Long-term immune responses to vaccination in HIV-infected patients: a systematic review and meta-analysis.
Vaccine-induced antibodies may wane more quickly in persons living with human immunodeficiency virus (HIV) than in healthy individuals. We reviewed the literature on vaccines routinely recommended in HIV-infected patients to estimate how seroprotection decreases over time in those who initially responded to immunization. For each study retrieved from the literature, the decrease of seroprotection was modeled with a log binomial generalized linear model, and data were pooled in a meta-analysis to provide estimates of seroprotection 2 and 5 years after the last vaccine administration. Our analyses confirmed that the duration of seroprotection was shorter in HIV-infected patients and that with current guidelines, a substantial proportion of patients would have lost protective antibodies before a booster was proposed. We therefore discuss the implications for the monitoring of antibody levels and timing of revaccination in these patients.


Donkey genomes provide new insights into domestication and selection for coat color.
Current knowledge about the evolutionary history of donkeys is still incomplete due to the lack of archeological and whole-genome diversity data. To fill this gap, we have de novo assembled a chromosome-level reference genome of one male Dezhou donkey and analyzed the genomes of 126 domestic donkeys and seven wild asses. Population genomics analyses indicate that donkeys were domesticated in Africa and conclusively show reduced levels of Y chromosome variability and discordant paternal and maternal histories, possibly reflecting the consequences of reproductive management. We also investigate the genetic basis of coat color. While wild asses show diluted gray pigmentation (Dun phenotype), domestic donkeys display non-diluted black or chestnut coat colors (non-Dun) that were probably established during domestication. Here, we show that the non-Dun phenotype is caused by a 1 bp deletion downstream of the TBX3 gene, which decreases the expression of this gene and its inhibitory effect on pigment deposition.


Alarming Rate of Substance Use in Motor Vehicle Collisions at an Appalachian Trauma Center.
Prescription drug use is a growing public health concern and studies show it is a contributing risk to motor vehicle collisions. The Appalachian region is also known to have an ever-increasing number of patients on controlled substances. This retrospective study of patients from the years 2011-2015 on controlled substances presenting to an Appalachian Level 1 trauma center after a motor vehicle or motorcycle collision was analyzed in order to determine the rate of opioid use among victims of motor vehicle collisions in the system, as well as evaluate for any differences in resource utilization between these patients and patients not using controlled substances. A total of 2,570 patients were included in the study. Seven-hundred sixty-eight (29.9%) individuals were found to be on a controlled substance. There was a similar mortality rate in both groups (2.8% vs 3.6%). There was no significant difference in hospital length of stay (LOS), intensive care unit (ICU) LOS, ventilator days, or injury severity score. Statistically significant findings include the type of crash (motor vehicle crash vs motorcycle crash) (p=0.003) and position in the vehicle (driver vs passenger) (p<0.001). Motor vehicle crashes and driver position were significantly associated with the presence of a controlled substance.


A New Application of Social Impact in Social Media for Overcoming Fake News in Health.
One of the challenges today is to face fake news (false information) in health due to its potential impact on people's lives. This article contributes to a new application of social impact in social media (SISM) methodology. This study focuses on the social impact of the research to identify what type of health information is false and what type of information is evidence of the social impact shared in social media. The analysis of social media includes Reddit, Facebook, and Twitter. This analysis contributes to identifying how interactions in these forms of social media depend on the type of information shared. The results indicate that messages focused on fake health information are mostly aggressive, those based on evidence of social impact are respectful and transformative, and finally, deliberation contexts promoted in social media overcome false information about health. These results contribute to advancing knowledge in overcoming fake health-related news shared in social media.


Comparison of optic nerve head assessment with a digital stereoscopic camera (discam), scanning laser ophthalmoscopy, and stereophotography.
To compare computer-assisted planimetry using the Discam system (Marcher Enterprises Ltd., Hereford, UK), confocal scanning laser ophthalmoscopy (CSLO), and stereoscopic disc photography with respect to optic nerve head (ONH) measurements and glaucoma status. Comparative, observational case series and interobserver variability study. Three hundred eighty-six eyes of 233 consecutive subjects were imaged with the Discam, and a subset underwent ONH evaluation with CSLO (n = 297), stereoscopic photography (n = 233), or both. Subjects were classified into normal, glaucoma suspect, and glaucoma groups based on clinical findings of slit-lamp disc examination and visual field testing. Agreement of cup-to-disc ratio measurements among the three technologies was assessed by the intraclass correlation coefficient (ICC) and areas under the receiver operator characteristic (AROC) curves. Cup-to-disc ratio as measured by Discam, CSLO, and stereography. Intraclass correlation coefficients calculated using the two-way random effects model for comparing Discam, CSLO, and stereography among cup-to-disc area ratio, vertical cup-to-disc ratio, and horizontal cup-to-disc ratio were 0.46 to 0.53. The ICC was higher for eyes with larger optic discs (0.51) than those with smaller ones (0.32). The ICC calculated using the fixed effects model for the Discam and CSLO comparison was 0.72. Areas under the receiver operator characteristic curves were 0.67 to 0.80 among the three technologies comparing normal with glaucomatous eyes. In general, there was no statistically significant difference between techniques with respect to sensitivity and specificity of glaucoma detection. There is good agreement between ONH measurements obtained by Discam, CSLO, and stereography; however, the results are not interchangeable. Similar AROC curve values among all three techniques imply that the Discam, CSLO, and stereography perform equally for the determination of glaucoma status.


Quantitatively plotting the human face for multivariate data visualisation illustrated by health assessments using laboratory parameters.
The purpose of this study was to describe a new data visualisation system by plotting the human face to observe the comprehensive effects of multivariate data. The Graphics Device Interface (GDI+) in the Visual Studio.NET development platform was used to write a program that enables facial image parameters to be recorded, such as cropping and rotation, and can generate a new facial image according to Z values from sets of normal data (Z > 3 was still counted as 3). The measured clinical laboratory parameters related to health status were obtained from senile people, glaucoma patients, and fatty liver patients to illustrate the facial data visualisation system. When the eyes, nose, and mouth were rotated around their own axes at the same angle, the deformation effects were similar. The deformation effects for any abnormality of the eyes, nose, or mouth should be slightly higher than those for simultaneous abnormalities. The facial changes in the populations with different health statuses were significant compared with a control population. The comprehensive effects of multivariate may not equal the sum of each variable. The 3Z facial data visualisation system can effectively distinguish people with poor health status from healthy people.


