microRNA-569 inhibits tumor metastasis in pancreatic cancer by directly targeting NUSAP1.
MicroRNAs (miRNAs) are known to be involved in the development and progression of pancreatic cancer (PC). In this study, the prognostic significance and mechanistic role of microRNA-569 in PC were explored. Quantitative real-time PCR was used to detect the expression of microRNA-569 in PC tissues and cell lines. Scratch test and Transwell assay were conducted to detect migration and invasion ability. The xenograft nude mice model was used to determine tumor metastasis in vivo. The direct targets of microRNA-569 were determined by using bioinformatics analysis and a dual-luciferase reporter assay. The expression level of microRNA-569 was down-regulated in PC patients with a poor prognosis. In vitro and in vivo experiments indicated that over-expression of microRNA-569 inhibited the migration and invasion of PC cells. MicroRNA-569 negatively regulated NUSAP1 by directly binding its 3'-untranslated region. Further mechanism research implied that the ZEB1 pathway was involved in microRNA-569/NUSAP1 mediation of the biological behaviors in PC. These data demonstrated that microRNA-569 may exert a tumor-suppressing effect in PC and maybe a potential therapeutic target for PC patients.


[Clinical characteristics of pneumonia in schizophrenics].
To examine clinical features of pneumonia in schizophrenics, its course was analysed in 115 patients of a mental hospital (91 men, 24 women, mean age 54.4 +/- 1.2 years). 63.3% patients stayed in hospital for more than a year, 70.4% had schizophrenia for 20 years. 86% pneumonia patients were at the age older than 40 years, 35%--older than 60 years. Unfavourable premorbid factors were dementia, weight loss, anemia, recurrent pneumonia and intestinal infections. Pneumonia was characterized by rare fever, pains in the chest, frequent hypotension, systemic symptoms. 58.2% of patients suffered from pneumonia longer than 4 weeks. Lethality was 23.5%. In patients who had schizophrenia up to 10 years lethal outcomes were absent. In lethal outcome, pneumonia was initially diagnosed as severe, it was accompanied by arterial hypotonia in 91.7% of cases, by leukopenia in 40.5% (below 10(9)/l). Lethal outcome was caused by rapid development of brain edema in vascular failure in more than half of the cases. Pneumonia in mental patients was connected with many factors: the disease as such, psychotropic therapy, conditions in the hospital stay.


Further studies on metachromasia in cultured human fibroblasts. Staining of glycosaminoglycans (mucopolysaccharides) by Alcian blue in salt solutions.
Staining with Alcian blue in various concentrations of magnesium chloride (alcianophilia) has been found to be a useful supplement to metachromatic staining to detect increased cellular concentrations of glycosaminoglycans (mucopolysaccharides). In many instances alcianophilia at 0.3 M MgCl(2) is more specific than metachromasia and does not give "false positives" sometimes found in normal individuals and in those with cystic fibrosis, Gaucher's disease, familial amaurotic idiocy, and pseudoxanthoma elasticum. On the other hand, it gives a "false negative" reaction in the Sanfilippo syndrome (perhaps because the characteristically elevated glycosaminoglycan in this disease, heparan sulfate, is not synthesized by cultured skin fibroblasts), and in the Marfan syndrome. It detects the Maroteaux-Lamy syndrome, which metachromasia does not. The "false positives" given by metachromasia in all six families studied thus far are genuine, reproducible reactions that can be traced through at least three generations of normal individuals within a family. There is therefore, in these families, a genetic factor that causes such metachromasia, but it is not increased glycosaminoglycan concentration.


Factors Associated with Return Migration of First-Generation Immigrants in Belgium (2001-2011).
Belgium is a country with a long and diverse history of migration. Given the diverse context of immigration to Belgium, reasons for return migration will most likely vary as well. With this study, we want to quantify the return migration of Belgium's immigrants and assess whether socio-economic, sociodemographic and health factors are related to return migration. Individually linked census and register data comprising the total Belgian first-generation immigrant population aged 25+ were used. Age-standardized emigration rates (ASER) by migrant origin and gender were calculated for the period 2001-2011. Additionally, relative return migration differences were calculated by country of origin and gender, adjusted for age group, length of stay, household composition, socio-economic indicators (education, home ownership and employment status) and self-rated health in 2001. Return migration was most common among immigrants from Spanish descent and from the neighbouring countries and higher among men than among women. Return migration was highly selective in terms of older age, lower length of stay in Belgium, not living with a partner or children, being high-educated, unemployed and in good health. Key issues for future research include examining the reasons for return migration, identifying the country of destination and accounting for household characteristics.


The role of hepatectomy for patients with liver metastases of gastric cancer.
Although the role of hepatectomy for patients with colorectal liver metastases is well established, few reports exist of hepatectomy for patients with metastases of gastric cancer origin. This study reviews cases of hepatectomy for metastatic gastric cancer at Fujita Health University Hospital. Between 1989 and 2004, 18 patients underwent hepatectomy for liver metastases from gastric cancer. The patients consisted of 16 men and 2 women and their ages ranged from 51-76 (median 64) years. Hepatic resection was indicated for patients with synchronous metastases who did not have peritoneal dissemination or any other distant metastases (11 patients), and patients with metachronous metastases who did not have any other recurrent lesions (7 patients). Overall survival rate for 1, 2, 3, and 5 years are 56.3, 36.5, 27.3, and 27.3%, respectively. Although the 5-year survival rate was considerable, an early and rapid decrease of survival rate occurred in the first 1-2 years (compared with the colorectal patients). Univariate analysis showed serosal invasion and lymphatic invasion of the primary tumor as significant prognostic factors for survival. Surgical resection for liver metastases of gastric cancer is thought to be beneficial for small part of the patients. For other patients, the procedure may only provide the limited beneficial effects on survival.


[Possibility of existence and multiplication of Mycobacteria in the soil].
The time of the survival of Mycobacterium bovis in the soil of pastures depended on the physicochemical composition and biological activity of the soil. In clay soils M. bovis retained their virulence for as long as 2 months (at the depth of 2 cm in high- and medium-posted solonetz) to 12 months (at the depth of 10 cm in crust solonetz). The M. bovis strains under study multiplied in soil extracts (the term of observation was 8 months). The cultures grown at 20-24 degrees C were found to have the prolonged exponential phase in comparison with that of the cultures grown at 37.5-38.5 degrees C. In the deep litter and the soil under it M. avium remained viable for 10 years.


A Genetic Marker Associated with De Quervain's Tenosynovitis.
De Quervain's tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain's tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain's tenosynovitis at genome-wide significance (p=1.9×10-8; OR=1.46; 95% CI=1.38-1.59). This study is the first genome-wide screen for de Quervain's tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.


Development of amino-oxazoline and amino-thiazoline organic catalysts for the ring-opening polymerisation of lactide.
The ring-opening polymerisation of lactide by a range of amino-oxazoline and amino-thiazoline catalysts is reported. The more electron-rich derivatives are demonstrated to be the most highly active and polymerisation is well controlled, as evidenced by the linear relationship between the molecular weight and both the monomer conversion and the monomer-to-initiator ratio. Mechanistic studies reveal significant interactions between the monomer, initiator and catalyst and that the polymerisation is first order with respect to each of these components. These observations indicate that the polymerisation operates by a general base/pseudo-anionic mechanism.


Online Proteolysis and Glycopeptide Enrichment with Thermoresponsive Porous Polymer Membrane Reactors for Nanoflow Liquid Chromatography-Tandem Mass Spectrometry.
In this Article, we have reported a fully automated online method to carry out proteolysis and glycopeptide enrichment in sequence for nanoflow liquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS) analysis. By implementing two serial thermoresponsive porous polymer membrane reactors (TPPMRs), in which the TPPM could be immobilized either with trypsin for proteolysis or with lectins for glycopeptide enrichment, the entire pretreatment procedure can be performed online in about an hour. The TPPM was fabricated by coating polystyrene-maleic anhydride- N-isopropylacrylamide (PS-MAn-PNIPAm), which was synthesized by reversible addition-fragmentation chain transfer polymerization, on a Nylon sheet. Because of the thermoresponsive nature of PNIPAm, it formed micelle cavities and changed its morphology at elevated temperatures, resulting in enhanced interactions between the enzyme or lectins and the proteins/peptides flowing through the membrane. The performances of the TPPMs were evaluated by varying the temperature conditions and the amount of standard proteins, showing that both proteolysis and glycopeptide enrichment with online deglycosylation were highly efficient at 37 °C. The developed online serial TPPMRs-nLC-ESI-MS/MS method was applied to the human plasma sample (1.5 μL) and a total of 262 N-glycopeptides could be identified from 155 glycoproteins. Thus, the present work demonstrates a fully automated high speed analytical protocol for online proteolysis and glycopeptide enrichment, which is extremely useful for analyzing small amounts of the proteome samples.


Alternative administration of camptothecin analogues.
The binding of camptothecin (CPT) to the DNA-topoisomerase complex is reversible, but it needs to be maintained for maximal inhibitory activity. It is also dependent on the chemical structure of CPT. The lactone form is thought to be necessary for the activity. In human serum, the equilibrium between lactone and carboxylate is in favor of the latter. For these reasons, alternative administration of CPT analogues is being evaluated. The ideal compound would remain in lactone form and would expose the host for long periods of time to its effects. Oral administration of irinotecan (CPT-11) and topotecan (TPT) is discussed by other investigators. We studied oral rubitecan and reported a low lactone to total drug area under the plasma concentration-time curve (AUCP) ratio (14.7%), with low plasma concentration over time despite repeated administrations and the presence of an enterohepatic cycle. Aerosolization of a liposomal formulation of rubitecan is currently under study. Six patients have been treated once a day for 5 days every 3 weeks. The dose was 6.7 micrograms/kg/day. Plasma levels are dose for dose higher than those after oral administration, but the ratio of lactone versus total drug is low. No toxicity was observed. The study will continue with increasing doses and lengths of administration. Intrathecal administration of topotecan has been studied in a phase I trial in children. Doses of 0.4 mg are tolerated without toxicity, and clinical responses have been seen in patients with refractory meningial carcinomatosis. Phase II studies are planned. Intraperitoneal (i.p.) administration of topotecan has been studied in a phase I trial as a 24-hour infusion in 5% dextrose at pH 3.5 every 21 days. Dose-limiting toxicity is 4 mg/m2. Toxic effects are neutropenia, anemia, emesis, fever, and pain. Five of 10 patients with ascites had symptomatic relief. Pharmacokinetic analysis demonstrates a second-order kinetics with elimination half-lives of 0.49 and 2.7 hours. The peritoneal to plasma AUC ratio was 31.2. Intramuscular, transdermal, and subcutaneous administrations have been extensively studied in the mouse.


