Improvement and validation of a female finite element model of the cervical spine.

Although the cervical spine supports and controls the kinematics of the head, it is vulnerable to injuries during mechanical loading. Severe injuries often result in damage to the spinal cord, leading to significant ramifications. The role of gender in determining the outcome of such injuries has been established as significant. In order to better understand the essential mechanics and develop treatments or preventative measures, various forms of research have been conducted. Computational modelling is one of the most useful and extensively utilised methods, as it provides information that would otherwise be difficult to obtain. As such, the primary goal of this research is to create a new finite element of the female cervical spine that will more accurately represent the group most affected by such injuries. This work is a continuation of a previous study where a model was created from the computer tomography scans of a 46-year-old female. A functioning spinal unit consisting of the C6-C7 segment was simulated as a validation procedure. The experimental data obtained from cadaveric specimens, that assessed the range of motion of different cervical segments in flexion-extension, axial rotation, and lateral bending, was used to validate the reduced model.

Interaction between poly(A)-binding protein PABPC4 and nuclear receptor corepressor NCoR1 modulates a metabolic stress response.

Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases.

From the investigation of RHD-CE hybrid genes to the recognition of RHCE variants and RHD zygosity. Expanding the analysis by QMPSF in Brazilian donors and in patients with sickle cell disease.

BACKGROUND: Hybrid genes are responsible for the formation of Rh variants and are common in patients with sickle cell disease (SCD). However, it is not usually possible to detect them by conventional molecular protocols. In the present study, hybrid genes were investigated using the Quantitative Multiplex Polymerase chain reaction of Short Fluorescent Fragments (QMPSF), a molecular protocol that quantifies the copy number of RHD and RHCE exons. In addition, we explored additional relevant information obtained with QMPSF, such as recognition of variant RHCE and RHD zygosity. MATERIALS AND METHODS: Three groups of subjects were selected for the study: patients with SCD, self-declared African descent donors (SDA), and D-negative donors. RHD and RHCE hybrids genes were investigated by the QMPSF method. Real-time multiplex polymerase chain reaction (PCR) assay was used to confirm the copy number of the RHD in two samples. Cloning was performed to investigate the allele. Relative RhD antigen density was investigated by flow cytometry, and RhCE phenotyping was performed with both tube and gel methods. RESULTS: In the 507 samples analysed, hybrid allele frequencies were found in 20.08% of patients with SCD, in 18.22% of individuals in the SDA group, and 3.67% of D-negative donors. The SCD and SDA groups had a higher frequency of hybrid alleles, most commonly involving exon 8, with which we found an association with c.733C>G, a common polymorphism observed in individuals of African descent. Of note, two patients with SCD were shown to carry three gene copies, as confirmed by quantitative PCR; no increase in D expression was observed in these patients. In addition, the QMPSF guided the investigation of 144 RHCE variants and RHD zygosity, and two novel alleles were identified. DISCUSSION: The QMPSF was shown to identify hybrid alleles involved in altered Rh phenotypes in Brazilian donors and patients with SCD. The association of the hybrid RHCE-D(8)-CE allele with c.733C>G suggests this hybrid allele may be used as a marker to detect the most frequent variants found in patients with SCD.

Differential gene co-expression network analyses reveal novel molecules associated with transcriptional dysregulation of key biological processes in osteoarthritis knee cartilage.

Objectives: To compare co-expression networks of normal and osteoarthritis knee cartilage to uncover molecules associated with the transcriptional misregulation compromising biological processes (BPs) critical for cartilage homeostasis. Design: Normal and osteoarthritis human knee cartilage RNA-seq GSE114007 dataset was obtained from the Gene Expression Omnibus database. Partial Correlation and Information Theory (PCIT) algorithm was used to build co-expression networks containing all nodes connecting to at least one differentially expressed gene (DEG) in normal and osteoarthritis networks. Hub and hub centrality genes were used to perform functional enrichment analysis. Enriched BPs known to be associated with both healthy and diseased cartilage were compared in depth. Results: Differential co-expression network analyses allowed the identification of DDX43 and USP42 as exclusively co-expressed with DEGs in normal and osteoarthritis networks, respectively. The top hub and hub centrality genes of these networks were HIST1H3A and SNHG12 (normal) and TAF9B and OTUD1 (osteoarthritis). Enrichment analysis revealed several shared BPs between the contrasting groups, which are well-known in osteoarthritis pathogenesis. Protein-protein interaction network analysis for these BPs showed a global down-regulation of transcription factors in osteoarthritis. Specific transcription factors were identified as pleiotropic mediators in articular cartilage maintenance since they take part in several BPs. In addition, chromatin organisation and modification proteins were found relevant for osteoarthritis development. Conclusion: Differential gene co-expression analysis allowed the identification of novel and high priority therapeutic candidate genes that may drive modifications in the transcriptional "status" of cartilage in osteoarthritis.