Protein collapse is encoded in the folded state architecture.
Folded states of single domain globular proteins are compact with high packing density. The radius of gyration, Rg, of both the folded and unfolded states increase as Nν where N is the number of amino acids in the protein. The values of the Flory exponent ν are, respectively, ≈⅓ and ≈0.6 in the folded and unfolded states, coinciding with those for homopolymers. However, the extent of compaction of the unfolded state of a protein under low denaturant concentration (collapsibility), conditions favoring the formation of the folded state, is unknown. We develop a theory that uses the contact map of proteins as input to quantitatively assess collapsibility of proteins. Although collapsibility is universal, the propensity to be compact depends on the protein architecture. Application of the theory to over two thousand proteins shows that collapsibility depends not only on N but also on the contact map reflecting the native structure. A major prediction of the theory is that β-sheet proteins are far more collapsible than structures dominated by α-helices. The theory and the accompanying simulations, validating the theoretical predictions, provide insights into the differing conclusions reached using different experimental probes assessing the extent of compaction of proteins. By calculating the criterion for collapsibility as a function of protein length we provide quantitative insights into the reasons why single domain proteins are small and the physical reasons for the origin of multi-domain proteins. Collapsibility of non-coding RNA molecules is similar β-sheet proteins structures adding support to "Compactness Selection Hypothesis".


Life-threatening hemorrhage from enterotomies and anastomoses in 7 horses.
To report our experience with horses that presumptively had severe intraluminal hemorrhage from enterotomy or anastomosis. Clinical study. Six adult horses and 1 adult donkey. A retrospective study was conducted at the University of Illinois (April 1994 to December 2001) to determine the clinical course and outcome of horses with melena and/or anemia and evidence of life-threatening hemorrhage from intestinal incisions. Medical records of all horses that had colic surgery were reviewed to determine the proportion of horses with this complication. In addition, horses that fit the same criteria identified in 3 other veterinary clinics were included. Three horses (1.3%) of those that had enterotomy or anastomosis at the University of Illinois and 4 horses from other clinics had complications presumptively related to severe hemorrhage from these intestinal procedures. Melena became evident within 72 hours of surgery and lasted 12 to 96 hours. Six horses had an acute and severe drop in packed cell volume (PCV), increased heart rates, and other signs of acute hemorrhage, and 1 horse had signs of colic postoperatively. Horses were administered intravenous formalin (3 horses) and whole blood transfusions (4 horses). Repeat celiotomy was performed on 2 horses. In 1 of these horses, a bleeding artery was ligated in the edge of the original enterotomy, and, in the other, a 25-cm-diameter intraluminal blood clot was found occluding the pelvic flexure. A horse that had jejunocolostomy for cecal impaction was not treated for hemorrhagic shock but was euthanatized and necropsied. Necropsy revealed blood-filled bowel from the jejunocolostomy to the anus. One of the remaining 6 horses died of enterocolitis and 5 survived to discharge. Hemorrhage from incisional edges, particularly in the large intestine, should be considered a rare but possibly fatal complication of enterotomy or anastomosis in horses. To prevent fatal hemorrhage from incisional edges during enterotomy or anastomosis, large vessels should be ligated at the original surgery, and hemostatic effects of different closure techniques should be considered. No intraoperative or postoperative findings were useful to predict this complication, and response to supportive medical therapy was favorable.


Effects of pH and Nutrients (Nitrogen) on Growth and Toxin Profile of the Ciguatera-Causing Dinoflagellate Gambierdiscus polynesiensis (Dinophyceae).
Ciguatera poisoning is a foodborne disease caused by the consumption of seafood contaminated with ciguatoxins (CTXs) produced by dinoflagellates in the genera Gambierdiscus and Fukuyoa. Ciguatera outbreaks are expected to increase worldwide with global change, in particular as a function of its main drivers, including changes in sea surface temperature, acidification, and coastal eutrophication. In French Polynesia, G. polynesiensis is regarded as the dominant source of CTXs entering the food web. The effects of pH (8.4, 8.2, and 7.9), Nitrogen:Phosphorus ratios (24N:1P vs. 48N:1P), and nitrogen source (nitrates vs. urea) on growth rate, biomass, CTX levels, and profiles were examined in four clones of G. polynesiensis at different culture age (D10, D21, and D30). Results highlight a decrease in growth rate and cellular biomass at low pH when urea is used as a N source. No significant effect of pH, N:P ratio, and N source on the overall CTX content was observed. Up to ten distinct analogs of Pacific ciguatoxins (P-CTXs) could be detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in clone NHA4 grown in urea, at D21. Amounts of more oxidized P-CTX analogs also increased under the lowest pH condition. These data provide interesting leads for the custom production of CTX standards.


Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients.
Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency. Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model. Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25-21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan-Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30-60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min. Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.


[Health conditions of elderly residents in Long-stay Institution second basic human needs].
The study aimed to characterize the elderly residents in long-stay nursing homes (HHs) according to gender, age, education, cause of admission and length of stay; and to describe their health conditions according to the theory of Basic Human Needs. This was an analytical, observational and cross-sectional study with a quantitative approach, conducted with 86 seniors from eight NHs in a city of Triângulo Mineiro, state of Minas Gerais. For data analysis, it was used the descriptive statistics, simple and average frequency and standard deviation. The elderly were predominantly female (70.9 %), 80 years or older (44.2 %) and illiterate (48.8 %). The physiological needs affected were: high blood pressure (30.2 %); cognitive decline (58.7 %) and urinary incontinence (50 %). As psychosocial needs, everyone was dependent to perform the instrumental activities of daily living and 52.3 % have indicative of depression. As for the psicoespiritual needs, 70.9 % did not practice any religion. The basic human needs identified as affected were contributing to a decreased on the quality of life of seniors.


The effects of vitamin B6 on lens antioxidant system in valproic acid-administered rats.
Valproic acid (VPA, 2-propyl pentanoic acid) is a broad-spectrum antiepileptic drug (AED) and is commonly used in the treatment of bipolar disorders and epilepsy. AEDs are known to result in vascular disturbances. Vitamin B6 (Vit B6) is water soluble vitamin essential for normal growth, development, and metabolism. In this study, we aimed to investigate the protective effects of Vit B6 against VPA-induced lens damage in experimental animals. In this study, male 4-month-old, Sprague-Dawley rats were used. The animals were divided into four groups. Group I was intact control animals. Group II rats were administered with Vit B6 (50 mg/kg/day) for 7 days. Group III rats were administered with only VPA (500 mg/kg/day) for 7 days. Group IV was given VPA + Vit B6 (in a same dose and time). Vit B6 was given to rats by gavage and VPA was given by intraperitoneally. On the 8th day of experiment, all of the animals were fasted overnight and then killed under ether anesthesia. Lens tissues were taken from animals, homogenized in 0.9% saline to make up a 10% homogenate. The homogenates was used for glutathione (GSH), lipid peroxidation (LPO), protein levels, and enzyme analysis. In VPA groups, levels of lens GSH and LPO and activities of glutathione-S-transferase, glutathione peroxidase, glutathione reductase, and aldose reductase were increased, while superoxide dismutase activity was decreased. Treatment with Vit B6 reversed these effects. These results demonstrated that administration of Vit B6 is potentially beneficial agent to reduce the lens damage in VPA toxicity, probably by decreasing oxidative stress.