[The role of embryoid bodies in the development of germinogenous tumors of complex structure and of the teratoma].
250 germinal gonadal and extragonadal tumors were studied in children and adolescents under 16 years of age. Germinal tumours of complex structure were found in 42 patients and in 36 of them embryoid bodies of various types (full, not-full, amorphous) were distinguished. Certain features were revealed indicating the development of the immature teratoma by means of maturation of preexisting embryoid bodies. The arguments in favour of complex germinal tumour development due to the loss of maturation and differentiation capacity of one or several structural elements of the embryoid bodies are presented. The observation of mature, immature embryonal tissues and proliferating elements of the embryoid bodies in the composition of one and the same tumour may be explained by different biological potency of individual clones of atypical and primordial germinal cells which are the source of the development of these tumours.


The sucrose transporter HbSUT3 plays an active role in sucrose loading to laticifer and rubber productivity in exploited trees of Hevea brasiliensis (para rubber tree).
Efficient sucrose loading in rubber-producing cells (laticifer cells) is essential for retaining rubber productivity in Hevea brasiliensis, but the molecular mechanisms underlying the regulation of this process remain unknown. Here, we functionally characterized a putative Hevea SUT member, HbSUT3, mainly in samples from regularly exploited trees. When expressed in yeast, HbSUT3 encodes a functional sucrose transporter that exhibits high sucrose affinity with a K(m) value of 1.24 mm at pH 4.0, and possesses features typical of sucrose/H(+) symporters. In planta, when compared to the expression of other Hevea SUT genes, HbSUT3 was found to be the predominant member expressed in the rubber-containing cytoplasm (latex) of laticifers. The comparison of HbSUT3 expression among twelve Hevea tissues demonstrates a relatively tissue-specific pattern, i.e. expression primarily in the latex and in female flowers. HbSUT3 expression is induced by the latex stimulator Ethrel (an ethylene generator), and relates to its yield-stimulating effect. Tapping (the act of rubber harvesting) markedly increased the expression of HbSUT3, whereas wounding alone had little effect. Moreover, the expression of HbSUT3 was found to be positively correlated with latex yield. Taken together, our results provide evidence favouring the involvement of HbSUT3 in sucrose loading into laticifers and in rubber productivity.


Identification of the first Alu-mediated large deletion involving the F5 gene in a compound heterozygous patient with severe factor V deficiency.
Factor V (FV) deficiency is a rare autosomal recessive haemorrhagic disorder associated with moderate to severe bleeding symptoms. Conventional mutational screening leads to a complete molecular genetic diagnosis only in about 80-90% of cases. Large gene rearrangements, which could explain at least part of the "missing alleles" have not been reported so far in FV-deficient patients. In this work, we investigated a family with hereditary FV deficiency, in which the proband is compound heterozygous for a 205-Kb deletion, involving the first seven exons of F5 , and the entire selectin P, L, and E genes, and for a novel splicing mutation (IVS12+5G>A). The deletion breakpoints, determined by using a combination of semi-quantitative real-time PCR and long PCR assays, occurred within AluY repeat sequences, suggesting an Alu-mediated unequal homologous recombination as the mechanism responsible for the deletion. The in vitro characterisation of the IVS12+5G>A mutation demonstrated that this mutation causes the skipping of exon 12 and the activation of a cryptic splice site. Low levels of residual wild-type splicing were also detectable, in agreement with the notion that the complete absence of FV may be not compatible with life.


CareSearch - online palliative care information for GPs.
General practitioners have always been involved in providing palliative care. As Australia's population ages, the number of patients living with cancer and end stage chronic disease will increase. This article looks at existing barriers to, and community expectations of, GP involvement in the provision of palliative care. It presents the CareSearch project as one initiative aimed at building GPs' awareness and skills in palliative care. Palliative care is traditionally viewed as being the intense care of a patient who is close to death. In recent years, the scope of palliative care has expanded to include patients who may live for many years with end stage organ failure or cancer. Care of these patients in the community inevitably involves input from the GP. Barriers to GPs' participation in palliative care include knowledge barriers and structural factors. Some GPs feel unprepared to deal with what they see as the complex clinical and psychosocial aspects of palliative care. A number of initiatives have been developed to build the awareness and skills of GPs in palliative care. The GP section of the CareSearch website has been specifically developed to provide knowledge, skills and practical advice for GPs who provide palliative care in the community.


DeepSec: a deep learning framework for secreted protein discovery in human body fluids.
Human proteins that are secreted into different body fluids from various cells and tissues can be promising disease indicators. Modern proteomics research empowered by both qualitative and quantitative profiling techniques has made great progress in protein discovery in various human fluids. However, due to the large number of proteins and diverse modifications present in the fluids, as well as the existing technical limits of major proteomics platforms (e.g. mass spectrometry), large discrepancies are often generated from different experimental studies. As a result, a comprehensive proteomics landscape across major human fluids are not well determined. To bridge this gap, we have developed a deep learning framework, named DeepSec, to identify secreted proteins in 12 types of human body fluids. DeepSec adopts an end-to-end sequence-based approach, where a Convolutional Neural Network is built to learn the abstract sequence features followed by a Bidirectional Gated Recurrent Unit with fully connected layer for protein classification. DeepSec has demonstrated promising performances with average area under the ROC curves of 0.85-0.94 on testing datasets in each type of fluids, which outperforms existing state-of-the-art methods available mostly on blood proteins. As an illustration of how to apply DeepSec in biomarker discovery research, we conducted a case study on kidney cancer by using genomics data from the cancer genome atlas and have identified 104 possible marker proteins. DeepSec is available at https://bmbl.bmi.osumc.edu/deepsec/. Supplementary data are available at Bioinformatics online.


The effectiveness of two active interventions compared to self-care advice in employees with non-acute low back symptoms: a randomised, controlled trial with a 4-year follow-up in the occupational health setting.
Evaluate the effectiveness of two active interventions, aimed at secondary prevention of low back pain (LBP), in occupational health. We performed a survey of LBP (n=2480; response rate 71%) and randomized 143 employees (66% males, 45 years) with LBP over 34 mm on VAS into Rehabilitation (n=43), Exercise (n=43) or self-care (n=40) groups. Primary outcomes were LBP, physical impairment (PI) and health-related quality of life (HRQoL) for two years and sickness absence (SA) days during four years (LBP specific, total). Compared to self-care, exercise reduced LBP at 12 months (mean difference (MD) -12 mm; 95% CI -21 to -2) and improved HRQoL at 12 and 24 months (0.03; 0.00 to 0.05), but did not reduce PI. The MDs of SA days in four years were -17 (-70 to 35, total) and -15 (-47 to 13, LBP specific). Exercise reduced the probability of LBP specific SA during the third and fourth year. Compared to self-care, Rehabilitation reduced LBP at 3 months (-10 mm; -19 to -1) and 6 months (-10 mm; -20 to - 1), but was not effective in HRQoL or PI. The MDs of SA days in four years were -41 (-93 to 8; total) and 5 (-30 to 47; LBP specific). Rehabilitation reduced the probability of total SA during first and second year and amount of total SA days in the fourth year. Among employees with relatively mild LBP, both interventions reduced pain, but the effects on SA and PI were minor. Exercise improved HRQoL. The effect sizes were rather small. ClinicalTrials.gov NCT00908102.


Critical concerns in Iraq/Afghanistan war veteran-forensic interface: veterans treatment court as diversion in rural communities.
The veteran-forensic interface is an emerging area of relevance to forensic clinicians assessing or treating returning Iraq and Afghanistan war veterans facing criminal sanctions. Veterans' Treatment Court (VTC) represents a recent diversion mechanism for low-level offenses that is based on a collaborative justice model. Thirty-nine percent of veterans who served in Iraq or Afghanistan and receiving VA services reside in rural areas. Rural veterans facing criminal justice charges may be at a disadvantage due to limited access to forensic psychiatrists with relevant expertise in providing veterans services for diversion. Therefore, widening the pool of forensic clinicians who have such expertise, as well as knowledge of the signature wounds of the wars as related to aggression and reckless behavior is necessary. This article presents an overview of VTCs and discusses the role of forensic clinicians as stakeholders in this process.


Visual outcome and prognostic factors after vitrectomy for posterior segment foreign bodies.
To identify the prognostic factors that predict final visual outcome in eyes with posterior segment intraocular foreign body (IOFB) injuries managed by primary pars plana vitrectomy. Ninety-six consecutive patients with posterior segment IOFB injuries were retrospectively reviewed. Factors analyzed included initial visual acuity (VA), time between injury and presentation, site of entrance wound, uveal prolapse, vitreous prolapse, traumatized iris, endophthalmitis, location and size of IOFB, use of scleral buckling and/or an encircling band, gas tamponade, lensectomy, number of surgical procedures, and development of retinal detachment. Data were analyzed using univariate and multivariate logistic regression analysis. After a mean follow-up of 8.6 months, 63 eyes (65.6%) achieved VA of 20/200 or better, and 9 eyes (9.4%) had total retinal detachment complicated by inoperable proliferative vitreoretinopathy. On univariate analysis, predictors of poor vision (hand movements or less) were poor initial VA, corneoscleral entrance wound, uveal prolapse, vitreous prolapse, traumatized iris, and development of retinal detachment. In contrast, predictors of good visual outcome (20/200 or better) were absence of uveal prolapse, no endophthalmitis, and no retinal detachment. Multivariate analysis identified corneoscleral entrance wound, uveal prolapse, and development of retinal detachment as the only factors significantly associated with poor visual outcome. Absence of uveal prolapse was the only factor significantly associated with good visual outcome. Final visual outcome is greatly determined by the severity of the primary injury. On multivariate analysis, significant predictive factors of final VA were corneoscleral entrance wound, presence or absence of uveal prolapse, and development of retinal detachment.