Targeting Hydroxybenzoic Acids to Mitochondria as a Strategy to Delay Skin Ageing: An In Vitro Approach.

Targeting antioxidants to mitochondria is considered a promising strategy to prevent cellular senescence and skin ageing. In this study, we investigate whether four hydroxybenzoic acid-based mitochondria-targeted antioxidants (MitoBENs, MB1-4) could be used as potential active ingredients to prevent senescence in skin cells. Firstly, we evaluated the chemical stability, cytotoxicity, genotoxicity and mitochondrial toxicity of all compounds. We followed this by testing the antioxidant protective capacity of the two less toxic compounds on human skin fibroblasts. We then assessed the effects of the best hit on senescence, inflammation and mitochondrial remodeling on a 3D skin cell model, while also testing its mutagenic potential. Cytotoxicity and mitochondrial toxicity rankings were produced: MB3 < MB4 ≃ MB1 < MB2 and MB3 < MB1 < MB4 < MB2, respectively. These results suggest that pyrogallol-based compounds (MB2 and MB4) have lower cytotoxicity. The pyrogallol derivative, MB2, containing a 6-carbon spacer, showed a more potent antioxidant protective activity against hydrogen peroxide cytotoxicity. In a 3D skin cell model, MB2 also decreased transcripts related to senescence. In sum, MB2's biological safety profile, good chemical stability and lack of mutagenicity, combined with its anti-senescence effect, converts MB2 into a good candidate for further development as an active ingredient for skin anti-ageing products.

Artificial intelligence and high-resolution anoscopy: automatic identification of anal squamous cell carcinoma precursors using a convolutional neural network.

BACKGROUND: High-resolution anoscopy (HRA) is the gold standard for detecting anal squamous cell cancer (ASCC) precursors. Although it is superior to other diagnostic methods, particularly cytology, the visual identification of areas suspected of having high-grade squamous intraepithelial lesions remains difficult. Convolutional neural networks (CNNs) have shown great potential for assessing endoscopic images. The aim of the present study was to develop a CNN-based system for automatic detection and differentiation of HSIL versus LSIL in HRA images. METHODS: A CNN was developed based on 78 HRA exams from a total of 71 patients who underwent HRA at a single high-volume center (GH Paris Saint-Joseph, Paris, France) between January 2021 and January 2022. A total of 5026 images were included, 1517 images containing HSIL and 3509 LSIL. A training dataset comprising 90% of the total pool of images was defined for the development of the network. The performance of the CNN was evaluated using an independent testing dataset comprising the remaining 10%. The sensitivity, specificity, accuracy, positive and negative predictive values, and area under the curve (AUC) were calculated. RESULTS: The algorithm was optimized for the automatic detection of HSIL and its differentiation from LSIL. Our model had an overall accuracy of 90.3%. The CNN had sensitivity, specificity, positive and negative predictive values of 91.4%, 89.7%, 80.9%, and 95.6%, respectively. The area under the curve was 0.97. CONCLUSIONS: The CNN architecture for application to HRA accurately detected precursors of squamous anal cancer. Further development and implementation of these tools in clinical practice may significantly modify the management of these patients.

EEF1A1 transcription cofactor gene polymorphism is associated with muscle gene expression and residual feed intake in Nelore cattle.

