Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value.

Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-ß-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free ß-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free ß-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-ß-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.

Longitudinal Changes in Placental Magnetic Resonance Imaging Relaxation Parameter in Murine Pregnancy: Compartmental Analysis.

OBJECTIVE: To quantify gestation-dependent longitudinal changes in the magnetic resonance transverse relaxation time (T2) parameter of the major constituent regions of the mouse placenta and to evaluate their relative contributions to changes in overall placental T2. METHODS: Timed-pregnant CD-1 mice underwent magnetic resonance imaging at 7.0 T field strength, on gestational day 13 (GD13), GD15 and GD17. T2 of the placenta and its constituent high and low blood perfusion regions were quantified. A linear mixed-effects model was used to fit the T2 across gestation, and the significance of coefficients was tested. RESULTS: A decrease in the T2 values of the placenta and its constituent regions was observed across gestation. The temporal change in T2 was estimated to be -1.85 ms/GD (p < 0.0001) for the placenta, -1.00 ms/GD (p < 0.001) for the high-perfusion zones (HPZs) and -1.66 ms/GD (p < 0.0001) for the low-perfusion zones (LPZs). CONCLUSION: T2 of the constituent zones of the murine placenta decreases with advancing gestation. While the T2 of the LPZ is smaller than that of the HPZ, there is no difference in their decrease rate relative to that of the whole placenta (p = 0.24). The results suggest an increased role of constituent volume fractions in affecting overall gestation-dependent placental T2 decrease in mice.

A genetic map of Peromyscus with chromosomal assignment of linkage groups (a Peromyscus genetic map).

The rodent genus Peromyscus is the most numerous and species-rich mammalian group in North America. The naturally occurring diversity within this genus allows opportunities to investigate the genetic basis of adaptation, monogamy, behavioral and physiological phenotypes, growth control, genomic imprinting, and disease processes. Increased genomic resources including a high quality genetic map are needed to capitalize on these opportunities. We produced interspecific hybrids between the prairie deer mouse (P. maniculatus bairdii) and the oldfield mouse (P. polionotus) and scored meiotic recombination events in backcross progeny. A genetic map was constructed by genotyping of backcross progeny at 185 gene-based and 155 microsatellite markers representing all autosomes and the X-chromosome. Comparison of the constructed genetic map with the molecular maps of Mus and Rattus and consideration of previous results from interspecific reciprocal whole chromosome painting allowed most linkage groups to be unambiguously assigned to specific Peromyscus chromosomes. Based on genomic comparisons, this Peromyscus genetic map covers ~83% of the Rattus genome and 79% of the Mus genome. This map supports previous results that the Peromyscus genome is more similar to Rattus than Mus. For example, coverage of the 20 Rattus autosomes and the X-chromosome is accomplished with only 28 segments of the Peromyscus map, but coverage of the 19 Mus autosomes and the X-chromosome requires 40 chromosomal segments of the Peromyscus map. Furthermore, a single Peromyscus linkage group corresponds to about 91% of the rat and only 76% of the mouse X-chromosomes.

Quantitative T2 changes and susceptibility-weighted magnetic resonance imaging in murine pregnancy.

OBJECTIVE: To evaluate gestational age-dependent changes in the T2 relaxation time in normal murine placentas in vivo. The role of susceptibility-weighted imaging (SWI) in visualization of the murine fetal anatomy was also elucidated. METHODS: Timed-pregnant CD-1 mice at gestational day (GD) 12 and GD17 underwent magnetic resonance imaging. Multi-echo spin echo and SWI data were acquired. The placental T2 values on GD12 and GD17 were quantified. To account for the influence of systemic maternal physiological factors on placental perfusion, maternal muscle was used as a reference for T2 normalization. A linear mixed-effects model was used to fit the normalized T2 values, and the significance of the coefficients was tested. Fetal SWI images were processed and reviewed for venous vasculature and skeletal structures. RESULTS: The average placental T2 value decreased significantly on GD17 (40.17 ± 4.10 ms) compared to the value on GD12 (55.78 ± 8.13 ms). The difference in normalized T2 values also remained significant (p = 0.001). Using SWI, major fetal venous structures like the cardinal vein, the subcardinal vein, and the portal vein were visualized on GD12. In addition, fetal skeletal structures could also be discerned on GD17. CONCLUSION: The T2 value of a normal murine placenta decreases with advancing gestation. SWI provided clear visualization of the fetal venous vasculature and bony structures. © 2014 S. Karger AG, Basel.

HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by abnormal hematopoietic cell maturation, increased apoptosis of bone marrow cells, and anemia. They are the most common myeloid blood cancers in American adults. The full complement of gene mutations that contribute to the phenotypes or clinical symptoms in MDS is not fully understood. Around 10%-25% of MDS patients harbor an interstitial heterozygous deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes, including HSPA9. The HSPA9 gene encodes for the protein mortalin, a highly conserved heat shock protein predominantly localized in mitochondria. Our prior study showed that knockdown of HSPA9 induces TP53-dependent apoptosis in human CD34+ hematopoietic progenitor cells. In this study, we explored the role of HSPA9 in regulating erythroid maturation using human CD34+ cells. We inhibited the expression of HSPA9 using gene knockdown and pharmacological inhibition and found that inhibition of HSPA9 disrupted erythroid maturation as well as increased expression of p53 in CD34+ cells. To test whether the molecular mechanism of HSPA9 regulating erythroid maturation is TP53-dependent, we knocked down HSPA9 and TP53 individually or in combination in human CD34+ cells. We found that the knockdown of TP53 partially rescued the erythroid maturation defect induced by HSPA9 knockdown, suggesting that the defect in cells with reduced HSPA9 expression is TP53-dependent. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to the anemia observed in del(5q)-associated MDS patients due to the activation of TP53.

Classification of preeclampsia according to molecular clusters with the goal of achieving personalized prevention.

The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.

Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy.

Systemic sclerosis or scleroderma (SSc) is a complex autoimmune connective tissue disease characterized by obliterative vasculopathy and tissue fibrosis. The molecular mechanisms underlying SSc vasculopathy are largely unknown. Friend leukemia integration factor 1 (Fli1), an important regulator of immune function and collagen fibrillogenesis, is expressed at reduced levels in endothelial cells in affected skin of patients with SSc. To develop a disease model and to investigate the function of Fli1 in the vasculature, we generated mice with a conditional deletion of Fli1 in endothelial cells (Fli1 CKO). Fli1 CKO mice showed a disorganized dermal vascular network with greatly compromised vessel integrity and markedly increased vessel permeability. We show that Fli1 regulates expression of genes involved in maintaining vascular homeostasis including VE-cadherin, platelet endothelial cell adhesion molecule 1, type IV collagen, matrix metalloproteinase 9, platelet-derived growth factor B, and S1P(1) receptor. Accordingly, Fli1 CKO mice are characterized by down-regulation of VE-cadherin and platelet endothelial cell adhesion molecule 1, impaired development of basement membrane, and a decreased presence of alpha-smooth muscle actin-positive cells in dermal microvessels. This phenotype is consistent with a role of Fli1 as a regulator of vessel maturation and stabilization. Importantly, vascular characteristics of Fli1 CKO mice are recapitulated by SSc microvasculature. Thus, persistently reduced levels of Fli1 in endothelial cells may play a critical role in the development of SSc vasculopathy.

[Primary systemic therapy in breast cancer patients (2007-2010)]. / Emlodaganatos betegek primer szisztémás terápiája során elért eredményeink (2007-2010).