Durable remission after aggressive chemotherapy for post-cardiac transplant lymphoproliferation.
A frequently fatal complication of organ transplantation, post-transplant lymphoproliferative disorder (PTLD) develops in 2%-6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality in the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly due to the concomitant use of immunosuppressives. An update report is provided on nineteen consecutive cardiac recipients with PTLD, studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented <6 months after transplantation (median 6 weeks). Only 1/4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease > or =6 months after transplantation. In 8/12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved CR; 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2/8 (25%) died during treatment, 6/8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 64 months. Neutropenic sepsis, and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is feasible and can produce very durable remissions in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.


Broviac catheter sepsis: the natural history of an iatrogenic infection.
Between January 1982 and December 1983, 335 Broviac catheters placed in 270 infants and children were prospectively evaluated. The average duration of catheter life was 99.7 days, yielding a total accumulated experience of 33,394 catheter days. Blood culture-proven bacteremia occurred on 77 occasions (23%), an average of one spetic episode for every 434 days of catheter use. Temperature elevation was the only consistent clinical sign of infection occurring in 91% of the children. White blood cell counts remained within the normal range in the majority of patients. The differential counts were most helpful, however, documenting a significant increase in the number of immature neutrophils. The rise in band forms was frequently observed 24 to 48 hours before the onset of clinically evident sepsis. Platelet counts did not change significantly. Eighty-eight microorganisms were identified on blood culture. Eighty-three bacterial isolates were recovered (94%) and five fungi. The vast majority of patients (86%) had a single organism on blood culture but polymicrobial sepsis was observed on 11 occasions. Staphylococcus sp (38%) and Streptococcus sp (25%) species were most common. Of particular importance, 48% of coagulase negative staphylococci were nafcillin-resistant. Of the gram negative bacteria, Klebsiella (10%) and Pseudomonas (6%) species were most frequent. In 53 patients, antibiotic therapy was administered in an attempt to salvage the catheter. Bacteremia was controlled successfully in 39 (74%), and in the other 14 children, persistent sepsis dictated catheter removal. One patient (0.4%) died as a result of catheter-related sepsis.


[Differentiation behavior of human vaginal epithelium exemplified by keratin expression].
The biochemical and immunohistochemical detection of keratins proves, that the human epithelium of the vagina is a mosaic of differentiation, because of its simultaneous realisation of opposite differentiation pathways in either nonkeratinizing squamous epithelium, identifiable by keratins 4/13, or in epidermis, marked by keratins 1/10. It is only during pregnancy, that the pure type of nonkeratinizing squamous epithelium is seen by the selective suppression of the epidermal keratins 1/10. This finding and the phenomenon of an unpaired expression of keratin pairs in the human vaginal epithelium are explained by a hormone-dependent synthesis of keratin proteins.


Regulatory mechanism of lncRNA NORAD on proliferation and invasion of ovarian cancer cells through miR-199a-3p.
To explore the regulatory mechanism of lncRNA NORAD on proliferation and invasion of ovarian cancer cells through miR-199a-3p. Eighty-six ovarian cancer tissues and 86 tissues adjacent to cancer, human ovarian cancer cell lines SKOV3, HO-8910, A2780, OVCAR-3, and human normal ovarian epithelial cell line IOSE80 were collected. MiR-199a-3p-mimics, miR-199a-3p-inhibitor, miR-NC, si-NORAD, Sh-NORAD, and NC were transfected into HO-8910 and A2780 cells, the expression levels of lncRNA NORAD and miR-199a-3p in ovarian cancer tissues and cells were detected by qRT-PCR, and the expression levels of N-cadherin, E-cadherin, and vimentin in cells were detected by WB. Cell Counting Kit-8 (CCK-8), transwell, and cell scratch tests were used to detect proliferation, invasion, and migration of cells, and the relationship between lncRNA NORAD and miR-199a-3p was confirmed by the Dual-Luciferase reporter assay. LncRNA NORAD was highly expressed and miR-199a-3p was lowly expressed in ovarian cancer, and the expression levels of LNCRNARAD and miR-199a-3p were negatively correlated. Cell experiments showed that inhibiting the expression of lncRNA NORAD or up-regulating the expression of miR-199a-3p could inhibit the proliferation, invasion, migration, and EMT of ovarian cancer cells, while up-regulating the expression of lncRNA NORAD or inhibiting the expression of miR-199a-3p could promote their proliferation, invasion, migration, and EMT. Dual-Luciferase reporter assay confirmed that there was a regulatory relationship between lncRNA NORAD and miR-199a-3p. LncRNA NORAD was highly expressed in ovarian cancer tissues, while silencing lncRNA NORAD expression could inhibit the proliferation, invasion, migration, and EMT of ovarian cancer cells by regulating miR-199a-3p, which might be a new target for the diagnosis and treatment of ovarian cancer.


Peripheral arterial disease diagnosed by ankle-brachial index: Predictor for early renal replacement therapy in chronic kidney disease.
Our study aimed to investigate the relationship between ankle-brachial index (ABI) and need for early renal replacement therapy (RRT) in predialysis patients with chronic kidney disease (CKD). A total of 112 patients (62% men) with pre-dialysis CKD, seen in the outpatient clinic, were included, and ABI was obtained as per standard protocol. Peripheral arterial disease (PAD) was defined as ABI <0.9 or >1.3 in either leg. The clinical data were analyzed, and the risk factors for early RRT were determined by multivariate logistic regression analysis. The prevalence of PAD was 44% in predialysis CKD patients. Over three years' follow- up, 14.2% required RRT; 11.3% developed major cardiovascular event (myocardial infarction, stroke, or death). A total of 26 events occurred. The incidence of all events was significantly higher in patients with abnormal ABI than in those with normal ABI (34.7% vs. 12.7%; log rank P = 0.02). PAD was associated with all events [hazard ratio (HR): 2.72; 95% CI: 1.04-7.17; P = 0.042] as also the need for RRT (HR 3.2; 95% Cl: 1.005-10.23; P = 0.049), on univariate cox proportional hazard analysis. Multivariate logistic regression analysis adjusted for other risk factors identified that PAD remained an independent predictor for the need for early RRT (HR: 12.2; 95%Cl: 2.2-66.5; P = 0.004) and all events (HR: 3.5; 95% Cl: 0.9-13.5; P = 0.032). PAD was an independent predictor for RRT requirement in predialysis CKD.


Consistent Learning-Based Breast Tumor Segmentation and Its Application in Sentinel Lymph Node Metastasis Prediction.
Accurate staging of lymph nodes provides crucial diagnostic information for breast cancer patients, where segmentation is of great importance by localizing and visualizing the breast tumor of interest. Nevertheless, current segmentation methods perform average when facing large span of tumor sizes, degraded image quality, blurred tumor boundaries, and resulting noise during manual annotation. Therefore, we develop a Multi-scale RepVGG-based Segmentation Network (MPSegNet) to segment breast tumor from MR images. In particular, we construct a consistent learning framework for the MPSegNet to alleviate the impact of noisy labels upon segmentation results. The rationale is that different views covering the same breast tumors are supposed to generate identical segmentation predictions. Then, we predict SLN metastasis given segmented breast tumors, where we evaluate the relationships between the predictive performance and tumor segmentations under different consistencies. The results show the superiority of our method over other state-of-the-art methods. A high consistency among multiple views can boost the segmentation performance during consistent learning. However, the optimal segmentation does not produce the best SLN metastatic prediction results, implying that the dependence of classification upon segmentation needs to be elaborately investigated further.Clinical Relevance- This study facilitates more accurate segmentation of breast tumors with consistent learning, and provides an initial analysis between tumor segmentation and subsequent prediction of SLN metastasis, which has potential significance for the precise medical care of breast cancer patients.


Artemisia annua L. as a promising medicinal plant for powerful wound healing applications.
Artemisia annua L. has been utilized for the first time in a nanofibrous wound dressing composition. The extract of this valuable plant provides anti-inflammatory, anti-bacterial and anti-microbial properties which can be considered as a promising medicinal component in therapeutic applications. In the present work, Artemisia annua L. was picked up from Gorgan forest area of Northern Iran and its extract was prepared by methanol as the extraction solvent. In the fabrication of wound dressing, Artemisia annua L. extract was mixed with gelatin and a nanofibrous structure was formed by electrospinning technique. To have a wound dressing with acceptable stability and optimum mechanical properties, this biologically active layer was formed on a PCL nanofibrous base layer. The fabricated double-layer wound dressing was analyzed chemically, structurally, mechanically and biologically. ATR-FTIR spectra of the prepared wound dressing contain functional groups of Artemisia annua L. as peroxide groups, etc. SEM micrographs of electrospun gelatin/Artemisia annua L. confirmed the successful electrospinning process for producing Artemisia annua L.-containing nanofibers with mean diameter of 242.00 ± 67.53 nm. In vitro Artemisia annua L. release study of the fabricated wound dressings suggests a sustain release over 7 days for the crosslinked sample. In addition, evaluation of the in vitro structural stability of the prepared wound dressings confirmed the stability of the crosslinked nanofibrous structures in PBS solution environment. Biological study of the Artemisia annua L.-containing wound dressing revealed no cytotoxicity, good proliferation and attachment of the seeded fibroblasts cells and acceptable antibacterial property against Staphylococcus aureus bacteria.


Complexity analysis of spontaneous EEG.
The aim of the present paper is the assessment of the overall complexity of spontaneous and non-paroxysmal EEG signals obtained from three groups of human subjects, e.g., healthy, seizure and mania. Linear complexity measure suitable for multi-variate signals, along with nonlinear measures such as approximate entropy (ApEn) and Taken's estimator are considered. The degree of linear complexity is significantly reduced for the pathological groups compared with healthy group. The nonlinear measures of complexity are significantly decreased in the seizure group for most of the electrodes, whereas a distinct discrimination between the maniac and healthy groups based on these nonlinear measures is not evident.


