Personality correlates of social attitudes and social distance.

BACKGROUND: Previous studies have shown that personality traits (i.e., openness to experience, conscientiousness, and agreeableness) relate to prejudicial attitudes. However, one of the aspects of prejudice is social distance; its association with personality traits was overlooked by previous studies. Therefore, this study examines the connection between the Big Five personality traits and social distance toward certain social groups. PARTICIPANTS AND PROCEDURE: Participants from the general population were recruited through leaflets, the institutional webpage, Facebook, and through the project recruitment website and assessed via paper-and-pencil or online form. A total of 214 participants were included (of whom 68.2% were women and the mean age was 32.65, SD = 11.27, range 18-72) who completed the Bogardus Social Distance Scale and the 44-item Big Five Inventory questionnaire. RESULTS: The results showed a relationship between social distance, agreeableness, and openness to experience. Agreeableness seems to lower the social distance toward all studied groups. In comparison, openness to experience seems to lower the social distance towards groups that evoke more polarized attitudes in the majority (e.g., migrants). Furthermore, the influence of demographic characteristics (i.e., age, education level, and gender) is also significant. CONCLUSIONS: This study shows that personality is significantly related to social distancing and expression of prejudicial attitudes. In particular, agreeableness and openness to experience have different effects on social distance and attitudes towards different groups. Further implications are discussed.

Adaptive Evolution in TRIF Leads to Discordance between Human and Mouse Innate Immune Signaling.

The TIR domain-containing adapter inducing IFN-ß (TRIF) protein is an innate immune system protein that mediates the MyD88-independent toll-like receptor response pathway in mice and humans. Previously, we identified positive selection at seven distinct residues in mouse TRIF (mTRIF), as compared with human and other mammalian orthologs, thus predicting protein functional shift in mTRIF. We reconstructed TRIF for the most recent common ancestor of mouse and human, and mutated this at the seven sites to their extant mouse/human states. We overexpressed these TRIF mutants in immortalized human and mouse cell lines and monitored TRIF-dependent cytokine production and gene expression induction. We show that optimal TRIF function in human and mouse is dependent on the identity of the positively selected sites. These data provide us with molecular data relating observed differences in response between mouse and human MyD88-independent signaling in the innate immune system with protein functional change.

N-acylethanolamine regulation of TLR3-induced hyperthermia and neuroinflammatory gene expression: A role for PPARα.

Increasing evidence suggests that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is associated with increased risk of developing neurological or psychiatric conditions such as depression, anxiety or dementia. While the precise mechanism underlying this association is unknown, aberrant activation of toll-like receptor (TLR)3, a viral recognizing pattern recognition receptor, may play a key role. Synthetic cannabinoids and enhancing cannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH) has been demonstrated to modulate TLR3-induced neuroimmune responses and associated sickness behaviour. However, the role of individual FAAH substrates, and the receptor mechanisms mediating these effects, are unknown. The present study examined the effects of intracerebral or systemic administration of the FAAH substrates N-oleoylethanolamide (OEA), N-palmitoylethanolamide (PEA) or the anandamide (AEA) analogue meth-AEA on hyperthermia and hypothalamic inflammatory gene expression following administration of the TLR3 agonist, and viral mimetic, poly I:C. The data demonstrate that meth-AEA does not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. In comparison, OEA and PEA attenuated the TLR3-induced hyperthermia, although only OEA attenuated the expression of hyperthermia-related genes (IL-1ß, iNOS, COX2 and m-PGES) in the hypothalamus. OEA, but not PEA, attenuated TLR3-induced increases in the expression of all IRF- and NFκB-related genes examined in the hypothalamus, but not in the spleen. Antagonism of PPARα prevented the OEA-induced attenuation of IRF- and NFκB-related genes in the hypothalamus following TLR3 activation but did not significantly alter temperature. PPARα agonism did not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. These data indicate that OEA may be the primary FAAH substrate that modulates TLR3-induced neuroinflammation and hyperthermia, effects partially mediated by PPARα.

Characterization of the substrate binding site of an iron detoxifying membrane transporter from Plasmodium falciparum.