INTRODUCTION/AIM: The importance of preoperative neoadjuvant (NA) systemic treatment in operable breast cancer has significantly increased in the last few years. The aim of our retrospective study was to determine the effect of NA therapy in breast cancer patients treated in our unit and analyze radiological and pathological response rates in the context of surgical treatment. MATERIALS AND METHODS: One hundred and fourteen cases of breast cancer with NA therapy were analyzed and clinical data were collected from March 2007 to December 2010. Twenty-two patients received NA treatment for inoperable tumours. As far as operable cancers (92 patients), the indications for NA treatment were high tumour grade, presence of axillary metastasis and relatively young age. 5-Fluorouracil-Epirubicin-Cyclophosphamid or Taxotere-Epirubicin regimens were administered in 6 cycles followed by radiological evaluation and surgery. Herein, we compared the preoperative staging with the pathological results after surgery. RESULTS: NA therapy resulted in complete regression in 17% of patients, significant regression in 21%, while moderate regression was achieved in 43% of patients. No regression was detected in 19%. The decrease in T stage was not followed by decrease in N stage in significant number of cases. Moreover, in some cases NA therapy caused complete radiological regression, while histologically it still remained positive. In certain cases, breast conserving surgery was feasible due to down-staging caused by NA therapy. CONCLUSION: NA therapy was effective primarily in decreasing tumour size; however, it was less effective on axillary lymph node metastases. Due to the presence of the residual DCIS component, the volume of resection could not be decreased as much as down-staging of the invasive cancer would have permitted.

Bee Attack or Heart Attack: Kounis Syndrome.

Kounis syndrome (KS) is defined as an allergic or hypersensitivity reaction leading to coronary vasospasm and acute coronary syndrome. The inflammatory mediators released during the body's reaction to an allergen causes vasoconstriction, plaque rupture, platelet aggregation, and even thrombosis of an existing coronary stent. Over the years, many allergens including drugs, environmental exposures, and animal and insect bites have been implicated in KS. Patients may present with elevated cardiac enzymes and electrocardiographic changes. We describe a case of a patient with no prior cardiac history who presented to the emergency department seeking treatment after multiple bee stings. The patient had non-specific electrocardiogram (ECG) changes and elevated cardiac enzymes consistent with a non-ST-elevation myocardial infarction. The patient underwent a pharmacologic stress test and myocardial perfusion imaging, which showed a perfusion defect consistent with ischemia. Selective right and left coronary angiography revealed a critical lesion at the proximal left circumflex artery. This was managed with percutaneous coronary intervention utilizing a bare-metal stent.

Animal reservoirs of SARS-CoV-2: calculable COVID-19 risk for older adults from animal to human transmission.

The current COVID-19 pandemic, caused by the highly contagious respiratory pathogen SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has already claimed close to three million lives. SARS-CoV-2 is a zoonotic disease: it emerged from a bat reservoir and it can infect a number of agricultural and companion animal species. SARS-CoV-2 can cause respiratory and intestinal infections, and potentially systemic multi-organ disease, in both humans and animals. The risk for severe illness and death with COVID-19 significantly increases with age, with older adults at highest risk. To combat the pandemic and protect the most susceptible group of older adults, understanding the human-animal interface and its relevance to disease transmission is vitally important. Currently high infection numbers are being sustained via human-to-human transmission of SARS-CoV-2. Yet, identifying potential animal reservoirs and potential vectors of the disease will contribute to stronger risk assessment strategies. In this review, the current information about SARS-CoV-2 infection in animals and the potential spread of SARS-CoV-2 to humans through contact with domestic animals (including dogs, cats, ferrets, hamsters), agricultural animals (e.g., farmed minks), laboratory animals, wild animals (e.g., deer mice), and zoo animals (felines, non-human primates) are discussed with a special focus on reducing mortality in older adults.

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene.

Breast cancer patients presenting with symptomatic brain metastases have poor prognosis, and current chemotherapeutic agents are largely ineffective. In this study, we evaluated the hypomethylating agent azacitidine (AZA) for its potential as a novel therapeutic in preclinical models of brain metastasis of breast cancer. We used the parental triple-negative breast cancer MDA-MB-231 (231) cells and their brain colonizing counterpart (231Br) to ascertain phenotypic differences in response to AZA. We observed that 231Br cells have higher metastatic potential compared to 231 cells. With regard to therapeutic value, the AZA IC50 value in 231Br cells is significantly lower than that in parental cells (P < .01). AZA treatment increased apoptosis and inhibited the Wnt signaling transduction pathway, angiogenesis, and cell metastatic capacity to a significantly higher extent in the 231Br line. AZA treatment in mice with experimental brain metastases significantly reduced tumor burden (P = .0112) and increased survival (P = .0026) compared to vehicle. Lastly, we observed a decreased expression of keratin 18 (an epithelial maker) in 231Br cells due to hypermethylation, elucidating a potential mechanism of action of AZA in treating brain metastases from breast cancer.