Plasmonic digital PCR for discriminative detection of SARS-CoV-2 variants.
We developed a novel strategy for discriminative detection of SARS-CoV-2 variants based on the plasmonic photothermal effect of gold nanofilms and digital polymerase chain reaction (dPCR) technology. This method consists of the gold nanofilm-based dPCR chip fabrication for ultrafast heating and cooling cycles by the plasmonic photothermal effect, the LED quencher immobilization through the interfacing compound on the surface of the gold nanofilm to prevent photoquenching of PCR signaling dye, and the discriminative detection of the variant viruses from the COVID-19 clinical samples by photothermal cycles with fabricated dPCR chips and a portable plasmonic PCR device. Compared to conventional sequencing or RT-qPCR-based variant detection methods, this technology can be effectively applied to point-of-care testing by enabling ultrafast quantitative analysis with a small device. With this method, we successfully detected the delta variant and the omicron variant with a high sensitivity of 10 copies from COVID-19 patients' clinical samples within 25 min, including reverse transcription. This method can be applied universally to rapid and accurate point-of-care testing for various pandemic viruses as well as the coronavirus.


Toward a Tree-of-Life for the boas and pythons: multilocus species-level phylogeny with unprecedented taxon sampling.
Snakes in the families Boidae and Pythonidae constitute some of the most spectacular reptiles and comprise an enormous diversity of morphology, behavior, and ecology. While many species of boas and pythons are familiar, taxonomy and evolutionary relationships within these families remain contentious and fluid. A major effort in evolutionary and conservation biology is to assemble a comprehensive Tree-of-Life, or a macro-scale phylogenetic hypothesis, for all known life on Earth. No previously published study has produced a species-level molecular phylogeny for more than 61% of boa species or 65% of python species. Using both novel and previously published sequence data, we have produced a species-level phylogeny for 84.5% of boid species and 82.5% of pythonid species, contextualized within a larger phylogeny of henophidian snakes. We obtained new sequence data for three boid, one pythonid, and two tropidophiid taxa which have never previously been included in a molecular study, in addition to generating novel sequences for seven genes across an additional 12 taxa. We compiled an 11-gene dataset for 127 taxa, consisting of the mitochondrial genes CYTB, 12S, and 16S, and the nuclear genes bdnf, bmp2, c-mos, gpr35, rag1, ntf3, odc, and slc30a1, totaling up to 7561 base pairs per taxon. We analyzed this dataset using both maximum likelihood and Bayesian inference and recovered a well-supported phylogeny for these species. We found significant evidence of discordance between taxonomy and evolutionary relationships in the genera Tropidophis, Morelia, Liasis, and Leiopython, and we found support for elevating two previously suggested boid species. We suggest a revised taxonomy for the boas (13 genera, 58 species) and pythons (8 genera, 40 species), review relationships between our study and the many other molecular phylogenetic studies of henophidian snakes, and present a taxonomic database and alignment which may be easily used and built upon by other researchers.


Prevalence of intestinal helminths in Khuzestan, Southwest Iran, 1977.
Large scale studies were performed to determine the prevalence of various intestinal helminth infections in urban and rural areas of Khuzestan Province, southwest Iran. A total of 16,361 stool samples from people in 105 villages and 14 small towns were examined by the formalin-ether concentration method. Ascaris, hookworms, Trichostrongylus, Trichuris, and Hymenolepis nana showed the highest prevalence. Hookworms and Trichostrongylus were twice as prevalent in rural than in urban areas; in contrast, H. nana was more prevalent in urban areas while the level of Ascaris infections was not significantly different. The intensity of Ascaris and hookworm infections, as estimated by the number of eggs/g of feces, was higher in rural than in urban areas.


Review. The multiple roles of cultural transmission experiments in understanding human cultural evolution.
In this paper, we explore how experimental studies of cultural transmission in adult humans can address general questions regarding the 'who, what, when and how' of human cultural transmission, and consequently inform a theory of human cultural evolution. Three methods are discussed. The transmission chain method, in which information is passed along linear chains of participants, has been used to identify content biases in cultural transmission. These concern the kind of information that is transmitted. Several such candidate content biases have now emerged from the experimental literature. The replacement method, in which participants in groups are gradually replaced or moved across groups, has been used to study phenomena such as cumulative cultural evolution, cultural group selection and cultural innovation. The closed-group method, in which participants learn in groups with no replacement, has been used to explore issues such as who people choose to learn from and when they learn culturally as opposed to individually. A number of the studies reviewed here have received relatively little attention within their own disciplines, but we suggest that these, and future experimental studies of cultural transmission that build on them, can play an important role in a broader science of cultural evolution.


Molecular Mechanisms of Functional Adrenocortical Adenoma and Carcinoma: Genetic Characterization and Intracellular Signaling Pathway.
The adrenal cortex produces steroid hormones as adrenocortical hormones in the body, secreting mineralocorticoids, glucocorticoids, and adrenal androgens, which are all considered essential for life. Adrenocortical tumors harbor divergent hormonal activity, frequently with steroid excess, and disrupt homeostasis of the body. Aldosterone-producing adenomas (APAs) cause primary aldosteronism (PA), and cortisol-producing adenomas (CPAs) are the primary cause of Cushing's syndrome. In addition, adrenocortical carcinoma (ACC) is a highly malignant cancer harboring poor prognosis. Various genetic abnormalities have been reported, which are associated with possible pathogenesis by the alteration of intracellular signaling and activation of transcription factors. In particular, somatic mutations in APAs have been detected in genes encoding membrane proteins, especially ion channels, resulting in hypersecretion of aldosterone due to activation of intracellular calcium signaling. In addition, somatic mutations have been detected in those encoding cAMP-PKA signaling-related factors, resulting in hypersecretion of cortisol due to its driven status in CPAs. In ACC, mutations in tumor suppressor genes and Wnt-β-catenin signaling-related factors have been implicated in its pathogenesis. In this article, we review recent findings on the genetic characteristics and regulation of intracellular signaling and transcription factors in individual tumors.


Clinical Characteristics of Heart Failure from Case Reports Presented at the Regional Meeting of the Japanese Society of Internal Medicine.
Objective To examine case reports presented at the Regional Meeting of the Japanese Society of Internal Medicine in order to clarify the underlying disease and prognosis of heart failure, which is often caused by non-cardiovascular diseases. Methods We examined 49,693 case reports from the Japanese Society of Internal Medicine database. A total of 2,893 reports were included after excluding 46,022 reports that did not include the term "heart failure" and 778 reports with no indications of symptoms of heart failure. We assessed each patient's basal disease, and according to the abstracts, we reported their prognosis as dead or alive. Results Of the 2,893 reports included, 1,952 (67.5%) and 941 (32.5%) had cardiovascular and non-cardiovascular diseases as the causes, respectively; these cases were attributed to 725 different diseases, 196 (27.0%) and 529 (73.0%) of which were cardiovascular and non-cardiovascular diseases, respectively. In addition, 91 different side effects were identified. The percentage of cases of heart failure-related mortality was significantly higher among the patients with non-cardiovascular diseases than in those with cardiovascular diseases (17.8% vs. 10.8%; p <0.001). Of the diseases reported as causes of heart failure in more than 10 reports, pulmonary tumor thrombotic microangiopathy (87%), multiple myeloma (50%), and amyloidosis (47%) accounted for the highest percentages of heart failure-related mortality. Conclusion Because heart failure is often caused by non-cardiovascular diseases, a broad study of case reports on internal medicine is important for cardiologists.


[Treatment of erectile dysfunction in cases of venous and corporovenous insufficiency of phallus].
A total of 230 patients of different age with impaired venous drainage of penis cavernous bodies were examined. Test with intracavernous injection of papaverin, dopplerography of the vessels and cavernosometry were employed. To treat venous and corporovenous insufficiency, it is suggested to make a resection of the deep dorsal vein, ligation of the superficial and circular veins with suturing tunica albuginea. In negative result of the surgery viagra in a done 50 (100) mg is recommended or penile implants.


Visual Function, Organization, and Development of the Mouse Superior Colliculus.
The superior colliculus (SC) is the most prominent visual center in mice. Studies over the past decade have greatly advanced our understanding of the function, organization, and development of the mouse SC, which has rapidly become a popular model in vision research. These studies have described the diverse and cell-type-specific visual response properties in the mouse SC, revealed their laminar and topographic organizations, and linked the mouse SC and downstream pathways with visually guided behaviors. Here, we summarize these findings, compare them with the rich literature of SC studies in other species, and highlight important gaps and exciting future directions. Given its clear importance in mouse vision and the available modern neuroscience tools, the mouse SC holds great promise for understanding the cellular, circuit, and developmental mechanisms that underlie visual processing, sensorimotor transformation, and, ultimately, behavior.


Prenatal diagnosis: chances, choices.
Genetic counseling for prenatal diagnostic testing should provide accurate, unbiased, and value-sensitive information to women and their families, enabling them to make decisions most consistent with their personal values and circumstances.


Ionization of tyrosine and lysine residues in native and modified horse cytochrome c.
1H-n.m.r. and 13C-n.m.r. spectroscopy of horse cytochrome c and 1H-n.m.r. spectroscopy of the lysine-modified proteins N epsilon-acetimidyl-, N epsilon-amidino-, N epsilon-trifluoroacetyl- and N epsilon-maleyl-cytochrome c have shown that, although the lysine modifications do not greatly perturb the protein structure at pH7 and 27 degrees C, at higher temperature or at alkaline pH some parts of the structure are markedly perturbed. At pH7 and 27 degrees C the region of the protein about Ile-57 is affected in all the modified proteins, though not all to the same degree. N epsilon-Maleylation most seriously affects the protein structure, and the fully maleylated protein is readily unfolded. At 27 degrees C all four of the tyrosine residues of native horse cytochrome c have pKa values above 11, but in N epsilon-acetimidyl-cytochrome c the pKa of one tyrosine residue is 10.2.