BACKGROUND: Plasmodium species are entirely dependent upon their host as a source of essential iron. Although it is an indispensable micronutrient, oxidation of excess ferrous iron to the ferric state in the cell cytoplasm can produce reactive oxygen species that are cytotoxic. The malaria parasite must therefore carefully regulate the processes involved in iron acquisition and storage. A 273 amino acid membrane transporter that is a member of the vacuolar iron transporter (VIT) family and an orthologue of the yeast Ca2+-sensitive cross complementer (CCC1) protein plays a major role in cytosolic iron detoxification of Plasmodium species and functions in transport of ferrous iron ions into the endoplasmic reticulum for storage. While this transporter, termed PfVIT, is not critical for viability of the parasite evidence from studies of mice infected with VIT-deficient Plasmodium suggests it could still provide an efficient target for chemoprophylactic treatment of malaria. Individual amino acid residues that constitute the Fe2+ binding site of the protein were identified to better understand the structural basis of substrate recognition and binding by PfVIT. METHODS: Using the crystal structure of a recently published plant VIT as a template, a high-quality homology model of PfVIT was constructed to identify the amino acid composition of the transporter's substrate binding site and to act as a guide for subsequent mutagenesis studies. To test the effect of mutation of the substrate binding-site residues on PfVIT function a yeast complementation assay assessed the ability of overexpressed, recombinant wild type and mutant PfVIT to rescue an iron-sensitive deletion strain (ccc1∆) of Saccharomyces cerevisiae yeast from the toxic effects of a high concentration of extracellular iron. RESULTS: The combined in silico and mutagenesis approach identified a methionine residue located within the cytoplasmic metal binding domain of the transporter as essential for PfVIT function and provided insight into the structural basis for the Fe2+-selectivity of the protein. CONCLUSION: The structural model of the metal binding site of PfVIT opens the door for rational design of therapeutics to interfere with iron homeostasis within the malaria parasite.

Mu-opioid receptor agonism differentially alters social behaviour and immediate early gene expression in male adolescent rats prenatally exposed to valproic acid versus controls.

Mu-opioid receptors (MOPs) mediate and modulate social reward and social interaction. However, few studies have examined the functionality of this system in rodent models of social impairment. Deficits in social motivation and cognition are observed in rodents following pre-natal exposure to the anti-epileptic valproic acid (VPA), however it is not known whether MOP functionality is altered in these animals. The present study examined the effects of acute administration of the prototypical MOP agonist morphine (1 mg/kg) on social behavioural responding in the 3-chamber test and immediate early gene expression in adolescent rats (postnatal day 28-43) prenatally exposed to VPA vs saline-exposed controls. Pharmacokinetic analysis of morphine concentration, MOP binding and expression were also examined. The data revealed that sociability and social novelty preference in the 3-chamber test were reduced in rats prenatally exposed to VPA compared to saline-exposed control counterparts. Morphine reduced both sociability and social novelty preference behaviour in saline-, but not VPA-, exposed rats. Analysis of immediate early gene expression revealed that morphine reduced the expression of cfos in the prefrontal cortex of both saline- and VPA-exposed rats and reduced expression of cfos and junb in the hippocampus of VPA-exposed rats only. Pharmacokinetic analysis revealed similar concentrations of morphine in the plasma and brain of both saline- and VPA-exposed rats and similar thalamic MOP occupancy levels. Gene and protein expression of MOP in prefrontal cortex and hippocampus did not differ between saline and VPA-exposed rats. These data indicate differential effects of morphine on social responding and immediate early gene expression in the hippocampus of VPA-exposed rats compared with saline-exposed controls. This study provides support for altered MOP functionality in rats prenatally exposed to VPA, which may underlie the social deficits observed in the model.

Abiraterone induces SLCO1B3 expression in prostate cancer via microRNA-579-3p.

Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the treatment of castration resistant prostate cancer, remains a priority. The organic anion polypeptide 1B3 (OATP1B3, encoded by SLCO1B3) transporter has been shown to transport androgens into prostate cancer cells. In this study we observed and investigated the mechanism of induction of SLCO1B3 by abiraterone. Prostate cancer cells (22Rv1, LNCaP, and VCAP) were treated with anti-androgens and assessed for SLCO1B3 expression by qPCR analysis. Abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3'-untranslated region (3'UTR) of the SLCO1B3. Using dual luciferase reporter assays, we verified that hsa-miR-579-3p indeed binds to the SLCO1B3 3'UTR and significantly inhibited SLCO1B3 reporter activity. Treatment with abiraterone significantly downregulated hsa-miR-579-3p, indicating its potential role in upregulating SLCO1B3 expression. In this study, we demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression, a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics.

Comparison of three different screw trajectories in osteoporotic vertebrae: a biomechanical investigation.

BACKGROUND: Pedicle screw insertion in osteoporotic patients is challenging. Achieving more screw-cortical bone purchase and invasiveness minimization, the cortical bone trajectory and the midline cortical techniques represent alternatives to traditional pedicle screws. This study compares the fatigue behavior and fixation strength of the cement-augmented traditional trajectory (TT), the cortical bone trajectory (CBT), and the midline cortical (MC). METHODS: Ten human cadaveric spine specimens (L1 - L5) were examined. The average age was 86.3 ± 7.2 years. CT scans were provided for preoperative planning. CBT and MC were implanted by using the patient-specific 3D-printed placement guide (MySpine®, Medacta International), TT were implanted freehand. All ten cadaveric specimens were randomized to group A (CBT vs. MC) or group B (MC vs. TT). Each screw was loaded for 10,000 cycles. The failure criterion was doubling of the initial screw displacement resulting from the compressive force (60 N) at the first cycle, the stop criterion was a doubling of the initial screw displacement. After dynamic testing, screws were pulled out axially at 5 mm/min to determine their remaining fixation strength. RESULTS: The mean pull-out forces did not differ significantly. Concerning the fatigue performance, only one out of ten MC of group A failed prematurely due to loosening after 1500 cycles (L3). Five CBT already loosened during the first 500 cycles. The mean displacement was always lower in the MC. In group B, all TT showed no signs of failure or loosening. Three MC failed already after 26 cycles, 1510 cycles or 2144 cycles. The TT showed always a lower mean displacement. In the subsequent pull-out tests, the remaining mean fixation strength of the MC (449.6 ± 298.9 N) was slightly higher compared to the mean pull-out force of the CBT (401.2 ± 261.4 N). However, MC (714.5 ± 488.0 N) were inferior to TT (990.2 ± 451.9 N). CONCLUSION: The current study demonstrated that cement-augmented TT have the best fatigue and pull-out characteristics in osteoporotic lumbar vertebrae, followed by the MC and CBT. MC represent a promising alternative in osteoporotic bone if cement augmentation should be avoided. Using the patient-specific placement guide contributes to the improvement of screws' biomechanical properties.

Upgrade rates and outcomes of screen-detected atypical intraductal epithelial proliferation (AIDEP) diagnosed on core needle biopsy.

INTRODUCTION: Atypical intraductal epithelial proliferation (AIDEP) is a breast lesion categorised as "indeterminate" if identified on core needle biopsy (CNB). The rate at which these lesions are upgraded following diagnostic excision varies in the literature. Women diagnosed with AIDEP are thought to be at increased risk of breast cancer. Our aim was to identify the rate of upgrade to invasive or in situ carcinoma in a group of patients diagnosed with AIDEP on screening mammography and to quantify their risk of subsequent breast cancer. METHODS: We conducted a retrospective review of a prospectively maintained database containing all patients diagnosed with AIDEP on CNB between 2005 and 2012 in an Irish breast screening centre. Basic demographic data was collected along with details of the original CNB result, rate of upgrade to carcinoma and details of any subsequent cancer diagnoses. RESULTS: In total 113 patients were diagnosed with AIDEP on CNB during the study period. The upgrade rate on diagnostic excision was 28.3% (n = 32). 6.2% (n = 7) were upgraded to invasive cancer and 22.1% (n = 25) to DCIS. 81 patients were not upgraded on diagnostic excision and were offered 5 years of annual mammographic surveillance. 9.88% (8/81) of these patients went on to receive a subsequent diagnosis of malignancy. The mean time to diagnosis of these subsequent cancers was 65.41 months (range 20.18-145.21). CONCLUSION: Our data showing an upgrade rate of 28% to carcinoma reflects recently published data and we believe it supports the continued practice of excising AIDEP to exclude co-existing carcinoma.