Toxicologic Pathology Forum: Opinion on Obligatory Microscopic Examination of Intermediate-Dose Groups in Toxicity Studies With Biotherapeutics in Cynomolgus Monkeys.
In nonrodent toxicity studies that are usually conducted in cynomolgus monkeys or beagle dogs, the added value of examining all tissues from all dose groups (current practice) versus all tissues in only control and high-dose groups and target tissues in intermediate-dose groups by default, is a subject of debate. A previous retrospective review of 325 nonrodent toxicity studies that included a limited number of biotherapeutics suggested that the evaluation of all tissues from all groups was not justified as a routine practice and recommended the examination of all tissues in control and high-dose groups and only target tissues in intermediate-dose groups. In contrast, the present retrospective review which examined 213 nonrodent studies (212 in cynomolgus monkeys and 1 in dog) from 4 multinational pharmaceutical companies (Bristol-Myers Squibb, Novartis, Pfizer Inc, and Roche) conducted only with biotherapeutics showed that restricting the microscopic examination in intermediate-dose groups to target tissues has the potential to miss findings in 6.6% of studies, possibly impacting the overall study interpretation and conclusion. In conclusion and in the opinion of the authors, all tissues from all dose groups should be examined in toxicity studies with biotherapeutics conducted in nonrodent species.


Pulsed magnetic fields enhance the rate of recovery of damaged nerve excitability.
Pulsed magnetic fields (PMFs) have well-known beneficial effects on nerve regeneration. However, little research has examined the nerve conduction characteristics of regenerating peripheral nerves under PMF. The main goal of this study was to examine the conduction characteristics of regenerating peripheral nerves under PMFs. The sucrose-gap recording technique was used to examine the conduction properties of injured sciatic nerves of rats exposed to PMF. Following the injury, peripheral nerves were very sensitive to repetitive stimulation. When the stimulation frequency was increased, the amplitude of the compound action potential (CAP) decreased more at 15 days post-crush injury (dpc) than at 38 dpc. PMF treatment for 38 days after injury caused significant differences in the conduction of CAPs. Moreover, application of PMF ameliorated the abnormal electrophysiological activities of nerves such as hyperpolarizing afterpotentials and delayed depolarizations that were revealed by 4-aminopyridine (4-AP). Consequently, characteristic findings in impulse conduction of recovered nerves under PMF indicate that the observed abnormalities in signaling or aberrant ion channel functions following injury may be restored by PMF application.


The relationship between gastrointestinal motility and secretion.
Few studies have addressed specifically or systematically the question of whether motility and secretion within the gastrointestinal tract are linked and if so by what mechanisms. The evidence for such a relationship is discussed in this review and we conclude that increased motor activity of the stomach is frequently associated with increased acid and pepsin secretion. Similarly, an increase in small intestinal motility is accompanied by elevated fluid and electrolyte secretion. Two possible mechanisms linking motility to secretion are considered. These could coexist. The first consists of parallel but separate neural pathways to smooth muscle and epithelium that might be activated synchronously and, therefore, produce simultaneous activation of motility and secretion. The existence of such parallel pathways in the stomach and small intestine are described, but their physiological significance is unresolved. The second mechanism we discuss is a sequential process in which increased motility provides a sensory stimulus for reflexly activated secretion. In the stomach the evidence for such a mechanism is largely deductive. In the intestine, however, we provide experimental evidence for an intrinsic neural mechanism activated by motor activity, which then stimulates fluid and electrolyte secretion. We conclude that such a sequential relationship exists and probably operates under physiological conditions but that further study is required.


Aboriginal Health Care and Bioethics: A Reflection on the Teaching of the Seven Grandfathers.
Contemporary bioethics recognizes the importance of the culture in shaping ethical issues, yet in practice, a process for ethical analysis and decision making is rarely adjusted to the culture and ethnicity of involved parties. This is of a particular concern in a health care system that is caring for a growing Aboriginal population. We raise the possibility of constructing a bioethics grounded in traditional Aboriginal knowledge. As an example of an element of traditional knowledge that contains strong ethical guidance, we present the story of the Gifts of the Seven Grandfathers. We note a resemblance of this Ojibway teaching to virtue ethics in European traditions, but we suggest that there are also important differences in how these two traditions are currently presented. We hope that further engagement with a variety of indigenous moral teachings and traditions could improve health care involving Aboriginal patients and communities, and enrich the discipline of bioethics.


The collaborative process in the making of Ciência & Saúde Coletiva.
This paper presents the different stages of the editorial process of Journal Ciência & Saúde Coletiva. Different processing work methods have been overcome over these 25 years, and others have been introduced. Each stage of this construction will be analyzed in-depth to discuss the "making" of an academic publication of such a large scale and complexity. The Journal Ciência & Saúde Coletiva delves into each issue a theme in the field, addressing its cross-sectionality and complexity. This thematization ranges from 10 to 35 papers. Thirty-five papers are published monthly (thematic and free subjects), mostly in Portuguese, English, and Spanish, fulfilling the most prestigious national and international open-access databases' deadline requirements. In this making, one of the significant issues is funding because the crucial development institutions' support is very scarce.


Ornithobacterium rhinotracheale and Mycoplasma synoviae in broiler chickens in Jordan.
A cross-sectional study was conducted from November 2008 to July 2010 in commercial broiler flocks in southern (n = 50) and northern (n = 50) areas of Jordan, to determine the flock-level prevalence of Ornithobacterium rhinotracheale (ORT) and Mycoplasma synoviae (MS) infections. Tracheal swabs were collected from commercial broilers with respiratory disease and tested by polymerase chain reaction. In total, 21% (95% CI: 18-45%) and 25% (95% CI: 20-51%) of commercial broiler flocks were positive for ORT and MS, respectively. In the southern areas the prevalence of flocks with positive tracheal swabs for ORT and MS was 16% and 10%; in the northern areas the prevalence was 26% and 40%, respectively. Of the flocks tested, 7% were infected with ORT and MS simultaneously. Further epidemiological studies are recommended to determine risk factors and evaluate the economic consequences of ORT and MS infections in the region. Furthermore, studies are required to isolate ORT and MS and develop vaccines against the local field isolates.