Proteomic identification of Placental Protein 1 (PP1), PP8, and PP22 and characterization of their placental expression in healthy pregnancies and in preeclampsia.

INTRODUCTION: Placental Protein 1 (PP1), PP8, and PP22 were isolated from the placenta. Herein, we aimed to identify PP1, PP8, and PP22 proteins and their placental and trophoblastic expression patterns to reveal potential involvement in pregnancy complications. METHODS: We analyzed PP1, PP8, and PP22 proteins with LC-MS. We compared the placental behaviors of PP1, PP8, and PP22 to the predominantly placenta-expressed PP5/TFPI-2. Placenta-specificity scores were generated from microarray data. Trophoblasts were isolated from healthy placentas and differentiated; total RNA was isolated and subjected to microarray analysis. We assigned the placentas to the following groups: preterm controls, early-onset preeclampsia, early-onset preeclampsia with HELLP syndrome, term controls, and late-onset preeclampsia. After histopathologic examination, placentas were used for tissue microarray construction, immunostaining with anti-PP1, anti-PP5, anti-PP8, or anti-PP22 antibodies, and immunoscoring. RESULTS: PP1, PP8, and PP22 were identified as 'nicotinate-nucleotide pyrophosphorylase', 'serpin B6', and 'protein disulfide-isomerase', respectively. Genes encoding PP1, PP8, and PP22 are not predominantly placenta-expressed, in contrast with PP5. PP1, PP8, and PP22 mRNA expression levels did not increase during trophoblast differentiation, in contrast with PP5. PP1, PP8, and PP22 immunostaining were detected primarily in trophoblasts, while PP5 expression was restricted to the syncytiotrophoblast. The PP1 immunoscore was higher in late-onset preeclampsia, while the PP5 immunoscore was higher in early-onset preeclampsia. DISCUSSION: PP1, PP8, and PP22 are expressed primarily in trophoblasts but do not have trophoblast-specific regulation or functions. The distinct dysregulation of PP1 and PP5 expression in either late-onset or early-onset preeclampsia reflects different pathophysiological pathways in these preeclampsia subsets.

Hybrid solution combining osteosynthesis and endoprosthesis for double column acetabular fractures in the elderly provide more stability with finite element model.

OBJECTIVES: This study aims to compare mechanical stability of osteosynthesis (plate and screw fixation) alone versus the same method supplemented with hip arthroplasty (hybrid solution) for double column fractures in elderly. PATIENTS AND METHODS: Mechanical investigations were performed on an advanced finite element pelvis model developed for double column fractures. The following simulated implant combinations were analyzed: modular acetabular basket with a ring with polyaxial screws and U-plate; plates with polyaxial screws placed on the medial-horizontal (linea terminalis) and quadrilateral bone surfaces; modular acetabular cup with U-plates; and polyaxial screws in sizes optimized based on a finite element model (FEM). Using the models, the possible shifts in peak load positions arising in different movement patterns caused by load and tension and implant deformation were measured. RESULTS: Hybrid systems resulted in minimal deformation of the implants already available on the market. We observed less possible shifts and greater stability in the acetabular fracture zones, compared to conventional osteosynthesis alone. Optimization with available and compatible implant sizes led to a further significant increase in stability. CONCLUSION: Hybrid method combining osteosynthesis and prosthesis implantation provide more stability in biomechanical models in the treatment of double column fractures in elderly.

Tissue expression pattern of class II and class V genes found in the Adh complex on mouse chromosome 3.

The alcohol dehydrogenase enzymes in mice and humans are encoded by a linked group of genes in the same transcriptional orientation. The enzymes play important roles in alcohol metabolism and retinoid signaling and homeostasis. The expression patterns at the mRNA level of the mouse Adh4 (class II) gene and the recently identified Adh6a and Adh6b genes (class V) are now reported to complete this analysis for the entire family. Adh4 is expressed at high levels in liver and is detectable in small intestine and testes. Adh6b is expressed in liver but Adh6a is not. Adh6a is expressed at high levels in small intestine while Adh6b is not. Adh6a expression is detectable in the female adrenal and not at all in the male adrenal, but Adh6b is expressed at moderate levels in both sexes. Although Adh6a and Adh6b have expression patterns different from each other, neither expresses like any other gene in the complex, suggesting different control mechanisms and possibly different functions.