Kappa Opioid Receptor-mediated Modulation of Social Responding in Adolescent Rats and in Rats Prenatally Exposed to Valproic Acid.

The kappa opioid receptor (KOP) system modulates social play responding, however a paucity of studies have examined effects on social motivation and cognition in the absence of play. Prenatal exposure to the anti-epileptic and mood stabiliser valproic acid (VPA) is associated with impaired social responding and altered gene expression of KOP (oprk1) and dynorphin (pdyn) in several brain regions. The present study examined if pharmacological modulation of KOP altered social motivation and cognition, immediate early gene (IEG) and oprk1-pdyn expression in adolescent male rats and rats prenatally exposed to VPA. In control rats, the KOP antagonist DIPPA enhanced sociability, while both DIPPA and the KOP agonist U50488 decreased social novelty preference. In rats exposed prenatally to VPA, neither U50488 nor DIPPA altered sociability or social novelty preference. Analysis of IEG expression revealed that DIPPA reduced expression of egr-1 expression in the prefrontal cortex of control rats and U50488 increased junb expression in the PFC of both control and VPA-exposed rats. VPA-exposed rats exhibited increased expression of oprk1 and pdyn in the prefrontal cortex and amygdala compared with control rats. DIPPA and U50488 increased oprk1 expression in the amygdala of control rats and decreased oprk1 expression in the prefrontal cortex of VPA-exposed rats. Taken together, these data demonstrate that pharmacological modulation of the KOP system alters social motivation and cognition in control rats, an effect not observed in rats prenatally exposed to VPA. These data provide support that prenatal exposure to VPA is associated with alterations in the expression and functionality of KOP system.

Prenatal exposure to valproic acid reduces social responses and alters mRNA levels of opioid receptor and pre-pro-peptide in discrete brain regions of adolescent and adult male rats.

Altered social behaviours are a hallmark of several psychiatric and developmental disorders. Clinical and preclinical data have demonstrated that prenatal exposure to valproic acid (VPA), an anti-epileptic and mood stabiliser, is associated with impaired social responses, and thus provides a useful model for the evaluation of neurobiological mechanisms underlying altered social behaviours. The opioid system is widely recognised to regulate and modulate social behaviours, however few studies have examined if the endogenous opioid system is altered in animal models of social impairment. The present study examined social behavioural responses of adolescent and adult male rats prenatally exposed to VPA, and the expression of mRNA encoding opioid receptors and pre-pro-peptides in discrete brain regions. Adolescent and adult rats prenatally exposed to VPA spent less time engaging in social behaviours in the direct social interaction test and exhibited reduced sociability and social novelty preference in the 3-chamber sociability test, compared to saline-treated counterparts. The VPA-exposed adolescent rats exhibited significantly reduced kappa opioid receptor (oprk1) and pre-pro-dynorphin (pdyn) mRNA expression in the cerebral cortex, and reduced oprk1 and nociceptin/orphanin FQ (oprl1) mRNA expression in the hypothalamus. Adult rats prenatally exposed to VPA exhibited decreased mRNA expression of oprk1 and pdyn in hypothalamus, reduced pro-opiomelanocortin(pomc) in the striatum and an increase in delta opioid receptor (oprd1) mRNA in the amygdaloid cortex, when compared to saline-treated counterparts. Mu opioid receptor (oprm1) mRNA expression did not differ between saline and VPA-exposed rats in any region examined. The data demonstrate that impaired social behaviours in adolescent and adult rats prenatally exposed to VPA is accompanied by altered mRNA expression of opioid receptors and pre-pro-peptides in a region specific manner. In particular, both adolescent and adult VPA-exposed rats exhibit reduced oprk1-pdyn mRNA expression in several brain regions, which are associated with deficits in social behavioural responding in the model.

Benign breast papilloma: Is surgical excision necessary?