Evaluation of approaches to monitor Staphylococcus aureus virulence factor expression during human disease.
Staphylococcus aureus is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic S. aureus 4-antigen (SA4Ag) vaccine comprising capsular polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development. This study was designed to characterize S. aureus isolates recovered from infected patients and also to investigate approaches for examining expression of S. aureus vaccine candidates and the host response during human infection. Confirmation of antigen expression in different disease states is important to support the inclusion of these antigens in a prophylactic vaccine. Hospitalized patients with diagnosed S. aureus wound (27) or bloodstream (24) infections were enrolled. Invasive and nasal carriage S. aureus isolates were recovered and characterized for genotypic diversity. S. aureus antigen expression was evaluated directly by real-time, quantitative, reverse-transcriptase PCR (qRT-PCR) analysis and indirectly by serology using a competitive Luminex immunoassay. Study isolates were genotypically diverse and all had the genes encoding the antigens present in the SA4Ag vaccine. S. aureus nasal carriage was detected in 55% of patients, and in those subjects 64% of the carriage isolates matched the invasive strain. In swab samples with detectable S. aureus triosephosphate isomerase housekeeping gene expression, RNA transcripts encoding the S. aureus virulence factors ClfA, MntC, and capsule polysaccharide were detected by qRT-PCR. Antigen expression was indirectly confirmed by increases in antibody titer during the course of infection from acute to convalescent phase. Demonstration of bacterial transcript expression together with immunological response to the SA4Ag antigens in a clinically relevant patient population provides support for inclusion of these antigens in a prophylactic vaccine.


Determinants and indicators of successful aging as a multidimensional outcome: a systematic review of longitudinal studies.
Successful aging (SA) has been coined as a term to describe the multidimensional aspects associated with achieving optimal combination of physical and mental health along with social well-being health, mental and social well-being at older age. In recent years there has been an increased interest in understanding the role of determinants of SA, such as demographic, biological, behavioral, psychological and social factors. To synthesize the recent evidence, we conducted a systematic review of longitudinal studies on a range of determinants and indicators of SA defined as a multidimensional outcome. A systematic search of PubMed, MEDLINE and Web of Science for finding eligible papers published between August 2016 and June 2023 was conducted following the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA) guidelines. The review protocol was registered in PROSPERO International Prospective Register of Systematic Reviews (Registration number: CRD42021250200). The web-based automated screening tool-Rayyan-was used for title and abstract screening. The study quality was assessed using the Quality in Prognosis Studies (QUIPS) tool. A total of 3,191 records were initially identified using the predefined search strategy. Out of 289 articles selected for full text screening, 22 were found eligible and included in the review. A variety of factors have been explored in relation to SA, ranging from socio-demographic factors, nutrition, lifestyle, biological pathways, psychological health, and well-being. Overall, the results of recent studies have confirmed the role of metabolic health, adherence to healthy dietary patterns, such as the Mediterranean diet, physical activity, non-smoking, and higher socio-economic status as main factors associated with higher odds for SA. Emerging research highlights the role of psycho-social factors and early life health as determinants of SA. In summary, this review highlights the importance of healthy living and monitoring metabolic risk along with sustaining psychological well-being in adult life as major determinants of SA. Further methodological and research work on SA would pave the way toward development of adequate health promotion policies in aging societies. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021250200, CRD42021250200.


Early- and medium-term results after aortic arch replacement with frozen elephant trunk techniques-a single center study.
The treatment of patients with extensive thoracic aortic disease involving the arch and descending thoracic/thoracoabdominal aorta is often performed using the frozen elephant trunk technique (FET). We retrospectively analyzed our results of the FET operation. A total of 51 consecutive patients underwent total aortic arch surgery with the FET technique between January 2006 and August 2013. For all patients, the E-vita hybrid open stent-graft (Jotec, Hechingen, Germany) was used. The patients had a mean age of 64±13 years, with 51.1% being female. Degenerative or atherosclerotic aneurysm was the indication for surgery in 62.7% of patients. Another 15.7% and 13.7% suffered from acute Type A, and Type B aortic dissection, respectively. The in-hospital and 30-day mortality was 7.8%. Stroke occurred in 11.8% (n=6), and new-onset paraplegia in 19.6% (n=10) of patients. The core body temperature ≥28 °C during circulatory arrest, in combination with a prolonged circulatory arrest time of more than 45 minutes, was an independent predictor of permanent spinal cord injury [odds ratios (OR), 4.8; 95% confidence intervals (CI), 1.1-21; P=0.04]. The estimated 1- and 5-year survival was (80.2±5.5)% and (59.7±10.2)%, respectively, with a mean survival time of 3.4±0.4 years. The estimated mean freedom from endovascular intervention was 4.2±0.4 years. The unadjusted 1- and 5-year freedom from thoracic endovascular aortic repair (TEVAR) was (84.9±5.9)% and (69.2±11.2)%, respectively. The FET procedure for extensive thoracic aortic disease is associated with an acceptable early and medium term mortality rate. This procedure is associated with a high incidence of perioperative spinal cord injury. In order to prevent the above complication, deep hypothermia is strongly recommended in patients with expected prolonged circulatory arrest time.