Cis-acting effects of noncoding variants on gene expression and regulatory molecules constitute a significant factor for phenotypic variation in complex traits. To provide new insights into the impacts of single-nucleotide polymorphisms (SNPs) on transcription factors (TFs) and transcription cofactors (TcoF) coding genes, we carried out a multi-omic analysis to identify cis-regulatory effects of SNPs on these genes' expression in muscle and describe their association with feed efficiency-related traits in Nelore cattle. As a result, we identified one SNP, the rs137256008C > T, predicted to impact the EEF1A1 gene expression (ß = 3.02; P-value = 3.51E-03) and the residual feed intake trait (ß = - 3.47; P-value = 0.02). This SNP was predicted to modify transcription factor sites and overlaps with several QTL for feed efficiency traits. In addition, co-expression network analyses showed that animals containing the T allele of the rs137256008 SNP may be triggering changes in the gene network. Therefore, our analyses reinforce and contribute to a better understanding of the biological mechanisms underlying gene expression control of feed efficiency traits in bovines. The cis-regulatory SNP can be used as biomarker for feed efficiency in Nelore cattle.

Assessment of the uterine dose in digital mammography and digital breast tomosynthesis.

INTRODUCTION: Digital Mammography (DM-2D) and more recently Digital Breast Tomosynthesis (DBT), are two of the most effective imaging modalities for breast cancer detection, often used in screening programmes. It may happen that exams using these two imaging modalities are inadvertently performed to pregnant women. The objective of this study is to assess the dose in the uterus due to DM-2D and DBT exams, according to two main irradiation scenarios: in the 1st scenario the exposure parameters were pre-selected directly by the imaging system, while in the 2nd scenario, the maximum exposure parameters were chosen. METHODS: The mammography equipment used was a Siemens Mammomat Inspiration. A physical anthropomorphic phantom, PMMA plates (simulating a breast thickness of 6 cm) and thermoluminescent dosimeters (TLDs) were used to measure entrance air kerma values on the phantom's breast and abdomen in order to successively estimate the mean glandular dose (MGD) and the dose in the uterus. For the two irradiation scenarios chosen, two-breast imaging modalities were selected: 1) DBT in Cranio-Caudal (CC) view (with 28 kV and 160 mAs as exposure parameters), 2) DBT and DM in Medio Lateral-Oblique (MLO) and CC views (with 34 kV and 250 mAs as exposure parameters). RESULTS: In the 1st scenario, the TLD measurements did not detect significant dose values in the abdomen whereas the MGD estimated using the D.R. Dance model was in close agreement with data available in the literature. In the 2nd scenario, there was no significant difference in MGD estimation between the different views, whereas the air kerma values in the abdomen (in DBT mode, CC and MLO) were 0.049 mGy and 0.004 mGy respectively. In CC DM-2D mode the abdomen air kerma value was 0.026 mGy, with no significant detected value in MLO view. CONCLUSIONS: For the dose in the uterus, the obtained values seem to indicate that DM-2D and DBT examinations inadvertently performed during pregnancy do not pose a significant radiological risk, even considering the case of overexposure in both breasts. IMPLICATIONS FOR PRACTICE: The accurate knowledge of the doses in DM-2D and DBT will contribute to raise the awareness among medical practitioners involved in breast imaging empowering them to provide accurate information about dose levels in the uterus, improving their radiation risk communication skills and consequently helping to reduce the anxiety of pregnant women undergoing this type of examinations.

Anaphylactic shock with pulmonary eosinophilic infiltration due to honeybee attack in a donkey: case report / [Choque anafilático com infiltração eosinófila pulmonar devido a ataque de abelhas em um burro: relato de caso]

A case of a donkey attacked by Africanized honeybee is reported here with clinical signs of agitation, dehydration, congestion of the ocular mucous membranes, tongue edema, tachycardia and inspiratory dyspnea, and progression to death. At necropsy, diffuse, severe subcutaneous edema at face and cervical regions and severe diffuse pulmonary hyperemia with abundant edema without parenchymal collapse were observed. Microscopically, marked, diffuse deep dermis and panniculus carnosus edema and marked diffuse alveolar edema, with moderate population of eosinophils predominantly around larger caliber vessels were noted. The final diagnosis of anaphylactic shock was supported by history, clinical signs, and anatomic pathology findings. This is the first report of a honeybee attack with pulmonary eosinophilic infiltration in a mammal.(AU)