In Trauma Patients, the Occurrence of Early-Onset Nosocomial Infections is Associated With Increased Plasma Concentrations of Chromogranin A.
In previously healthy persons suffering from acute illnesses, nosocomial infections (NIs) are frequent. Their prevalence suggests the existence of as yet unknown conditions that may promote care-related infection. This study assessed whether the measurement of plasma chromogranin A, a stress-related protein involved in innate defense, is related to NI risk, and whether any chromogranin A-derived fragment included in vasostatin-I displays immunosuppressive activities related to AP-1 or NF-kappa B downregulation. At the clinical level, trauma patients and healthy controls were recruited to be eligible. Clinical histories were recorded, and standard biological tests (including plasma chromogranin A) were performed. For 9 randomly chosen patients and 16 controls, the time-dependent concentrations of chromogranin A (CGA) were assessed twice a day over 66 h. The data show that trauma patients present a higher value of CGA concentration during 66 h in comparison with healthy controls. In addition, patients maintaining this significant increase in CGA readily develop NIs. We therefore studied the effects of chromogranin A-derived peptides on monocytes, focusing on transcription factors that play a central role in inflammation. In vitro assay demonstrated that a chromogranin A-derived fragment (CGA47-70) displays a significant inhibition of NF-kappa B and AP-1 transcriptional activities in these cells. In conclusion, the occurrence of NI in trauma patients is associated with significantly increased plasma CGA concentrations. Downregulation of the two transcription factors by CGA47-70 might induce early acquired immune defect after a serious medical stress.


[Evaluation of radionuclide impurities in several radiopharmaceuticals].
Revisions to German radiation protection laws have resulted in updated limit values, which could affect the unrestricted release of waste produced by nuclear medicine therapy. In addition, signs of long-lived concomitant nuclides in 153Sm and 223Ra radiopharmaceuticals have been seen in the past. Therefore, the goal of this article was to analyze the radionuclidic purity of selected radiopharmaceuticals. 48 samples from 12 different radiopharmaceuticals were examined. A high purity germanium semiconductor detector (HPGe detector) was used for the qualitative and quantitative evaluation of concomitant nuclides. Various europium isotopes were identified in 90Y-citrate, 153Sm-Quadramet, 166Ho-QuiremSpheres, and 169Er-erbium citrate, with the greatest amount being found in 153Sm (7.0 ppm (152Eu), 8.4 ppm (154Eu), and 2.1 ppm (155Eu)). 169Yb was the most significant impurity in 169Er (513 ppm). In the case of 177Lu radiopharmaceuticals, there was a significant difference in the 177mLu content (0.8 ppm vs. 0.0024 ppm) between two different manufacturers. No concomitant nuclides could be found within the detection limits in the case of 90Y spheres, 223Ra, and 225Ac. The limit values for unrestricted release are exceeded manyfold in the case of the identified concomitant nuclides. As a result, alternative release procedures (extension of the decay time, specific release, release in the individual case) or transfer to collection facilities must be considered. Technical methods for reducing or preventing impurities could also be a possible solution. Consequences for patient radiation exposure were able to be ruled out.


Renal tubular apoptosis after complete ureteral obstruction in the presence of hyperoxaluria.
Hyperoxaluria is a well-known cause of renal stone disease and in vitro studies have shown that oxalate crystals have a stimulatory effect on apoptosis of renal tubular epithelial cells. Total and partial ureteral obstruction also have an accelerating effect on apoptosis of renal tubular epithelial cells. The aim of the present study was to investigate the apoptotic effect of unilateral ureteral obstruction in the presence of hyperoxaluria on the rat kidney. Twenty-eight male Wistar rats were divided into four groups, with seven rats in each. The groups were named G1 (control), G2 (hyperoxaluric), G3 (obstructive) and G4 (hyperoxaluric + obstructive). G2 and G4 rats were given 1% ethylene glycol (a precursor for oxalates) in their drinking water. G1 and G2 rats underwent sham operation, while left proximal ureteral ligation with a 5-zero silk suture was performed on G3 and G4 animals. The rats were sacrificed 2 weeks after the operation; left nephrectomy was then performed. We searched for the apoptotic cells by direct immuno-peroxidase detection of digoxigenin-labeled genomic DNA. The mean +/- SD values of the apoptotic cell count was 0.86+/-0.90 in G1 and 4.33+/-3.81 in G2. The values for G3 and G4 were 30.17+/-16.85 and 302.67+/-184.45, respectively. We found a statistically significant difference between all groups (P < 0.001). When compared with the control group (G1), the mean apoptotic cell count was fivefold that of G2 and 35- and 351-fold those of G3 and G4, respectively. Our study demonstrated that hyperoxaluria with complete ureteral obstruction induces an excessive level of apoptosis, which is responsible for renal damage, and that ureteral obstruction is a more important factor for apoptosis than hyperoxaluria. Considering these data, we also believe that research studies for medical preventive measures must be considered for patients with ureteral obstruction and/or hyperoxaluria.


Duration of acute exposures to vibration and finger circulation.
This study investigated changes in finger circulation after different durations of exposure to hand-transmitted vibration. Finger skin temperature (FST), finger blood flow (FBF), and finger systolic blood pressure (FSBP) were measured in the middle fingers of both hands of 10 healthy men. Finger vascular resistance was also estimated. The right hand was exposed for 7.5, 15, and 30 minutes (static load 10 N) to 125-Hz vibration (root-mean-square acceleration 87 m/s2). Static load only was used as a control. Finger circulation was measured before the vibration and static load exposure and at fixed intervals during exposure and a 45-minute recovery period. No significant changes were found with the static load. The FST and FSBP did not change significantly during vibration exposure, whereas vibration produced significant reductions in FBF and increases in vascular resistance at each duration when compared with preexposure and contralateral (non-vibrated) finger values. Temporary vasodilation occurred in the vibrated finger immediately after each vibration exposure. Recovery was complete for FBF and vascular resistance after the 7.5-minute vibration, whereas a progressive FBF reduction occurred in both the vibrated and the nonvibrated fingers after 15- and 30-minute exposure. The longer the duration of vibration exposure, the stronger the vasoconstriction in the vibrated finger during recovery. Vasoregulatory mechanisms mediated by both intrinsic (local) and extrinsic (neural or endocrine) control systems seem to be related to digital circulatory changes during 125-Hz vibration. It is concluded that, not only the frequency and magnitude of vibration, but also its duration contributes to the reaction of the digital vessels to acute vibration.


Inflammatory Stroma of Lymphoepithelioma-like Carcinoma of the Cervix: Immunohistochemical Study of 3 Cases and Review of the Literature.
The aim of this study was to characterize the inflammatory infiltrate of the lymphoepithelioma-like carcinoma, a variant of squamous cell carcinoma clinically associated with a good prognosis. Immunohistochemistry was used to characterize 3 cases of lymphoepithelioma-like carcinoma in the uterine cervix, diagnosed over a period of 3 yr. The patients were between 30 and 50 yr old. Their cervical smears had shown atypical squamous cells of unknown significance or high-grade squamous intraepithelial lesions, and the initial cervical biopsy showed high-grade cervical intraepithelial neoplasia (CIN3) or squamous cell carcinoma. All patients underwent a Wertheim operation, 2 of which were preceded by a cervicectomy. Microscopically, all tumors were characterized by poorly defined sheets of undifferentiated squamous cells with a syncytial pattern and a dense background of infiltrating lymphocytes. Immunohistochemical analysis revealed that the lymphocytes were predominantly CD3 and CD8 T cells. The tumor lobules contained isolated CD8 T cells, whereas CD4 T cells and CD20 B cells surrounded the tumor lobules. CD56 NK cells and CD79 B cells were scattered in the tumor tissue. An in situ hybridization staining for Epstein-Barr encoding region was negative but all cases were immunohistochemically positive for P16. Follow-up varied between 2 mo and 2.7 yr. All 3 patients were disease free. Lymphoepithelioma-like carcinoma of the uterine cervix is a variant of squamous cell carcinoma, known for its better prognosis. The good prognosis of this tumor is potentially explained by the high levels of infiltrating CD8 T cells.


Implementation of community-acquired pneumonia guidelines at a public hospital in Brazil.
To implement community-acquired pneumonia (CAP) guidelines at a public hospital in Brazil and to evaluate the impact of these guidelines on health care quality. A quasi-experimental study, with a before-and-after design, involving adult patients diagnosed with CAP and hospitalized between July of 2007 and October of 2008 in the general ward of the Marília School of Medicine Hospital das Clínicas, located in the city of Marília, Brazil. During the study period, 68 patients were diagnosed with CAP: 48 before the implementation of the guidelines and 20 after their implementation. After the implementation of the guidelines, 85% of the cases were treated in accordance with the guidelines, and there was a significant increase in the use of antibiotic therapy for atypical bacteria in patients with severe CAP (6.3% vs. 75.0%; p < 0.001). Comparing the pre-implementation and post-implementation periods, we observed a trend toward a decrease in the mortality (35.4% vs. 15.0%; p = 0.09) and toward an increase in the recording of SpO₂ in the medical charts of the patients (18% vs. 30%; p = 0.42). During the study period, the degree of severity was not recorded on the medical charts of most patients. In addition, the initiation of antibiotic therapy followed a pre-established schedule, regardless of the severity of the infection. This study showed that, although the development and implementation of CAP guidelines promoted the optimization of the treatment, there were no significant differences regarding the assessment of severity, SpO₂ recording, or the initiation of antibiotic therapy. Therefore, strategies that are more effective are needed in order to modify variables related to the work of physicians and nurses.


Out-of-equilibrium characteristics of a forced translocating chain through a nanopore.
Polymer translocation through a nanopore in a thin membrane is studied using a coarse-grained bead-spring model and Langevin dynamics simulation with a particular emphasis to explore out of equilibrium characteristics of the translocating chain. We analyze the out of equilibrium chain conformations both at the cis and the trans side separately either as a function of the time during the translocation process or as as function of the monomer index m inside the pore. A detailed picture of translocation emerges by monitoring the center of mass of the translocating chain, longitudinal and transverse components of the gyration radii and the end to end vector. We observe that polymer configurations at the cis side are distinctly different from those at the trans side. During the translocation and immediately afterwards, the chain is clearly out of equilibrium, as different parts of the chain are characterized by a series of effective Flory exponents. We further notice that immediately after the translocation the last set of beads that have just translocated take a relatively compact structure compared to the first set of beads that translocated earlier and the chain immediately after translocation is described by an effective Flory exponent 0.45+/-0.01. The analysis of these results is further strengthened by looking at the conformations of chain segments of equal length as they cross from the cis to the trans side, We discuss implications of these results to the theoretical estimates and numerical simulation studies of the translocation exponent reported by various groups.