Protein synthesis in isolated rabbit forelimb muscles. The possible role of metabolites of arachidonic acid in the response to intermittent stretching.
Protein synthesis was measured in isolated intact rabbit muscles by the incorporation of [3H]phenylalanine added at a high concentration (2.5 mM) to the incubation medium. Intermittent mechanical stretching substantially increased the rate of protein synthesis relative to that in control muscles incubated under a constant tension. Indomethacin and meclofenamic acid, inhibitors of the enzyme cyclo-oxygenase, which converts free arachidonic acid into the prostaglandins, prostacyclins and thromboxanes, decreased the rate of protein synthesis in intermittently stretched muscles, but had no effect on synthesis rates in the unstimulated controls. Arachidonic acid at concentrations of 0.2 and 1.0 microM gave a highly significant increase in the rate of protein synthesis in muscles incubated under a constant tension. The ability of arachidonic acid to increase protein-synthesis rates was abolished by the addition of indomethacin. Activation of protein synthesis by intermittent stretching persisted for 10-20 min after the stretch stimulation had ceased. Indomethacin, added either during the initial incubation with intermittent stretching or during the subsequent period when protein synthesis was measured after stimulation had ceased, decreased protein-synthesis rates. This decrease was similar whether indomethacin was present during the initial, final or entire incubation period. In experiments analogous with those in (4) above, when Ca2+ was withheld and EGTA added for the entire incubation, rates of protein synthesis were again decreased. The rates of protein synthesis observed when Ca2+ was present during either an initial stimulation phase or a final, unstimulated, measurement phase were similar, and were intermediate between control rates and those in muscles incubated without Ca2+ for the whole experiment. Two prostaglandins, F2 alpha (2.8 microM) and A1 (28 microM), increased rates of protein synthesis in unstimulated muscles, but prostaglandins E2 and D2 and the leukotrienes C4 and D4 failed to do so. It is concluded that the stretch-stimulated increase in protein synthesis may be caused by activation of membrane phospholipases, release of arachidonic acid and a consequent increase in prostaglandin synthesis.


Selection and evolution of resistance to antimicrobial drugs.
The overuse and misuse of antibiotics over many years has selected a high frequency of resistance among medically important bacterial pathogens. The evolution of resistance is complex, frequently involving multiple genetic alterations that minimize biological fitness costs and/or increase the resistance level. Resistance is selected at very low drug concentrations, such as found widely distributed in the environment, and this selects for resistant mutants with a high fitness. Once resistance with high fitness is established in a community it is very difficult to reduce its frequency. Addressing the problem of resistance is essential if we are to ensure a future where we can continue to enjoy effective medical control of bacterial infections. This will require several actions including the discovery and development of novel antibiotics, the creation of a continuous pipeline of drug discovery, and the implementation of effective global antibiotic stewardship to reduce the misuse of antibiotics and their release into the environment.


The Cys-Arg/N-End Rule Pathway Is a General Sensor of Abiotic Stress in Flowering Plants.
Abiotic stresses impact negatively on plant growth, profoundly affecting yield and quality of crops. Although much is known about plant responses, very little is understood at the molecular level about the initial sensing of environmental stress. In plants, hypoxia (low oxygen, which occurs during flooding) is directly sensed by the Cys-Arg/N-end rule pathway of ubiquitin-mediated proteolysis, through oxygen-dependent degradation of group VII Ethylene Response Factor transcription factors (ERFVIIs) via amino-terminal (Nt-) cysteine [1, 2]. Using Arabidopsis (Arabidopsis thaliana) and barley (Hordeum vulgare), we show that the pathway regulates plant responses to multiple abiotic stresses. In Arabidopsis, genetic analyses revealed that response to these stresses is controlled by N-end rule regulation of ERFVII function. Oxygen sensing via the Cys-Arg/N-end rule in higher eukaryotes is linked through a single mechanism to nitric oxide (NO) sensing [3, 4]. In plants, the major mechanism of NO synthesis is via NITRATE REDUCTASE (NR), an enzyme of nitrogen assimilation [5]. Here, we identify a negative relationship between NR activity and NO levels and stabilization of an artificial Nt-Cys substrate and ERFVII function in response to environmental changes. Furthermore, we show that ERFVIIs enhance abiotic stress responses via physical and genetic interactions with the chromatin-remodeling ATPase BRAHMA. We propose that plants sense multiple abiotic stresses through the Cys-Arg/N-end rule pathway either directly (via oxygen sensing) or indirectly (via NO sensing downstream of NR activity). This single mechanism can therefore integrate environment and response to enhance plant survival.


Different stages of primary Sjogren's syndrome involving lymphotoxin and type 1 IFN.
Primary Sjögren's syndrome (pSS) is a complex autoimmune disease starting in the salivary and lacrimal glands and continuing to involve the lungs and kidneys with the eventual development of lymphoma. Many studies have emphasized the role of type 1 IFN (IFN-α) and lymphotoxin α (LTα) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-α in pSS using an animal model, the IL-14α (IL14αTG) transgenic mouse. IL14αTG mice lacking the type 1 IFNR (IL14αTG.IFNR(-/-)) had the same submandibular gland and lacrimal gland injury as did the IL14αTG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14αTG.IFNR(-/-) mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14αTG mice was inhibited in IL14αTG.IFNR(-/-) mice. Production of LTα was identified in both IL14αTG mice and IL14αTG.IFNR(-/-) mice at the time that salivary gland injury was occurring. These and previous studies suggest a model for pSS that separates the disease into several stages: 1) initial injury to the submandibular and lacrimal glands via an environmental insult and LTα; 2) amplification of local injury via the production of type 1 IFN; injury to the parotid glands, lungs, and kidneys is seen; 3) progression of systemic inflammation with the eventual development of large B cell lymphoma. Understanding these different stages will help to develop strategies for treatment of patients with pSS based on the status of their disease.


Plasma exchange in rapidly progressive renal failure due to multiple myeloma. A retrospective case series.
To evaluate the effect of plasma exchange on renal function in patients with rapidly progressive renal failure secondary to multiple myeloma. The study was done through a retrospective chart review using a standardized form at a tertiary care centre in southwestern Ontario. Patients were included in the study if they had a diagnosis of multiple myeloma and rapidly progressive renal failure. Multiple myeloma was defined by a bone marrow aspirate >15% plasma cells plus one of the following: serum monoclonal paraproteins, monoclonal light-chain excretion, or lytic lesions. Patients were excluded if they had evidence of chronic renal failure or failed to complete three plasma exchanges. Twenty-six patients were reviewed; of these 24 were followed up to 1 year. All patients received hydration, standard chemotherapy, and plasma exchange. The plasma exchange volume was 50 ml/kg of 50% normal saline and 50% human serum albumin. Primary outcome measures included (1) prevention of acute dialysis and (2) prevention of progression from acute to chronic dialysis; secondary end points included (1) a decrease in creatinine of 25% or more within 3 months of the last plasma exchange and (2) survival at 1 year. Sixteen of 24 patients, followed up to 1 year, did not require dialysis. Two patients required dialysis initially, but were able to come off dialysis after 3 months. Fourteen patients were alive at 1 year, 13 of whom were dialysis independent. Twelve of 13 dialysis-independent patients had a >25% reduction in creatinine at 3 months. Two patients were lost to follow-up after discharge and were not included in the analysis. This retrospective study suggests that plasma exchange may offer some benefit in preventing the initiation or continuation of dialysis in patients with rapidly progressive renal failure secondary to multiple myeloma. A randomized controlled prospective study is needed to determine whether plasma exchange should be recommended as a standard treatment for patients with rapidly progressive renal failure due to multiple myeloma.


