcomes were no need for any adjuvant treatment 3 months after surgery, based on biochemical results (GH nadir after OGTT <1 µg/L and normal IGF-1 for age and gender), quality of life and mortality. The included trials were analyzed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: A total of 2.099 references were identified and two reviewers independently screened the titles and abstracts. From the 14 potentially eligible studies, four were included and ten were excluded due to lack of randomization or different outcomes. A pool of 261 patients was randomly assigned to Pre-SA or No-SA. Meta-analysis of IGF1 normalization showed a significant difference in favor of Pre-SA (RR 2.47; 95% CI 1.66, 3.77). Adding a GH nadir on OGTT ≤1 µg/L, we found a RR of 2.15 (95% CI 1.39, 3.33). Quality of evidence for no need of adjuvant postoperative treatment was moderate, but for improving quality of life was very low and for mortality was absent. CONCLUSION: Pre-SA increases the chance of biochemical control of acromegaly 3 months after TSS in patients harboring GH-secreting pituitary macroadenomas.

Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism.

Progesterone has been associated with the development of gestational diabetes (GD) due to the enhancement of insulin resistance. As ß-cell apoptosis participates in type 1 and type 2 diabetes pathophysiology, we proposed the hypothesis that progesterone might contribute to the development of GD through a mechanism that also involves ß-cell death. To address this question, RINm5F insulin-producing cells were incubated with progesterone (25-100 µM), in the presence or absence of α-tocopherol (40 µM). After 24 or 48 h, membrane integrity and DNA fragmentation were analyzed by flow cytometry. Caspase activity was used to identify the mode of cell death. The involvement of endoplasmic reticulum stress in the action of progesterone was investigated by western blotting. Oxidative stress was measured by 2',7'-dichlorofluorescein diacetate (DCFDA) oxidation. Isolated rat islets were used in similar experiments in order to confirm the effect of progesterone in primary ß-cells. Incubation of RINm5F cells with progesterone increased the number of cells with loss of membrane integrity and DNA fragmentation. Progesterone induced generation of reactive species. Pre-incubation with α-tocopherol attenuated progesterone-induced apoptosis. Western blot analyses revealed increased expression of CREB2 and CHOP in progesterone-treated cells. Progesterone caused apoptotic death of rat islet cells and enhanced generation of reactive species. Our results show that progesterone can be toxic to pancreatic ß-cells through an oxidative-stress-dependent mechanism that induces apoptosis. This effect may contribute to the development of GD during pregnancy, particularly under conditions that require administration of pharmacological doses of this hormone.