Descreve-se um caso de ataque de abelha africanizada em um burro, com sinais clínicos de agitação, desidratação, mucosas oculares congestas, edema de língua, taquicardia e dispneia inspiratória, com progressão e morte. Na necropsia, foram verificados edema subcutâneo difuso grave nas regiões de face e cervical, hiperemia pulmonar difusa grave com edema abundante e sem colapso do parênquima. Microscopicamente, foram observados edema marcado difuso na derme profunda e panículo carnoso e edema alveolar difuso acentuado, com população moderada de eosinófilos predominantemente em torno de vasos de maior calibre. O diagnóstico de choque anafilático foi baseado no histórico, em sinais clínicos e em achados anatomopatológicos. Este é o primeiro relato de ataque de abelhas com infiltração eosinofílica pulmonar em um mamífero.(AU)

Cytotoxicity and Mitochondrial Effects of Phenolic and Quinone-Based Mitochondria-Targeted and Untargeted Antioxidants on Human Neuronal and Hepatic Cell Lines: A Comparative Analysis.

Mitochondriotropic antioxidants (MC3, MC6.2, MC4 and MC7.2) based on dietary antioxidants and analogs (caffeic, hydrocaffeic, trihydroxyphenylpropanoic and trihydroxycinnamic acids) were developed. In this study, we evaluate and compare the cytotoxicity profile of novel mitochondria-targeted molecules (generally known as MitoCINs) on human HepG2 and differentiated SH-SY5Y cells with the quinone-based mitochondria-targeted antioxidants MitoQ and SkQ1 and with two non-targeted antioxidants, resveratrol and coenzyme Q10 (CoQ10). We further evaluate their effects on mitochondrial membrane potential, cellular oxygen consumption and extracellular acidification rates. Overall, MitoCINs derivatives reduced cell viability at concentrations about six times higher than those observed with MitoQ and SkQ1. A toxicity ranking for both cell lines was produced: MC4 < MC7.2 < MC3 < MC6.2. These results suggest that C-6 carbon linker and the presence of a pyrogallol group result in lower cytotoxicity. MC3 and MC6.2 affected the mitochondrial function more significantly relative to MitoQ, SkQ1, resveratrol and CoQ10, while MC4 and MC7.2 displayed around 100-1000 times less cytotoxicity than SkQ1 and MitoQ. Based on the mitochondrial and cytotoxicity cellular data, MC4 and MC7.2 are proposed as leads that can be optimized to develop safe drug candidates with therapeutic application in mitochondrial oxidative stress-related diseases.

Artificial intelligence and colon capsule endoscopy: development of an automated diagnostic system of protruding lesions in colon capsule endoscopy.

BACKGROUND: Colon capsule endoscopy (CCE) is a minimally invasive alternative for patients unwilling to undergo conventional colonoscopy, or for whom the latter exam is contraindicated. This is particularly important in the setting of colorectal cancer screening. Nevertheless, these exams produce large numbers of images, and reading them is a monotonous and time-consuming task, with the risk of overlooking important lesions. The development of automated tools based on artificial intelligence (AI) technology may improve some of the drawbacks of this diagnostic instrument. METHODS: A database of CCE images was used for development of a Convolutional Neural Network (CNN) model. This database included anonymized images of patients with protruding lesions in the colon or patients with normal colonic mucosa or with other pathologic findings. A total of 3,387,259 frames from 24 CCE exams were retrospectively reviewed. For CNN development, 3640 images (860 protruding lesions and 2780 with normal mucosa or other findings) were ultimately extracted. Training and validation datasets were constructed for the development and testing of the CNN. RESULTS: The CNN detected protruding lesions with a sensitivity, specificity, positive and negative predictive values of 90.7, 92.6, 79.2 and 96.9%, respectively. The area under the receiver operating characteristic curve for detection of protruding lesions was 0.97. CONCLUSIONS: The deep learning algorithm we developed is capable of accurately detecting protruding lesions. The application of AI technology to CCE may increase its diagnostic accuracy and acceptance for screening of colorectal neoplasia.