Matched Molecular Series: Measuring SAR Similarity.
Suggesting novel compounds to be made on the basis of similarity to a previously seen structure-activity relationship (SAR) requires a measure for SAR similarity. While SAR similarity has intuitively been used by medicinal chemists for decades, no systematic comparison of candidate similarity metrics has been published to date. With this publication, we attempt to close that gap by providing a statistical framework that allows comparison of SAR similarity metrics by their ability to rank series that provide the best activity prediction of novel substituents. This prediction is a result of a two-step process that involves (a) judging the similarity between series and (b) transferring the SAR from one series to the other. We tested several SAR similarity metrics and found that a centered RMSD (cRMSD) in combination with a lineaar-regression-based prediction interpolation ranks SAR profiles best. Based on that ranking we can, with a given confidence, suggest novel substituents to be tested. The superiority of the cRMSD can be explained on the basis of experimental uncertainty of affinity data and measured affinity differences. The ability to measure SAR similarity is central to applications like matched molecular series (MMS) analysis, whose applicability depends on whether there is a potential for SAR transferability between series. With the new SAR similarity metric introduced here, we show how MMS can be used in a medicinal chemistry setting as an idea generator and a semiquantitative prediction tool.


Renal functional status and patterns of catecholamine excretion.
Twenty-four hour urinary catecholamine measurements were obtained in seven normal individuals and 23 patients with essential hypertension or renal disease. As renal function decreased, large reductions in the excretion of free catecholamines and total dopamine were measured. Since urinary catecholamine measurements are used for diagnostic and physiologic studies, our data indicate a need to assess renal function for accurate interpretation of these measurements. Our results are also consistent with a renal origin for a major portion of the urinary dopamine content.


Adverse events and drug-drug interactions of sodium glucose co-transporter 2 inhibitors in patients treated for heart failure.
Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug-drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF. Literature-search-terms in PubMed were 'adverse event/drug-drug interaction' and 'heart failure AND 'dapagliflozin' OR 'empagliflozin' OR 'sotagliflozin.'AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier's gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months.DDI were mainly studied in healthy volunteers for 3-8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron. Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable.


A study on retention "projection" as a supplementary means for compound identification by liquid chromatography-mass spectrometry capable of predicting retention with different gradients, flow rates, and instruments.
Using current data analysis techniques, even the most advanced LC-MS instrumentation can identify only a small fraction of compounds found in typical biological extracts. Augmenting MS information with HPLC retention information allows many more to be identified. In fact, our calculations indicate that a quadrupole MS is able to identify more compounds than an FTICR-MS when the quadrupole spectrum is augmented with retention information. Unfortunately, retention information is extremely difficult to harness for compound identification. Here, we demonstrate the first use of isocratic data measured on one LC-MS to "project" gradient retention on to different LC-MS systems. Using 35 chemically diverse solutes chosen to encompass the full range of reversed-phase alkylsilica interactions, and using experimental conditions typical of metabolomics experiments, gradient retention was projected from one instrument to another with only 1.2-2.6% error-enough accuracy to considerably improve compound identification. Besides accounting for nonlinear relationships of retention versus solvent composition as well as dead time versus solvent composition, accounting for the precise shape of the gradient profile (not just the dwell volume) improved projection accuracy on one instrument by up to 4 fold whereas flow rate non-idealities likely caused considerable error on the other instrument. Thus, these two factors must be taken into account to accurately project retention on diverse instrumentation.


Effect of Heart Rate on Arterial Stiffness as Assessed by Pulse Wave Velocity.
Vascular assessment is becoming increasingly important in the diagnosis of cardiovascular diseases. In particular, clinical assessment of arterial stiffness, as measured by pulse wave velocity (PWV), is gaining increased interest due to the recognition of PWV as an influential factor on the prognosis of hypertension as well as being an independent predictor of cardiovascular and all-cause mortality. Whilst age and blood pressure are established as the two major determinants of PWV, the influence of heart rate on PWV measurements remains controversial with conflicting results being observed in both acute and epidemiological studies. In a majority of studies investigating the acute effects of heart rate on PWV, results were confounded by concomitant changes in blood pressure. Observations from epidemiological studies have also failed to converge, with approximately just half of such studies reporting a significant blood-pressure-independent association between heart rate and PWV. Further to the lack of consensus on the effects of heart rate on PWV, the possible mechanisms contributing to observed PWV changes with heart rate have yet to be fully elucidated, although many investigators have attributed heart-rate related changes in arterial stiffness to the viscoelasticity of the arterial wall. With elevated heart rate being an independent prognostic factor of cardiovascular disease and its association with hypertension, the interaction between heart rate and PWV continues to be relevant in assessing cardiovascular risk.


Early experience with popliteal to infrapopliteal bypass for limb salvage.
In an attempt to improve graft patency and limb salvage in patients with isolated tibial vessel and/or popliteal-tibial vessel occlusive disease, bypass grafts from the popliteal or distal superficial femoral artery to infrapopliteal arteries were used in patients requiring bypass for limb salvage. During a 2 1/2-year period, 23 patients with patent axial vessels and hemodynamically normal inflow to the level of the knee underwent such bypasses. Cumulative graft patency and limb salvage rates at 31 months were 84% and 70%, respectively. Five of the six patients who required below-knee amputation did so because of progressive gangrene in the presence of a patent bypass. Short bypasses between the popliteal and infrapopliteal arteries can significantly contribute to limb salvage in patients with tibial vessel occlusive disease and may be particularly useful in patients with saphenous veins too short for longer bypasses.


The role of SLX4 and its associated nucleases in DNA interstrand crosslink repair.
A key step in the Fanconi anemia pathway of DNA interstrand crosslink (ICL) repair is the ICL unhooking by dual endonucleolytic incisions. SLX4/FANCP is a large scaffold protein that plays a central role in ICL unhooking. It contains multiple domains that interact with many proteins including three different endonucleases and also acts in several other DNA repair pathways. While it is known that its interaction with the endonuclease XPF-ERCC1 is required for its function in ICL repair, which other domains act in this process is unclear. Here, we used Xenopus egg extracts to determine ICL repair specific features of SLX4. We show that the SLX4-interacting endonuclease SLX1 is not required for ICL repair and demonstrate that all essential SLX4 domains are located at the N-terminal half of the protein. The MLR domain is crucial for the recruitment of XPF-ERCC1 but also has an unanticipated function in recruiting SLX4 to the site of damage. Although we find the BTB is not essential for ICL repair in our system, dimerization of SLX4 could be important. Our data provide new insights into the mechanism by which SLX4 acts in ICL repair.