Electron Transfer Assisted by Vibronic Coupling from Multiple Modes.
Understanding the effect of vibronic coupling on electron transfer (ET) rates is a challenge common to a wide range of applications, from electrochemical synthesis and catalysis to biochemical reactions and solar energy conversion. The Marcus-Jortner-Levich (MJL) theory offers a model of ET rates based on a simple analytic expression with a few adjustable parameters. However, the MJL equation in conjunction with density functional theory (DFT) has yet to be established as a predictive first-principles methodology. A framework is presented for calculating transfer rates modulated by molecular vibrations, that circumvents the steep computational cost which has previously necessitated approximations such as condensing the vibrational manifold into a single empirical frequency. Our DFT-MJL approach provides robust and accurate predictions of ET rates spanning over 4 orders of magnitude in the 106-1010 s-1 range. We evaluate the full MJL equation with a Monte Carlo sampling of the entire active space of thermally accessible vibrational modes, while using no empirical parameters. The contribution to the rate of individual modes is illustrated, providing insight into the interplay between vibrational degrees of freedom and changes in electronic state. The reported findings are valuable for understanding ET rates modulated by multiple vibrational modes, relevant to a broad range of systems within the chemical sciences.


New evidence for the inhibition by harringtonine in the formation of the first peptide bond in protein synthesis.
New evidence for the inhibition by harringtonine in the formation of the first peptide bond in protein synthesis was obtained by means of experiments in the cell-free system. The antitumour drug strongly blocked dipeptide synthesis in the system without elongation factor G and GTP. Furthermore, it inhibited N-Acetyl-phenylalanyl-puromycin formation from N-Acetyl-phenylalanyl-tRNA, puromycin, and ribosomes.


The novel heterocyclic trioxirane [(1,3,5-tris oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione (TATT)] exhibits a better anticancer effect than platinum-based chemotherapy by induction of apoptosis and curcumin further enhances its chemosensitivity.
The heterocyclic trioxirane compound [1,3,5-tris((oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione (TATT)] is a synthetic compound which has been used as an experimental anticancer agent in human clinical trials. Curcumin, an active natural compound in turmeric and curry, is an ingredient commonly used in the traditional diet of many Asian countries. In the present study, we observed that TATT exhibited a better anticancer effect on chemoresistant human colorectal cancer HT-29 cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with FDA-approved anticancer drugs (cisplatin, carboplatin, or oxaliplatin) using MTT assay. TATT also induced a stronger apoptotic effect than that seen with the three studied anticancer drugs, as characterized by externalization of phosphatidylserine using flow cytometry. Administration of caspase 8-specific inhibitor (z-IETD-fmk) and mitochondrial permeability transition pore inhibitor (cyclosporin A) demonstrated that TATT-induced apoptosis proceeded via both extrinsic and intrinsic signaling pathways. It is noteworthy that coadministration of curcumin further significantly increased TATT-induced cytotoxicity, externalization of phosphatidylserine (representing early apoptosis), and the percentages of cells at the sub-G1 phase (representing late apoptosis), producing an additivity and/or synergistic effect, and vice versa. Suppression of nuclear NF-κB was involved in curcumin-enhanced chemosensitivity of TATT. Overall, our data indicate that TATT exerts a chemotherapeutic effect on colorectal cancer cells and coadministration of curcumin enhances the treatment effect of TATT.


Identification of specific BRCA1 and BRCA2 variants by DHPLC.
Denaturing high performance liquid chromatography (DHPLC) is generating increasing interest in clinical genetics as a reliable tool for the analysis of genetic alterations. In the work presented here our intentions were to optimize primer design and DHPLC analysis conditions for a qualitative detection of BRCA1 and BRCA2 variations. The BRCA1 and BRAC2 genes display a high proportion of polymorphisms. Sequencing efforts geared towards the distinction of tumor-related mutations and benign variants still remain time-consuming and expensive. DHPLC elution profiles, however, permit the correlation of a characteristic chromatographic profile with a specific sequence alteration. In this study we evaluate the sensitivity of DHPLC for the identification of unique polymorphisms, which are frequent in the Caucasian population, in lieu of sequence analysis. The complete BRCA1 gene and parts of BRCA2 were examined. In the case of BRCA1, 431 out of 432 heterozygotes were identified correctly. In addition, 18 new profiles were identified which had not been detected previously in our studies and which represented new mutations or rare polymorphisms. For BRCA2, 135 out of 137 simple sequence variants were classified correctly. In addition, six new profiles were identified which represented new mutations or rare polymorphisms.


Quantitative Analysis of Operating Room Inventory Management Practices at a Tertiary Cancer Center.
In Ontario, health care spending has grown to 45% of total government expenditures. In a public health care system, changes in demographics and the emergence of innovative technologies challenge our ability to adapt to evolving patient needs. To maintain a high standard of clinical effectiveness, there is a need to identify opportunities to improve health care delivery. This study was structured to meet the following objectives: to understand the operating room (OR) inventory practices at a tertiary academic hospital, to mathematically model this process to ascertain service levels based on changes in inventory and demand, and to define the appropriate level of reusable inventory for open and laparoscopic colorectal surgery. We retrospectively reviewed OR throughput for all cases of colorectal cancer from January 1, 2010, to January 31, 2011. The process flow of OR instrumentation was studied to understand delays in the provision of inventory. Combining total surgeries performed with surgeon-specific instrument preferences generated daily instrument demand. We fitted parametric demand distributions for two instrument sets for major colon resections. Markovian models were used to estimate the distribution of available inventory and the likelihood of insufficient instruments on any given day. We reviewed 1,458 cases, 39.5% of which involved major open surgery, whereas 26.2% involved laparoscopic surgery. Demand for open and laparoscopic instrument sets was observed to fit binomial (20, 0.15) and Poisson (1.41) distributions, respectively. On the basis of these curves, we estimated the probability distribution of the in-stock inventory and, subsequently, the probability that demand would exceed supply on any given day ( Table 1 ). In particular, with 10 open and six laparoscopic sets currently owned by the institution, the probabilities that there would be insufficient inventory were 3.02% and 2.17%, respectively. [Table: see text] Conclusion: This analysis will guide purchasing decisions based on desired service levels and forecasted changes in demand. Furthermore, by ensuring that demand is being serviced, this analysis will help to curb loss of revenue, decrease wait times, and limit potential patient morbidity. Strategic purchasing can also reduce excessive inventory and therefore minimize shrinkage and obsolescence and increase working capital and institutional flexibility.


Neuronal degeneration and gliosis time-course in the mouse hippocampal formation after pilocarpine-induced status epilepticus.
Temporal lobe epilepsy (TLE) is the most common type of human epilepsy and has been related with extensive loss of hippocampal pyramidal and dentate hilar neurons and gliosis. Many characteristics of TLE are reproduced in the pilocarpine model of epilepsy in mice. This study analyzed the neuronal damage, assessed with Fluoro-Jade (FJB) and cresyl violet, and gliosis, investigated with glial fibrilary acidic protein (GFAP) immunohistochemistry, occurring in the hippocampal formation of mice at 3, 6, 12 and 24h, 1 and 3 weeks after the pilocarpine-induced status-epilepticus (SE) onset. The maximum neuronal damage score and the FJB-positive neurons peak were found in the hilus of dentate gyrus 3 and 12 h after SE onset (P<0.05), respectively. At 1 week after SE onset, the greatest neuronal damage score was detected in the CA1 pyramidal cell layer and the greatest numbers of FJB-positive neurons were found both in the CA1 and CA3 pyramidal cell layers (P<0.05). The molecular, CA3 and CA1 pyramidal cell layers expressed highest presence of GFAP immunoreaction at 1 and 3 weeks after SE onset (P<0.05). Our findings show that, depending on the affected area, neuronal death and gliosis can occur within few hours or weeks after SE onset. Our results corroborate previous studies and characterize short time points of temporal evolution of neuropathological changes after the onset of pilocarpine-induced SE in mice and evidences that additional studies of this temporal evolution may be useful to the comprehension of the cellular mechanisms underlying epileptogenesis.


Nosocomial sinusitis.
During a 24-month period, 34 cases of nosocomial sinusitis associated with nasopharyngeal instrumentation were identified in 32 severely traumatized patients, accounting for 5% of all nosocomial infections. Diagnosis was based on roentgenographic findings consistent with acute sinusitis and either purulent material aspirated from the involved sinus or purulent nasal discharge. All patients had fever and most had leukocytosis. Forty-one pathogens, mostly Gram-negative bacilli, were recovered from 25 patients by aspiration of their sinuses; 14 infections were polymicrobic. Possible predisposing factors were nasotracheal tubes, nasogastric tubes, nasal packing, high-dose corticosteroids, prior antibiotic therapy, and facial and cranial fractures. With treatment and removal of the nasal tube, 20 patients had clinical resolution of their disease. Seven, although asymptomatic, had persistent radiological abnormalities consistent with chronic sinusitis. Five patients died of intercurrent disease before resolution of their sinusitis. Sinusitis should be ruled out as a cause of infection in febrile intensive care patients with an indwelling nasal tube.