Meningoencephalitis caused by Bovine alphaherpesvirus 5 in Pernambuco, Brazil / [Meningoencefalite causada pelo Bovine alphaherpesvirus 5 em Pernambuco, Brasil]

Objetivou-se descrever a ocorrência do Bovine alphaherpesvirus 5 (BoHV5) como causa de meningoencefalite não supurativa em bovinos do estado de Pernambuco, Brasil. Para tanto, 32 amostras de sistema nervoso embebidas em parafina foram obtidas de animais acometidos por doenças neurológicas atendidos na Clínica de Bovinos de Garanhuns da Universidade Federal Rural de Pernambuco (CBG-UFRPE), entre 2012 e 2016. As amostras foram analisadas quanto à presença do gene da glicoproteína C do BoHV5 por reação em cadeia da polimerase (PCR). Dois animais (6,25%) tiveram resultado positivo à PCR, e sua análise de sequenciamento indicou 100% de similaridade para o BoHV5. Os resultados histopatológicos desses dois animais revelaram lesões multifocais de meningoencefalite não supurativa associada à polioencefalomalácia, presença de corpúsculos de inclusão basofílicos, infiltração de células de Gitter e presença de manguitos perivasculares. A PCR se mostra uma importante ferramenta para diferenciação das infecções por BoHV5 de outras enfermidades neurológicas de bovinos, especialmente a raiva.(AU)

Metastatic melanoma in a Saanen goat: clinical, ultrasonographic and anatomopathological aspects - case report / [Melanoma metastático em cabra Saanen: aspectos clínicos, ultrassonográficos e Anatomopatológicos - relato de caso]

This report describes clinical, ultrasonographic and anatomopathological findings in a case of metastatic melanoma in an adult Saanen goat. Clinically, the goat had apathy, an intra-abdominal palpable firm structure, and exophytic keratinized areas on the skin of the udder. Ultrasound revealed non-encapsulated oval structures, with heterogeneous echogenicity and marked central and peripheral vascularization, and hypoechoic hepatic multifocal to coalescent areas. In the udder, there were non-encapsulated oval structures with heterogeneous echogenicity and hyperechoic center surrounded by hypoechogenic tissue. Grossly, there were black multifocal to coalescent areas in the liver, as well as black nodules in mammary and mesenteric lymph nodes, uterus, spleen, and myocardium. Microscopically, multifocal melanocytic neoplastic proliferation was observed in the dermis and junction of the udder epidermis. Most of the neoplastic cells had cytoplasmic granules of melanin. In the liver there were areas of neoplastic tissue compressing the adjacent parenchyma, with central foci of necrosis, mild desmoplasia, and multifocal infiltration of malignant cells into the adjacent tissues. Similar findings were observed in the mammary and mesenteric lymph nodes, uterus, spleen, and myocardium, which characterized metastatic melanoma. Ultrasonography played a key role for establishing the diagnosis of a metastatic melanoma and helped establish a proper clinical management protocol.(AU)

Este relato descreve os achados clínicos, ultrassonográficos e anatomopatológicos em um caso de melanoma metastático em uma cabra Saanen adulta. Clinicamente, a cabra apresentava apatia, estrutura firme palpável intra-abdominal e áreas exofíticas queratinizadas na pele do úbere. A ultrassonografia revelou estruturas ovais não encapsuladas, com ecogenicidade heterogênea e marcada vascularização central e periférica, além de áreas hepáticas multifocais a coalescentes hipoecoicas. No úbere, havia estruturas ovais não encapsuladas, com ecogenicidade heterogênea e centro hiperecogênico circundado por tecido hipoecogênico. Macroscopicamente, havia áreas pretas multifocais a coalescentes no fígado, bem como nódulos pretos nos linfonodos mamários e mesentéricos, no útero, no baço e no miocárdio; microscopicamente, proliferação neoplásica melanocítica multifocal foi observada na derme e na junção da epiderme do úbere. A maioria das células neoplásicas apresentava grânulos citoplasmáticos de melanina. No fígado, havia áreas de tecido neoplásico comprimindo o parênquima adjacente, com focos centrais de necrose, desmoplasia leve e infiltração multifocal de células malignas nos tecidos adjacentes. Achados semelhantes foram observados nos nódulos linfáticos mamários e mesentéricos, no útero, no baço e no miocárdio, que caracterizaram o melanoma metastático. A ultrassonografia desempenhou um papel fundamental para estipular o diagnóstico de um melanoma metastático e ajudou a estabelecer um protocolo de manejo clínico adequado.(AU)

[Evolution of antimicrobial resistance and mortality in Staphylococcus aureus endocarditis during 15 years in a university hospital]. / Evolución de la resistencia antimicrobiana y mortalidad en la endocarditis por Staphylococcus aureus durante 15 años en un hospital universitario.