The inhibition of insulin-stimulated proliferation of vascular smooth muscle cells by rosiglitazone is mediated by the Akt-mTOR-P70S6K pathway.
Thiazolidinediones (TZDs) are known to inhibit the proliferation of vascular smooth muscle cell (VSMC) by increasing the activity of p27Kip1 and retinoblastoma protein (RB). However, the upstream signaling mechanisms associated with this pathway have not been elucidated. The Akt-mTOR-P70S6 kinase pathway is the central regulator of cell growth and proliferation, and increases cell proliferation by inhibiting the activities of p27Kip1 and retinoblastoma protein (RB). Therefore, we hypothesized in this study that rosiglitazone inhibits VSMC proliferation through the inhibition of the Akt-TOR-P70S6K signaling pathway. Rat aortic smooth muscle cells (RAoSMCs) were treated with 10microM of rosiglitazone 24 hours before the addition of insulin as a mitogenic stimulus. Western blot analysis was performed to determine the inhibitory effect of rosiglitazone treatment on the Akt-mTOR-P70S6K signaling pathway. Carotid balloon injury was also performed in Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rats that were pretreated with 3 mg/kg of rosiglitazone. Western blot analysis demonstrated significant inhibition of activation of p-Akt, p-m-TOR, and p-p70S6K in cells treated with rosiglitazone. The inhibition of the activation of the p-mTOR-p-p70S6K pathway seemed to be mediated by both the upstream PI3K pathway and MEK-ERK complex. The inhibitory effect of rosiglitazone on RAoSMC proliferation in vitro and in vivo is mediated by the inhibition of the Akt-mTOR-P70S6K pathway.


Asbestos exposure in Israel: findings, issues and needs.
In Israel, since the 1950s, at least several thousand workers, their wives and children, and possibly many others, have been or still may be exposed to hazardous amounts of airborne asbestos fibers. These are found both in asbestos-based industries (asbestos cement, textiles and brake linings) and trades with asbestos exposure (construction, shipyard repair, boiler maintenance, insulation work). These people are at increased risk for disability or illness, or for premature death from asbestosis, from lung cancer, from exacerbation of preexisting respiratory disease (especially if they smoke), from mesothelioma, from gastrointestinal cancer, and from other malignancies. Although there has been progress, much still has to be done in the areas of legislation, standard setting, exposure control, technology, surveillance, smoking cessation, and medical care and follow-up. Compensation is needed to care for those workers currently or previously exposed, as well as for their families and others at risk. A national policy for protecting and caring for those formerly or currently exposed is indicated by the review of the situation in Israel.


Diffusion and sorption of methanol and water in Nafion using time-resolved Fourier transform infrared-attenuated total reflectance spectroscopy.
Direct methanol fuel cells (DMFCs) are promising portable power sources. However, their performance diminishes significantly because of high methanol crossover (flux) in the polymer electrolyte membrane (e.g., Nafion 117) at the desired stoichiometric methanol feed concentration. In this study, the diffusion and sorption of methanol and water in Nafion 117 were measured using time-resolved Fourier transform infrared-attenuated total reflectance (FTIR-ATR) spectroscopy. This technique is unique because of its ability to measure multicomponent diffusion and sorption within a polymer on a molecular level in real time as function of concentration. Both the effective mutual diffusion coefficients and concentrations of methanol and water in Nafion 117 were determined with time-resolved FTIR-ATR spectroscopy as a function of methanol solution concentration. The methanol flux, calculated from FTIR-ATR, matched that determined from a conventional technique (permeation cell) and increased by almost 3 orders of magnitude over the methanol solution concentration range studied (0.1-16 M). Furthermore, the data obtained in this study reveal that the main contribution to the increase in methanol flux is due to methanol sorption in the membrane.


ICAAR, a novel member of a new family of transmembrane, tyrosine phosphatase-like proteins.
We have isolated a cDNA from human foetal brain cDNA library which encodes a putative transmembrane protein bearing an intracellular protein tyrosine phosphatase (PTPase) like domain. The PTPase like domain contains an alanine to aspartate amino acid change relative to other PTPases in the catalytic core domain. This amino acid change is found in only three other known proteins, islet cell autoantigens; human, murine and rat IA-2, murine IA-2b and its rat orthologue phogrin, which have a similar overall structure to ICAAR, and the recently identified X-linked myotubular myopathy (MTM1) gene. ICAAR, IA-2 and IA-2b clearly represent a new family of PTP-like proteins for which catalytic activity has yet to be demonstrated. An abundant ICAAR mRNA is detectable in the brain and pancreas but not in the other normal human tissues surveyed. We have localised ICAAR to human chromosome 7q36.


The effect of dynamical fluctuations of hydration structures on the absorption spectra of oxyluciferin anions in an aqueous solution.
In this study, the effect of hydration on the absorption spectra of oxyluciferin anion isomers in an aqueous solution is investigated for elucidating the influence of characteristic hydration structures. Using a canonical ensemble of hydration structures obtained from first-principles molecular dynamics simulations, the instantaneous absorption spectra of keto-, enol-, and enolate-type aqueous oxyluciferin anions at room temperature are computed from a collection of QM/MM calculations using an explicit solvent. It is demonstrated that the calculations reproduce experimental results concerning spectral shifts and broadening, for which traditional methods based on quantum chemistry and the Franck-Condon approximation fail because of the molecular vibrations of oxyluciferin anions and dynamical fluctuations of their hydration structures. Although the first absorption band associated with the lowest energy excitation corresponds to a π-π* transition for all oxyluciferin anion isomers, the changes in this band upon hydration are different among the isomers. In particular, the bands of enol- and enolate-type of oxyluciferin anions are significantly blue-shifted by hydration, whereas those of the keto-type oxylucifeion anion are shifted relatively less. Thus, the order of the first-peak positions in the aqueous solution changed relative to that in vacuo. We ascribe this to the nature of the oxyluciferin anion being more hydrophobic in the keto form as compared with the enol and enolate isomers.