In many centers internationally, current standard of care is to excise all papillomas of the breast, despite recently reported low rates of upgrade to malignancy on final excision. The objective of this study was to determine the upgrade rate to malignancy in patients with papilloma without atypia. A retrospective review of a prospectively maintained database of all cases of benign intraductal papilloma in a tertiary referral symptomatic breast unit between July 2008 and July 2018 was performed. Patients with evidence of malignancy or atypia on core biopsy and those with a history of breast cancer or genetic mutations predisposing to breast cancer were excluded. One hundred and seventy-three cases of benign papilloma diagnosed on core biopsy were identified. Following exclusions, the final cohort comprised of 138 patients. Mean age at presentation was 51. Mean follow-up time was 9.6 months. The most common symptom was a lump (40%). Of the 124 patients who underwent excision, three had ductal carcinoma in situ and there were no cases of invasive disease, giving an upgrade rate to malignancy of 2.4%. Upgrade to other high-risk lesions (atypical lobular and ductal hyperplasia and lobular carcinoma in situ) was demonstrated in 15 cases (12.1%). Benign papilloma was confirmed in 100 cases (81.5%), and 6 (4.8%) had no residual papilloma found on final excision. Twelve patients (8.7%) were managed conservatively. Of those, one later went on to develop malignancy. Patients with a diagnosis of benign papilloma without atypia on core biopsy have a low risk of upgrade to malignancy on final pathology, suggesting that observation may be a safe alternative to surgical excision. Further research is warranted to determine which patients can be safely managed conservatively.

Gene Fusions Derived by Transcriptional Readthrough are Driven by Segmental Duplication in Human.

Gene fusion occurs when two or more individual genes with independent open reading frames becoming juxtaposed under the same open reading frame creating a new fused gene. A small number of gene fusions described in detail have been associated with novel functions, for example, the hominid-specific PIPSL gene, TNFSF12, and the TWE-PRIL gene family. We use Sequence Similarity Networks and species level comparisons of great ape genomes to identify 45 new genes that have emerged by transcriptional readthrough, that is, transcription-derived gene fusion. For 35 of these putative gene fusions, we have been able to assess available RNAseq data to determine whether there are reads that map to each breakpoint. A total of 29 of the putative gene fusions had annotated transcripts (9/29 of which are human-specific). We carried out RT-qPCR in a range of human tissues (placenta, lung, liver, brain, and testes) and found that 23 of the putative gene fusion events were expressed in at least one tissue. Examining the available ribosome foot-printing data, we find evidence for translation of three of the fused genes in human. Finally, we find enrichment for transcription-derived gene fusions in regions of known segmental duplication in human. Together, our results implicate chromosomal structural variation brought about by segmental duplication with the emergence of novel transcripts and translated protein products.

Gut microbiota alterations associated with reduced bone mineral density in older adults.

OBJECTIVE: To investigate compositional differences in the gut microbiota associated with bone homeostasis and fractures in a cohort of older adults. METHODS: Faecal microbiota profiles were determined from 181 individuals with osteopenia (n = 61) or osteoporosis (n = 60), and an age- and gender-matched group with normal BMD (n = 60). Analysis of the 16S (V3-V4 region) amplicon dataset classified to the genus level was used to identify significantly differentially abundant taxa. Adjustments were made for potential confounding variables identified from the literature using several statistical models. RESULTS: We identified six genera that were significantly altered in abundance in the osteoporosis or osteopenic groups compared with age- and gender-matched controls. A detailed study of microbiota associations with meta-data variables that included BMI, health status, diet and medication revealed that these meta-data explained 15-17% of the variance within the microbiota dataset. BMD measurements were significantly associated with alterations in the microbiota. After controlling for known biological confounders, five of the six taxa remained significant. Overall microbiota alpha diversity did not correlate to BMD in this study. CONCLUSION: Reduced BMD in osteopenia and osteoporosis is associated with an altered microbiota. These alterations may be useful as biomarkers or therapeutic targets in individuals at high risk of reductions in BMD. These observations will lead to a better understanding of the relationship between the microbiota and bone homeostasis.

Severe Hepatotoxicity of Mithramycin Therapy Caused by Altered Expression of Hepatocellular Bile Transporters.

Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; P < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter α/ß) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.

Disección espontánea de arterias coronarias en el puerperio. Presentación de caso / Spontaneous dissection of coronary arteries in the puerperium. Case report

RESUMEN La disección espontánea de una arteria coronaria durante el embarazo es una causa poco común de infarto agudo de miocardio, con un alto riesgo de muerte materna. El diagnóstico se realiza mediante angiografía, aunque muchos casos son diagnosticados durante la autopsia. Se presenta el caso de una mujer blanca de 38 años de edad, fumadora, multípara, que al quinto día del puerperio presentó dolor centrotorácico, opresivo e intenso, y en el electrocardiograma se evidenció un infarto agudo de miocardio anterior extenso. La coronariografía demostró disección de la arteria coronaria izquierda incluido el tronco, la descendente anterior y la circunfleja. Se realizó angioplastia primaria y se produjo trombosis hiperaguda del stent implantado. La paciente falleció al quinto día en cuadro de shock cardiogénico refractario. No hay recomendaciones de tratamiento estándar, se considera que la angioplastia primaria es el tratamiento de elección. Es esencial la integración multidisciplinaria de cardiólogo, obstetra, cardiocirujano y anestesiólogo para decidir el mejor tratamiento.

ABSTRACT The spontaneous dissection of a coronary artery during pregnancy is a rare cause of acute myocardial infarction, with a high risk of maternal death. It can be diagnosed through coronary angiography, although many cases are diagnosed during autopsy. There is presented the case of a 38-year-old white woman, smoker, multiparous, that at the fifth day postpartum presented midthoracic, oppressive and intense pain, and the electrocardiogram evidenced an extensive acute anterior myocardial infarction. The coronary angiography showed dissection of the left coronary artery including the left main, the left anterior descending and the circumflex artery. A primary angioplasty was performed and there was a hyperacute thrombosis of the implanted stent. The patient died on the fifth day in refractory cardiogenic shock. There are no standard treatment recommendations, the primary angioplasty is considered the treatment of choice. The multidisciplinary integration of cardiologist, obstetrician, cardiac surgeon and anesthesiologist is essential to decide the best treatment.

Yeast epigenetics: the inheritance of histone modification states.

Saccharomyces cerevisiae (budding yeast) and Schizosaccharomyces pombe (fission yeast) are two of the most recognised and well-studied model systems for epigenetic regulation and the inheritance of chromatin states. Their silent loci serve as a proxy for heterochromatic chromatin in higher eukaryotes, and as such both species have provided a wealth of information on the mechanisms behind the establishment and maintenance of epigenetic states, not only in yeast, but in higher eukaryotes. This review focuses specifically on the role of histone modifications in governing telomeric silencing in S. cerevisiae and centromeric silencing in S. pombe as examples of genetic loci that exemplify epigenetic inheritance. We discuss the recent advancements that for the first time provide a mechanistic understanding of how heterochromatin, dictated by histone modifications specifically, is preserved during S-phase. We also discuss the current state of our understanding of yeast nucleosome dynamics during DNA replication, an essential component in delineating the contribution of histone modifications to epigenetic inheritance.

Low-grade infections as a possible cause of arthrofibrosis after total knee arthroplasty.

PURPOSE: Arthrofibrosis after total knee arthroplasty represents a considerable burden for the patient and a therapeutic challenge for the practitioner. One possible cause discussed in the literature is a low-grade infection. This hypothesis should be examined within the scope of this retrospective study. PATIENTS AND METHODS: Nineteen patients with clinical symptoms of arthrofibrosis after primary total knee arthroplasty were examined between January, 1999 and January, 2012. Incorrect positioning was radiologically ruled out. All patients were examined clinically (score of Freeman as well as Blauth and Jäger), radiologically (component and leg alignment, patella height according to Insall and Salvati), microbiologically (culture-based procedures), molecular biologically (PCR) and histologically in the course of an open revision of the prosthesis. RESULTS: According to the score of Freeman et al. (1977), a highly significant improvement in pain (p = 0.007) and in the overall score (p = 0.003) was shown. The knee joint mobility did not change significantly (p = 0.795). PCR was negative in 17 patients. One patient showed a PCR-positive result of the synovial membrane for Corynebacterium spp., while Staphylococcus warneri was detected in the culture. Another patient had a positive result of synovia PCR for Enterococcus cecorum as well as Corynebacterium spp. However, this culture was sterile. In 16 patient samples, no bacterial growth was detectable. Two samples were not evaluable. The main histopathological findings were synovialitis and fibrosis. CONCLUSION: The hypothesis of low-grade-infection-induced arthrofibrosis after total knee arthroplasty could not be confirmed in this study. However, based on this small study population the conclusion needs to be confirmed by new and larger studies, ideally prospectively designed including a control group.