OBJECTIVE: One of the most aggressive microorganisms in infective endocarditis (IE) is Staphylococcus aureus. We analyse the resistance of S. aureus to antibiotics and its impact on the clinical course of IE in a recent 15-year period. METHODS: Retrospective study of patients with IE in a university hospital from 2005 to 2019. Bivariate and multivariate analysis of severity at admission, comorbidities, minimum inhibitory concentrations (MIC) and mortality. RESULTS: Of the 293 IE cases, 66 (22.5%) were due to S. aureus, and 21 (7.2%) were methicillin-resistant S. aureus (MRSA). The prevalence of strains with a MIC to vancomycin ≥ 1mg/L increased from 4.8% to 63.6% (p <0.001) and the cases of MRSA from 38 to 27.3% (p = 0.045). Older age (p= 0.02), comorbidity (p <0.01) and nosohusial origin (p = 0.01), were factors associated with MRSA. But the antimicrobial resistance and severity on admission were not associated with exitus; predictive factors were the right-sided IE (OR = 0.08; 95% CI: 0.01-0.51), comorbidities (OR per Charlson index point = 1.30; 95% CI: 1.01-1.69) and creatinine on admission (OR per mg / dL = 1.56; 95% CI = 1.01- 2.35; p = 0.04). CONCLUSIONS: We have experienced an increase in IE cases with MIC to vancomycin ≥ 1mg/L, without significant variation in infections due to MRSA. Antimicrobial resistance was not associated with mortality, but comorbidity and left involvement were predictive factors.

Prognostic factors for survival after allogeneic transplantation in acute lymphoblastic leukemia.

Allogeneic stem cell transplantation (allo-SCT) offers a curative option in adult patients with acute lymphoblastic leukemia (ALL). Prognostic factors for survival after allo-SCT have not been sufficiently defined: pheno-/genotype, patients´ age, conditioning regimens and remission at allo-SCT are under discussion. We analyzed the outcome of 180 consecutive adult ALL-patients undergoing allo-SCT at our center between 1995 and 2018 to identify specific prognostic factors. In our cohort 19% were older than 55 years, 28% had Philadelphia-positive B-ALL, 24% T-ALL. 54% were transplanted in first complete remission (CR1), 13% in CR2 after salvage therapy, 31% reached no remission (8% within first-line, 23% within salvage therapy). In 66% conditioning contained total body irradiation (TBI). With a median follow-up of 10 years, we observed an overall survival of 33% at 10 years, and a progression free survival of 31%. The cumulative incidence of relapse was 41% at 10 years, the cumulative incidence of non-relapse mortality 28%. Acute graft-versus-host disease (GvHD) II°-IV° occurred in 31%, moderate/severe chronic GvHD in 27%. Survival was better in patients reaching CR before allo-SCT and in those receiving TBI. No difference between patients younger/older than 55 years and between different phenotypes was observed. Survival after allo-SCT improved considerably over the last decades.

Changes in cardiac biomarkers in goats naturally affected by pregnancy toxemia.

Pregnancy toxemia (PT) is considered one of the most common metabolic diseases with high impact on the production of small ruminants. The objective of this study was investigate possible myocardial damage in goats affected with PT by the determination of serum myocardial biomarkers CK-MB and cTnI. A total of 44 goats affected with PT, and 10 apparently healthy goats (control group or CG) were used in the study. In goats with PT, the serum concentrations of cTnI (0.43 ng/mL) were significantly higher than that in CG goats (0.06 ng/mL). Although CK-MB showed no significant difference, it was approximately three times higher in animals with PT. The serum concentrations of insulin were significantly lower in PT goats (5.03 ppmol/L) compared to CG goats (10.66 pmol/L). The serum concentrations of cortisol in PT goats (155.41 nmol/L) were significantly higher than that in CG goats (36.58 nmol/L). Results of this study indicate that a clinically significant myocardial damage might occur in goats affected with PT leading to significant elevations in values of cTnI and CK-MB. Therefore, these parameters could be used as a potential prognostic indicator in goats affected with this important disease.

Low Golimumab Trough Levels at Week 6 Are Associated With Poor Clinical, Endoscopic and Histological Outcomes in Ulcerative Colitis Patients: Pharmacokinetic and Pharmacodynamic Sub-analysis of the Evolution Study.