Physical compatibility of MCT/LCT propofol emulsions with crystalloids during simulated Y-site administration.

OBJECTIVE: In intensive care units numerous drugs have to be infused simultaneously, resulting inline incompatibility. Propofol is formulated as a lipid emulsion and it is well known that electrolytes can affect the stability of an emulsion system. Our goal was to evaluate and to compare the physical compatibility of three commercial propofol lipid emulsions of different manufacturers, mixing them with the most commonly used crystalloids in intensive care units. METHODS: Simulated Y-site administration was accomplished by mixing the 2% MCT/LCT propofol emulsions with the commonly used crystalloids in the intensive care unit in a 1:1 ratio in a polypropylene syringe. The aliquot samples were evaluated immediately and at 15, 30, 60 and 120 min after preparation by visual observation, pH and droplet size measurement. RESULTS: There was no emulsion breakdown or any visible change during the study period. Mixing the propofols with crystalloids, 10% magnesium sulphate or 10% potassium chloride there was no significant change in the droplet size compared with the original propofol emulsions. A slight alteration in droplet size was noticed in a few of the propofol samples, when magnesium, potassium or both were the secondary additives to the crystalloids, but this is not considered clinically relevant. CONCLUSION: The physical properties of emulsions are determined by component, therefore the compatibility data in literature has to be evaluated prudently. All three commercially available MCT/LCT propofol emulsions are considered physically compatible with the tested crystalloids.

Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.

Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.

The use of a smartphone application for fast lung cancer risk assessment†.

OBJECTIVES: The overall prognosis of lung cancer is poor: Only every 8 patient survives 5 years after diagnosis. This outcome is partly attributable to late diagnosis. To implement a screening program for early diagnosis, selection of high-risk individuals is essential. Our aim was to construct a personalized lung cancer risk assessment tool using geographic localization to lead the high-risk individuals to the local health care provider. METHODS: A smartphone application was created for Android and iOS mobile platforms using a risk assessment questionnaire. The software provides immediate classification into low, moderate and high-risk groups. The high-risk group is directed to the nearest screening centre based on GPS location. The complete test data set is recorded on a collection server database for further analysis. RESULTS: The application was downloaded 13 890 times and completed by 89 500 persons over a period of 20 months. The mean age of the tested users was 36.91 years (9-93 years); the majority were men living in an urban area (62.3%). The test was completed by 38 850 active smokers and 26 710 persons who reported having already quit smoking, resulting in 30 072 moderate and 10 740 high-risk users. CONCLUSIONS: This free application is an active communication tool for most smartphone owners. It helps those who might need further medical attention. The affected users can be easily connected and localized via the smartphone, which helps recruit individuals into screening programs.

Medication use and risk of falls among nursing home residents: a retrospective cohort study.