Precision medicine applications in prostate cancer.

Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival.

Influence of bull age, ejaculate number, and season of collection on semen production and sperm motility parameters in Holstein Friesian bulls in a commercial artificial insemination centre.

In the current era of genomic selection, there is an increased demand to collect semen from genomically selected sires at a young age. The objective of this study was to assess the effect of bull age, ejaculate number, and season of collection on semen production (ejaculate volume, sperm concentration, and total sperm number; TSN) and sperm motility (prefreeze and post-thaw total and gross motility) parameters in Holstein Friesian bulls in a commercial artificial insemination (AI) center. The study involved the interrogation of a large dataset collected over a 4-yr period, (n = 8,983 ejaculates; n = 176 Holstein Friesian bulls aged between 9 mo and 8 yr). Bulls aged less than 1 yr had the poorest semen production and sperm motility values for all parameters assessed compared with bulls older than 1 yr (P < 0.01). First ejaculates had greater semen production and greater prefreeze motility values than second consecutive ejaculates (P < 0.01), but despite this, there was no difference in post-thaw motility. When subsequent ejaculates were collected from bulls aged less than 1 yr, semen production and sperm motility did not differ compared with mature bulls. Semen collected in winter was poorest in terms of sperm concentration and TSN, but best in terms of post-thaw motility (P < 0.01). In conclusion, second ejaculates can be collected, particularly from bulls aged less than 1 yr, without a significant decrease in post-thaw sperm motility, thus may be a useful strategy to increase semen availability from young genomically selected AI bulls in high demand.

Yeast heterochromatin regulators Sir2 and Sir3 act directly at euchromatic DNA replication origins.

Most active DNA replication origins are found within euchromatin, while origins within heterochromatin are often inactive or inhibited. In yeast, origin activity within heterochromatin is negatively controlled by the histone H4K16 deacetylase, Sir2, and at some heterochromatic loci also by the nucleosome binding protein, Sir3. The prevailing view has been that direct functions of Sir2 and Sir3 are confined to heterochromatin. However, growth defects in yeast mutants compromised for loading the MCM helicase, such as cdc6-4, are suppressed by deletion of either SIR2 or SIR3. While these and other observations indicate that SIR2,3 can have a negative impact on at least some euchromatic origins, the genomic scale of this effect was unknown. It was also unknown whether this suppression resulted from direct functions of Sir2,3 within euchromatin, or was an indirect effect of their previously established roles within heterochromatin. Using MCM ChIP-Seq, we show that a SIR2 deletion rescued MCM complex loading at ~80% of euchromatic origins in cdc6-4 cells. Therefore, Sir2 exhibited a pervasive effect at the majority of euchromatic origins. Using MNase-H4K16ac ChIP-Seq, we show that origin-adjacent nucleosomes were depleted for H4K16 acetylation in a SIR2-dependent manner in wild type (i.e. CDC6) cells. In addition, we present evidence that both Sir2 and Sir3 bound to nucleosomes adjacent to euchromatic origins. The relative levels of each of these molecular hallmarks of yeast heterochromatin-SIR2-dependent H4K16 hypoacetylation, Sir2, and Sir3 -correlated with how strongly a SIR2 deletion suppressed the MCM loading defect in cdc6-4 cells. Finally, a screen for histone H3 and H4 mutants that could suppress the cdc6-4 growth defect identified amino acids that map to a surface of the nucleosome important for Sir3 binding. We conclude that heterochromatin proteins directly modify the local chromatin environment of euchromatic DNA replication origins.