BACKGROUND AND AIMS: Golimumab has an established exposure-response relationship in patients with ulcerative colitis [UC]. However, the association of serum golimumab trough levels [TL] with objective markers of disease activity, such as endoscopic and histological activity scores and concentrations of biomarkers, remains less understood. This report describes the relationship of serum golimumab TL at the end of the induction period [Week 6] with clinical, endoscopic, histological, and biomarker parameters. METHODS: This was an open-label, uncontrolled, prospective and interventional study. Moderate to severely active UC patients naïve to biologic therapy were treated with golimumab. Serum golimumab TL and faecal calprotectin levels were measured at baseline [Week 0 of induction] and Week 6. RESULTS: A total of 34 patients completed the induction phase [Week 6] and were included in this analysis. Overall, 47.1% and 14.7% of patients achieved clinical response and remission with significantly higher serum golimumab TL in patients with early response or remission [3.7 µg/mL vs 1.3 µg/mL, p = 0.0013; and 3.1 µg/mL vs 1.7 µg/mL, p = 0.0164, respectively]. In addition, golimumab TL were significantly higher in patients achieving histological remission [4.2 µg/mL vs 1.7 µg/mL, p = 0.0049]. Week 6 golimumab TL were inversely correlated with the total Mayo score [rs = -0.546; p = 0.0008], the Mayo endoscopic subscore [rs = -0.381; p = 0.0262], the Geboes histological activity score [rs = -0.464; p = 0.0057], and faecal calprotectin levels [rs = -0.497; p = 0.0044]. CONCLUSIONS: A higher early exposure to golimumab is associated with a better objective response in active UC patients and appears to drive the outcome at Week 6.

SMIM1 polymorphisms in a donor population from southeast Brazil and their correlation with VEL expression.

BACKGROUND: Vel is a high frequency blood group antigen and its alloantibody is involved in haemolytic transfusion reactions. After elucidation of the molecular basis of the Vel-negative phenotype defined by a 17-base pair deletion in SMIM1, genotyping has been the technique of choice to identify the Vel-negative phenotype, and molecular investigations have contributed to explain Vel expression variability. The present study was aimed at screening for Vel negative blood donors and characterising the genetic changes found in Brazilian donors with altered Vel expression. MATERIALS AND METHODS: Molecular screening for the SMIM1*64_80del allele was performed in 1,595 blood donor samples using a SNaPshot protocol previously standardised in our laboratory. Four hundred donor samples were also submitted to serological screening using a polyclonal anti-Vel from our inventory. Samples with variability in antigen strength were selected for SMIM1 sequencing. RESULTS: No homozygous SMIM1*64_80del allele was found and the SMIM1*64_80del allele frequency was 1.01%. Different patterns of reactivity were observed in serological testing varying from negative to 3+. Through sequencing analysis we highlighted two polymorphisms: rs1175550 and rs6673829. The minor G allele of rs1175550 was found in 16/20 samples reacting 3+, while the major A allele was found in 21/23 samples reacting 2+. Regarding rs6673829, the minor A allele was present in 14/23 and 3/20 samples reacting 2+ and 3+ respectively. DISCUSSION: We included molecular VEL screening in a previously standardised SNaPshot protocol, which besides enabling detection of Vel-negative donors, also searches for eight other rare blood types. Additionally, the present study demonstrated that although the SMIM1*64_80del allele is responsible for some variation of Vel phenotype in this donor population, Vel expression is also controlled by molecular changes in SMIM1 intron 2.

Chemotherapy management for unfit patients with metastatic castration-resistant prostate cancer.

Administration of chemotherapy in prostate cancer depends on patient fitness. In unfit patients, physiological impairment determines the optimum treatment. Although no consensus on assessing patient fitness currently exists, this article proposes an algorithm combining the available information for administering chemotherapy, and in particular docetaxel, in unfit patients. It was constructed by reviewing factors that can influence treatment, such as performance status, taxane-related comorbidities and nutritional status. Geriatric scales for prostate cancer patients and alternative treatment regimens for this population are also reviewed. In summary, patients require overall assessment to optimise treatment. Use of docetaxel should be restricted in unfit patients, and other options must be evaluated, because of high toxicity and low efficacy.