Metagenomic-based surveillance systems for antibiotic resistance in non-clinical settings.
The success of antibiotics as a therapeutic agent has led to their ineffectiveness. The continuous use and misuse in clinical and non-clinical areas have led to the emergence and spread of antibiotic-resistant bacteria and its genetic determinants. This is a multi-dimensional problem that has now become a global health crisis. Antibiotic resistance research has primarily focused on the clinical healthcare sectors while overlooking the non-clinical sectors. The increasing antibiotic usage in the environment - including animals, plants, soil, and water - are drivers of antibiotic resistance and function as a transmission route for antibiotic resistant pathogens and is a source for resistance genes. These natural compartments are interconnected with each other and humans, allowing the spread of antibiotic resistance via horizontal gene transfer between commensal and pathogenic bacteria. Identifying and understanding genetic exchange within and between natural compartments can provide insight into the transmission, dissemination, and emergence mechanisms. The development of high-throughput DNA sequencing technologies has made antibiotic resistance research more accessible and feasible. In particular, the combination of metagenomics and powerful bioinformatic tools and platforms have facilitated the identification of microbial communities and has allowed access to genomic data by bypassing the need for isolating and culturing microorganisms. This review aimed to reflect on the different sequencing techniques, metagenomic approaches, and bioinformatics tools and pipelines with their respective advantages and limitations for antibiotic resistance research. These approaches can provide insight into resistance mechanisms, the microbial population, emerging pathogens, resistance genes, and their dissemination. This information can influence policies, develop preventative measures and alleviate the burden caused by antibiotic resistance.


Challenges in updating habitat suitability models: An example with the lesser prairie-chicken.
Habitat loss from land-use change is one of the top causes of declines in wildlife species of concern. As such, it is critical to assess and reassess habitat suitability as land cover and anthropogenic features change for both monitoring and developing current information to inform management decisions. However, there are obstacles that must be overcome to develop consistent assessments through time. A range-wide lek habitat suitability model for the lesser prairie-chicken (Tympanuchus pallidicinctus), currently under review by the U. S. Fish and Wildlife Service for potential listing under the Endangered Species Act, was published in 2016. This model was based on lek data from 2002 to 2012, land cover data ranging from 2001 to 2013, and anthropogenic features from circa 2011, and has been used to help guide lesser prairie-chicken management and anthropogenic development actions. We created a second iteration model based on new lek surveys (2015 to 2019) and updated predictors (2016 land cover and cleaned/updated anthropogenic data) to evaluate changes in lek suitability and to quantify current range-wide habitat suitability. Only three of 11 predictor variables were directly comparable between the iterations, making it difficult to directly assess what predicted changes resulted from changes in model inputs versus actual landscape change. The second iteration model showed a similar positive relationship with land cover and negative relationship with anthropogenic features to the first iteration, but exhibited more variation among candidate models. Range-wide, more suitable habitat was predicted in the second iteration. The Shinnery Oak Ecoregion, however, exhibited a loss in predicted suitable habitat that could be due to predictor source changes. Iterated models such as this are important to ensure current information is being used in conservation and development decisions.


Elucidating the constitutive relationship of calcium-silicate-hydrate gel using high throughput reactive molecular simulations and machine learning.
Prediction of material behavior using machine learning (ML) requires consistent, accurate, and, representative large data for training. However, such consistent and reliable experimental datasets are not always available for materials. To address this challenge, we synergistically integrate ML with high-throughput reactive molecular dynamics (MD) simulations to elucidate the constitutive relationship of calcium-silicate-hydrate (C-S-H) gel-the primary binding phase in concrete formed via the hydration of ordinary portland cement. Specifically, a highly consistent dataset on the nine elastic constants of more than 300 compositions of C-S-H gel is developed using high-throughput reactive simulations. From a comparative analysis of various ML algorithms including neural networks (NN) and Gaussian process (GP), we observe that NN provides excellent predictions. To interpret the predicted results from NN, we employ SHapley Additive exPlanations (SHAP), which reveals that the influence of silicate network on all the elastic constants of C-S-H is significantly higher than that of water and CaO content. Additionally, the water content is found to have a more prominent influence on the shear components than the normal components along the direction of the interlayer spaces within C-S-H. This result suggests that the in-plane elastic response is controlled by water molecules whereas the transverse response is mainly governed by the silicate network. Overall, by seamlessly integrating MD simulations with ML, this paper can be used as a starting point toward accelerated optimization of C-S-H nanostructures to design efficient cementitious binders with targeted properties.


Interferon regulatory factor 6 differentially regulates Toll-like receptor 2-dependent chemokine gene expression in epithelial cells.
Epidermal and mucosal epithelial cells are integral to host defense. They not only act as a physical barrier but also utilize pattern recognition receptors, such as the Toll-like receptors (TLRs), to detect and respond to pathogens. Members of the interferon regulatory factor (IRF) family of transcription factors are key components of TLR signaling as they impart specificity to downstream responses. Although IRF6 is a critical regulator of epithelial cell proliferation and differentiation, its role in TLR signaling has not previously been addressed. We show here that IRF6 is activated by IRAK1 as well as by MyD88 but not by TRIF or TBK1. Co-immunoprecipitation experiments further demonstrated that IRF6 can interact with IRAK1. Gene silencing in epithelial cells along with gene promoter reporter assays showed that IRAK1 mediates TLR2-inducible CCL5 gene expression at least in part by promoting IRF6 activation. Conversely, IRAK1 regulated CXCL8 gene expression independently of IRF6, thus identifying a molecular mechanism by which TLR2 signaling differentially regulates the expression of specific chemokines in epithelial cells. Bioinformatics analysis and mutagenesis-based experiments identified Ser-413 and Ser-424 as key regulatory sites in IRF6. Phosphomimetic mutation of these residues resulted in greatly enhanced IRF6 dimerization and trans-activator function. Collectively, our findings suggest that, in addition to its importance for epithelial barrier function, IRF6 also contributes to host defense by providing specificity to the regulation of inflammatory chemokine expression by TLR2 in epithelial cells.


Successful implementation of evidence-based routines in Ukrainian maternities.
To describe the process of change and assess compliance and effect on maternal and infant outcome when the WHO package Effective Perinatal Care (EPC) was implemented at maternities in Ukraine. Intervention study comparing outcomes before and during 2.5 years after training. Three maternities in Donetsk, Lutsk and Lviv 2003-2006. Baseline data were collected for 652, 742 and 302 deliveries and 420, 381 and 135 infants, respectively, in Donetsk, Lutsk and Lviv. Follow-up data included 4,561, 9,865 and 7,227 deliveries and 3,829, 8,658 and 6,401 infants. Staff training on evidence-based guideline. Interventions during labor, maternal outcomes and hypothermia in the infants. EPC procedures were successfully implemented and adherence to the protocols was excellent. For most variables, the change occurred during the first three months but was well sustained. The use of partogram increased fourfold in Donetsk and from 0% to 60% in Lviv. Induction and augmentation of labor decreased to less than 1% and less than 5%, respectively. Cesarean section rate dropped significantly in two of the maternities. The proportion of hypothermic infants decreased from 60% (Donetsk), 85% (Lutsk) and 77% (Lviv) to 1% in all three maternities during the first three months and was stable throughout the study period. Admission to Neonatal Intensive Care Unit decreased significantly in two of the maternities and there was no effect on early neonatal mortality. The process of education and change was well anchored in the organization, and implementation of new procedures was quick and successful.


Phylogenetic ecology of the freshwater Actinobacteria acI lineage.
The acI lineage of freshwater Actinobacteria is a cosmopolitan and often numerically dominant member of lake bacterial communities. We conducted a survey of acI 16S rRNA genes and 16S-23S rRNA internal transcribed spacer regions from 18 Wisconsin lakes and used standard nonphylogenetic and phylogenetic statistical approaches to investigate the factors that determine acI community composition at the local scale (within lakes) and at the regional scale (across lakes). Phylogenetic reconstruction of 434 acI 16S rRNA genes revealed a well-defined and highly resolved phylogeny. Eleven previously unrecognized monophyletic clades, each with > or =97.9% within-clade 16S rRNA gene sequence identity, were identified. Clade community similarity positively correlated with lake environmental similarity but not with geographic distance, implying that the lakes represent a single biotic region containing environmental filters for communities that have similar compositions. Phylogenetically disparate clades within the acI lineage were most abundant at the regional scale, and local communities were comprised of more closely related clades. Lake pH was a strong predictor of the community composition, but only when lakes with a pH below 6 were included in the data set. In the remaining lakes (pH above 6) biogeographic patterns in the landscape were instead a predictor of the observed acI community structure. The nonrandom distribution of the newly defined acI clades suggests potential ecophysiological differences between the clades, with acI clades AI, BII, and BIII preferring acidic lakes and acI clades AII, AVI, and BI preferring more alkaline lakes.


Effective Communication of Health Messages regarding Noise-Induced Health Effects.
Noise exposure in both residential and occupational settings produces a range of auditory and nonauditory health problems. Efforts of the relevant authorities to reduce these effects may be supplemented by the adoption of various self-protective behaviours by individuals. Unfortunately campaigns designed to encourage such self-protective behaviours are likely to meet with limited success. The present paper considers the shortcomings of such campaigns and offers prescriptions for improving them. Campaigns based on these prescriptions and on thorough research of the factors involved in health promotion generally, as well as those particular to each case, should significantly advance efforts toward individuals protecting themselves against the ill effects of noise exposure.


Biosynthesis of Trypanosoma brucei variant surface glycoproteins. N-glycosylation and addition of a phosphatidylinositol membrane anchor.
The variant surface glycoproteins (VSGs) of Trypanosoma brucei are synthesized with a hydrophobic COOH-terminal peptide that is cleaved and replaced by a glycophospholipid, which anchors VSG to the surface membrane. The kinetics of VSG processing were studied by metabolic labeling with [35S]methionine and [3H]myristic acid. The COOH-terminal oligosaccharide-containing structure remaining after phospholipase removal of dimyristyl glycerol from membrane-form VSG could be detected serologically within 1 min of polypeptide synthesis in two T. brucei variants studied. Addition of the oligosaccharide-containing structure was resistant to tunicamycin. VSGs synthesized in the presence of tunicamycin displayed lower apparent molecular weights, consistent with the complete inhibition of N-glycosylation at one (variant 117), two (variant 221), or at least three (variant 118) internal asparagine sites. In most experiments, N-glycosylation appeared to occur during or immediately after polypeptide synthesis but in a few cases N-glycosylation was delayed or incomplete. In all cases, addition of the COOH-terminal oligosaccharide-containing structure occurred normally. In dual-labeling studies, cycloheximide caused rapid inhibition of both [35S]methionine and [3H]myristic acid incorporation, suggesting that myristic acid addition also occurs immediately after polypeptide synthesis. Our data suggest that the complex ethanolamine-glycosyl-dimyristylphosphatidylinositol structure of membrane-form VSG is added en bloc within 1 min of completion of the polypeptide.