Background Geriatric falls are leading causes of hospital trauma admissions and injury-related deaths. Medication use is a crucial element among extrinsic risk factors for falls. To reduce fall risk and the prevalence of adverse drug reactions, potentially inappropriate medication (PIM) lists are widely used. Objective Our aim was to investigate the possible predictors of geriatric falls annualized over a 5-year-long period, as well as to evaluate the medication use of nursing home residents. Setting Nursing home residents were recruited from the same institution between 2010 and 2015 in Szeged, Hungary. Method A retrospective epidemiological study was performed. Patient data were analysed for the first 12 months of residency. Chi-squared test and Fisher's-test were applied to compare the categorical variables, Student's t test to compare the continuous variables between groups. Binary logistic regression analysis was carried out to determine the association of falls with other variables found significant in univariate analysis. Microsoft Excel, IBM SPSS Statistics (version 23) and R (3.2.2) programs were used for data analysis. Main outcome measure Falls affected by age, gender, number of chronic medications, polypharmacy, PIM meds. Results A total of 197 nursing home residents were included, 150 (76.2%) women and 47 (23.8%) men, 55 fallers (annual fall prevalence rate was 27.9%) and 142 non-fallers. Gender was not a predisposing factor for falls (prevalence in males: 23.4 vs 29.3% in females, p > 0.05). Fallers were older (mean years ± SD; 84.0 ± 7.0) than non-fallers (80.1 ± 9.3, p < 0.01). The age ≥80 years was a significant risk factor for falls (p < 0.001). The number of chronic medications was higher in male fallers (12.4 ± 4.0) than in non-fallers (6.9 ± 4.2, p < 0.001). Polypharmacy (taking four or more chronic medications) was a significant risk factor of falls (p < 0.01). Those PIMs carrying fall risk were taken by 70.9% of fallers and 75.3% of non-fallers (p > 0.05). Taking pantoprazole, vinpocetine or trimetazidine was a significant risk factor for falls. Conclusion Older age, polypharmacy and the independent use of pantoprazole, vinpocetine, and trimetazidine were found to be major risk factors for falls. Further real-life epidemiological studies are necessary to confirm the role of particular active agents, and to help professionals prescribe, evaluate and review geriatric medication use.

Impaired Protein Quality Control During Left Ventricular Remodeling in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor.

BACKGROUND: Sustained inflammation in the heart is sufficient to provoke left ventricular dysfunction and left ventricular remodeling. Although inflammation has been linked to many of the biological changes responsible for adverse left ventricular remodeling, the relationship between inflammation and protein quality control in the heart is not well understood. METHODS AND RESULTS: To study the relationship between chronic inflammation and protein quality control, we used a mouse model of dilated cardiomyopathy driven by cardiac restricted overexpression of TNF (tumor necrosis factor; Myh6-sTNF). Myh6-sTNF mice develop protein aggregates containing ubiquitin-tagged proteins within cardiac myocytes related to proteasome dysfunction and impaired autophagy. The 26S proteasome was dysfunctional despite normal function of the core 20S subunit. We found an accumulation of autophagy substrates in Myh6-sTNF mice, which were also seen in tissue from patients with end-stage heart failure. Moreover, there was evidence of impaired autophagosome clearance after chloroquine administration in these mice indicative of impaired autophagic flux. Finally, there was increased mammalian target of rapamycin complex 1 (mTORC1) activation, which has been linked to inhibition of both the proteasome and autophagy. CONCLUSIONS: Myh6-sTNF mice with sustained inflammatory signaling develop proteasome dysfunction and impaired autophagic flux that is associated with enhanced mTORC1 activation.

A longitudinal study of placental perfusion using dynamic contrast enhanced magnetic resonance imaging in murine pregnancy.

INTRODUCTION: To evaluate changes in placental perfusion with advancing gestation in normal murine pregnancy using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). METHODS: Seven timed-pregnant CD-1 mice underwent DCE-MRI scanning longitudinally on gestational days (GD) 13, 15 and 17. Placentas were segmented into high (HPZ) and low perfusion zones (LPZ) using tissue similarity mapping. Blood perfusion of the respective regions and the whole placenta was quantified using the steepest slope method. The diameter of the maternal central canal (CC) was also measured. RESULTS: An increase in perfusion was observed between GD13 and GD17 in the overall placenta (p = 0.04) and in the HPZ (p = 0.02). Although perfusion in the LPZ showed a slight increasing trend, it was not significant (p = 0.07). Perfusion, in units of ml/min/100 ml, in the overall placenta and the HPZ was respectively 61.2 ± 31.2 and 106.2 ± 56.3 at GD13 (n = 19 placentas); 90.3 ± 43.7 and 139 ± 55.4 at GD15 (n = 20); and 104.9 ± 76.1 and 172.2 ± 85.6 at GD17 (n = 14). The size of the CC increased with advancing gestation (p < 0.05). DISCUSSION: Using longitudinal DCE-MRI, the gestational age-dependent perfusion change in the normal murine placenta and in its regional compartments was quantified. In mid and late gestations, placental constituent regions differ significantly in their perfusion rates. The CC diameter also showed increase with advancing gestation, which may be playing an important role toward the gestational age-dependent increase in placental perfusion.