Erythromycin therapy for streptococcal pharyngitis.
Streptococcal eradication rates of 86% were demonstrated in 97 patients seen on day 14 and in 73 patients seen on both days 14 and 28 after a ten-day course of erythromycin estolate therapy given at a dosage of 20 mg/kg/day, administered in two equal doses. The efficacy of this regimen compares favorably with other results in which this and other erythromycin preparations have been employed at higher doses, usually in the range of 30 to 50 mg/kg/day. Our reported effectiveness at a lower than usual dose of erythromycin is probably explained by the following factors: the known susceptibility of group A streptococci to low concentrations of erythromycin, the uniform absorption of the estolate formulation of erythromycin, and adequate compliance in adhering to the treatment regimen by the majority of our patients. This dosage schedule of erythromycin is simple to administer; and a reduction by half of the total dose usually recommended provides an economical advantage for patients.


Developmental Adaptation to Stress: An Evolutionary Perspective.
The assumption that early stress leads to dysregulation and impairment is widespread in developmental science and informs prevailing models (e.g., toxic stress). An alternative evolutionary-developmental approach, which complements the standard emphasis on dysregulation, proposes that early stress may prompt the development of costly but adaptive strategies that promote survival and reproduction under adverse conditions. In this review, we survey this growing theoretical and empirical literature, highlighting recent developments and outstanding questions. We review concepts of adaptive plasticity and conditional adaptation, introduce the life history framework and the adaptive calibration model, and consider how physiological stress response systems and related neuroendocrine processes may function as plasticity mechanisms. We then address the evolution of individual differences in susceptibility to the environment, which engenders systematic person-environment interactions in the effects of stress on development. Finally, we discuss stress-mediated regulation of pubertal development as a case study of how an evolutionary-developmental approach can foster theoretical integration.


ERK hyperactivation serves as a unified mechanism of escape in intrinsic and acquired CDK4/6 inhibitor resistance in acral lentiginous melanoma.
Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in >60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression serve as a mechanism of intrinsic early/adaptive CDK4i/6i resistance. ALM cells that have acquired CDK4i/6i resistance following chronic treatment exposure also exhibit hyperactivation of the MAPK pathway. MEK and/or ERK inhibition increases CDK4i/6i efficacy against therapy naïve and CDK4i/6i-resistant AM cells in xenograft and patient-derived xenograft (PDX) models and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach for patients with metastatic ALM to improve outcomes.


Coxiella burnetii glycomics and proteomics--tools for linking structure to function.
Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular bacterium and a highly infectious pathogen. The disease is a widespread zoonosis and is endemic throughout the world. An easy aerosol dissemination, environmental persistence, and high infectivity make the bacterium a serious threat for humans and animals. Lipopolysaccharide is considered one of the major factors of virulence expression and infection of the bacterium. Detailed glycomic studies enabled to better understand structural and functional peculiarities of this biopolymer and its role in pathogenesis and immunity of Q fever. Recent proteomic studies of C. burnetii have brought new approaches in accurate detection of the infectious agent and offered new insights into the inter- or intra-species relatedness. Thus, structure/function relationship studies are currently of utmost importance in the field. This paper will focus on glycomic and proteomic approaches providing information on unique glycan and protein species of the microorganism as the candidate molecules for the use in detection/diagnosis, therapy, and prophylaxis.


Endovascular repair after stent elephant trunk procedure for extensive thoracic aortic aneurysm.
Hybrid surgical-endovascular procedure was conducted in a 46-year-old male with extensive thoracic aortic aneurysm. Ascending aorta and arch replacement combined with stent elephant trunk implantation was performed first. An open stent-graft was implanted into the descending aorta. One month later, endovascular repair was conducted. Postoperative CTA showed total coverage of the descending aorta by stent-grafts and the descending aortic aneurysm was totally thrombo-excluded. Stent elephant trunk may be a better alternative to conventional elephant trunk in hybrid surgical-endovascular approaches in treatment of extensive thoracic aortic aneurysm.


Amphotericin B colloidal dispersion for treatment of candidemia in immunocompromised patients.
The efficacy and safety of amphotericin B colloidal dispersion (ABCD; Amphotec, Sequus Pharmaceuticals, Menlo Park, CA), a lipid complex of amphotericin B, were evaluated in immunocompromised patients with candidemia. These patients were recruited from five open-label clinical trials of ABCD therapy for fungal infections subsequent to bone marrow transplantation, hematologic malignancies, solid tumors, solid-organ transplantation, or other severe underlying disorders. ABCD was given intravenously in a median daily dose of 3.9 mg/kg for < or =72 days. Response rates were as follows: 53% overall (n = 88), 66% for patients with candidemia alone (n = 67), and 14% for patients with disseminated candidemia (n = 21). Nephrotoxicity occurred in 16% of patients, with either doubling of the baseline serum creatinine level or an increase of > or =1 mg/dL or a > or =50% decrease in calculated creatinine clearance. On average, there were no significant changes in the levels of serum creatinine or bilirubin from baseline to the end of treatment. In conclusion, ABCD was safe and effective for treating immunocompromised patients with candidemia.


Animal density and track counts: understanding the nature of observations based on animal movements.
Counting animals to estimate their population sizes is often essential for their management and conservation. Since practitioners frequently rely on indirect observations of animals, it is important to better understand the relationship between such indirect indices and animal abundance. The Formozov-Malyshev-Pereleshin (FMP) formula provides a theoretical foundation for understanding the relationship between animal track counts and the true density of species. Although this analytical method potentially has universal applicability wherever animals are readily detectable by their tracks, it has long been unique to Russia and remains widely underappreciated. In this paper, we provide a test of the FMP formula by isolating the influence of animal travel path tortuosity (i.e., convolutedness) on track counts. We employed simulations using virtual and empirical data, in addition to a field test comparing FMP estimates with independent estimates from line transect distance sampling. We verify that track counts (total intersections between animals and transects) are determined entirely by density and daily movement distances. Hence, the FMP estimator is theoretically robust against potential biases from specific shapes or patterns of animal movement paths if transects are randomly situated with respect to those movements (i.e., the transects do not influence animals' movements). However, detectability (the detection probability of individual animals) is not determined simply by daily travel distance but also by tortuosity, so ensuring that all intersections with transects are counted regardless of the number of individual animals that made them becomes critical for an accurate density estimate. Additionally, although tortuosity has no bearing on mean track encounter rates, it does affect encounter rate variance and therefore estimate precision. We discuss how these fundamental principles made explicit by the FMP formula have widespread implications for methods of assessing animal abundance that rely on indirect observations.


Parent-of-origin effects on glucose homeostasis in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a highly heritable complex trait. Parents of affected women have reproductive and metabolic phenotypes. We tested the hypothesis that there are parental effects on the heritability of fasting dysglycemia in women with PCOS. This was a cross-sectional study at an academic medical center. PARTICIPANTS included 367 women with PCOS and their parents (1101 total subjects). We compared maternal and paternal contributions to heritability of fasting dysglycemia and to transmission of the PCOS susceptibility allele of D19S884 within the fibrillin-3 gene (D19S884-A8) on fasting dysglycemia. Fathers had higher fasting glucose levels, prevalence of fasting dysglycemia and proinsulin to insulin molar ratios (P < .0001), a marker of defective insulin processing, compared with mothers. Heritability of fasting dysglycemia was significant in PCOS families (h(2) = 37%, SE = 10%, P = .001). Maternal heritability (h(2) = 51%, SE = 15%, P = .0009) was higher than paternal heritability (h(2) = 23 %, SE = 23%, P = .186) of fasting dysglycemia after adjustment for age and body mass index. Within dysglycemic probands, there was increased maternal compared with paternal transmission of D19S884-A8 (maternal 84% vs paternal 45%, χ(2) = 6.51, P = .011). There was a sex difference in the parental metabolic phenotype with fathers having an increased risk of fasting dysglycemia and evidence for pancreatic β-cell dysfunction compared with mothers. However, only maternal heritability had significant effects on the prevalence of fasting dysglycemia in women with PCOS. Furthermore, there were maternal parent-of-origin effects on transmission of D19S884-A8 probands with fasting dysglycemia. These findings suggest that maternal factors, genetic and perhaps epigenetic, contribute to the metabolic phenotype in affected women.


Cell specific, cross-species expression of myrosinases in Brassica napus, Arabidopsis thaliana and Nicotiana tabacum.
A prototypical characteristic of the Brassicaceae is the presence of the myrosinase-glucosinolate system. Myrosinase, the only known S-glycosidase in plants, degrades glucosinolates, thereby initiating the formation of isothiocyanates, nitriles and other reactive products with biological activities. We have used myrosinase gene promoters from Brassica napus and Arabidopsis thaliana fused to the beta -glucuronidase (GUS) reporter gene and introduced into Arabidopsis thaliana, Brassica napus and/or Nicotiana tabacum plants to compare and determine the cell types expressing the myrosinase genes and the GUS expression regulated by these promoters. The A. thaliana TGG1 promoter directs expression to guard cells and phloem myrosin cell idioblasts of transgenic A. thaliana plants. Expression from the same promoter construct in transgenic tobacco plants lacking the myrosinase enzyme system also directs expression to guard cells. The B. napus Myr1.Bn1 promoter directs a cell specific expression to idioblast myrosin cells of immature and mature seeds and myrosin cells of phloem of B. napus. In A. thaliana the B. napus promoter directs expression to guard cells similar to the expression pattern of TGG1. The Myr1.Bn1 signal peptide targets the gene product to the reticular myrosin grains of myrosin cells. Our results indicate that myrosinase gene promoters from Brassicaceae direct cell, organ and developmental specific expression in B. napus, A. thaliana and N. tabacum.