Metabolism of glycoprotein-derived sialic acid and N-acetylglucosamine by Streptococcus oralis.
Nine strains of Streptococcus oralis, isolated from blood cultures of patients with infective endocarditis or from the oral cavity as part of the normal flora, were examined for their ability to elaborate sialidase (neuraminidase) and N-acetylglucosaminidase, enzymes which are involved in the degradation of glycoproteins. Both glycosidases were induced when bacteria were grown in a minimal medium supplemented with porcine gastric mucin, a model glycoprotein, and repressed when growth occurred in the presence of glucose. Cell-free extracts mucin-grown cultures expressed elevated levels of N-acetylneuraminate pyruvate-lyase (the first intracellular enzyme in the pathway of N-acetylneuraminate catabolism), N-acetylglucosamine (glcNAc)-6-phosphate deacetylase and glucosamine-6-phosphate deaminase (enzymes involved in the intracellular catabolism of GlcNAc 6-phosphate); activity of each of these intracellular enzymes was markedly repressed when bacteria were grown in media supplemented with alpha 1-acid glycoprotein, a major component of human plasma. Cells from these cultures expressed high levels of sialidase, N-acetylglucosaminidase, and the intracellular enzymes involved in the catabolism of N-acetyl-sugars released by action of these glycosidases. High-resolution 1H-NMR spectroscopy of spent culture supernatants revealed that sialic acid and GlcNAc residues of the molecularly mobile oligosaccharide side-chains of alpha 1-acid glycoprotein had been hydrolysed and the released sugars internalized by the bacteria. These data indicate that S. oralis has the ability to hydrolyse constituents of oligosaccharide side-chains of host-derived glycoproteins and to utilize simultaneously these released carbohydrates. The biochemical characteristics induced by the growth of S. oralis on glycoproteins may play a role in the survival and persistence of these bacteria at the infection site in vivo.


Retinoic acid signaling is necessary for the development of the organ of Corti.
The cellular mosaic of the mammalian organ of Corti represents one of the most highly ordered structures in any vertebrate system. A single row of inner hair cells and three or four rows of outer hair cells extend along the basal-to-apical axis of the cochlea. The factors that play a role in the development of specific cell types within the cochlea are largely unknown; however, the results of previous studies have strongly suggested that retinoic acid plays a role in the development of cells as hair cells. To determine whether cochlear progenitor cells can respond directly to retinoic acid, the expression patterns for each of the RAR and RXR receptors within the embryonic cochlear duct were determined by in situ hybridization. Results indicate that RARalpha, RXRalpha, and RXRgamma are initially expressed throughout the cochlear duct. As development continues, the expression of each receptor becomes more intense in cells that will develop as hair cells. At the same time, receptor expression is down-regulated in cells that will develop as nonsensory cell types. To determine the effects of retinoic acid signaling during the development of the organ of Corti, activation of retinoid receptors was blocked in cultures of the embryonic cochlea through receptor-specific antagonism or inhibition of retinoic acid synthesis. Results indicate that inhibition of retinoic acid signaling induces a significant decrease in the number of cells that develop as hair cells and a disruption in the development of the organ of Corti. These results demonstrate that cells within the developing cochlea can respond to retinoic acid and that signaling by retinoic acid is necessary for the normal development of the organ of Corti.


Preemptive Caffeine Administration Blocks the Increase in Postoperative Pain Caused by Previous Sleep Loss in the Rat: A Potential Role for Preoptic Adenosine A2A Receptors in Sleep-Pain Interactions.
Sleep and pain are reciprocally related, but the precise mechanisms underlying this relationship are poorly understood. This study used a rat model of surgical pain to examine the effect of previous sleep loss on postoperative pain and tested the hypothesis that preoptic adenosinergic mechanisms regulate sleep-pain interactions. Relative to ad libitum sleep, 6 hours of total sleep deprivation prior to a surgical incision significantly enhanced postoperative mechanical hypersensitivity in the affected paw and prolonged the time to recovery from surgery. There were no sex-specific differences in these measures. There were also no changes in adrenocorticotropic hormone and corticosterone levels after sleep deprivation, suggesting that this effect was not mediated by the stress associated with the sleep perturbation. Systemic administration of the nonselective adenosine receptor antagonist caffeine at the onset of sleep deprivation prevented the sleep deprivation-induced increase in postoperative hypersensitivity. Microinjection of the adenosine A2A receptor antagonist ZM 241385 into the median preoptic nucleus (MnPO) blocked the increase in surgical pain levels and duration caused by prior sleep deprivation and eliminated the thermal hyperalgesia induced by sleep deprivation in a group of nonoperated (i.e., without surgical incision) rats. These data show that even a brief sleep disturbance prior to surgery worsens postoperative pain and are consistent with our hypothesis that adenosine A2A receptors in the MnPO contribute to regulate these sleep-pain interactions.


NIH Stroke Scale reliability in ratings from a large sample of clinicians.
The NIH Stroke Scale (NIHSS) is widely used in stroke clinical care and trials. Certification in its use, most commonly through rating of video vignettes, is routinely required. To investigate the reliability of the NIHSS in a representative sample of raters, we examined the results of the most frequently used certification examination. At the invitation of the National Stroke Association, we analyzed the results of all raters who completed one of two multiple patient videotaped certification examinations from 1998 to 2004. Total scores for each vignette were calculated and ratings were compared based on percentile of responses and modified kappa scores. There were 7,405 unique raters with 38,148 individual NIHSS item responses; median scores for each vignette ranged from 0 to 31. Total NIHSS scores varied widely between raters; scoring for 7 of the 11 patients (64%) had a four or more point difference in NIHSS score from the 5th to 95th percentile. The aphasia (kappa = 0.60) and facial palsy (0.65) items on the test contributed most to the variance in the total NIHSS score. Nurses agreed with the most common response on scoring more frequently than physicians (p < 0.0001). Taking the certification examination multiple times did not improve agreement. In a large diverse sample of clinicians, inter-rater reliability for individual elements of the NIHSS on videotaped vignettes was generally good, but overall scoring was inconsistent and could impact clinical trial results. Whether additional training, modification of examination elements, or clearer definitions for scoring could improve reliability requires further study.


Isolation medium for the recovery of Pseudomonas cepacia from respiratory secretions of patients with cystic fibrosis.
A new medium for the isolation of Pseudomonas cepacia from respiratory tract secretions of patients with cystic fibrosis (CF) is described. This medium consists of inorganic salts, 0.5% pyruvate, and 0.1% proteose peptone as nutritive components and 0.0001% crystal violet, 0.15% bile salts, 100 micrograms of ticarcillin per ml, and 300 U of polymyxin B per ml as selective agents. The medium, designated PC medium, supported superior growth of 38 of 50 stock isolates of P. cepacia after 48 h of incubation when compared with MacConkey agar (0 of 50). The medium completely inhibited the growth of 112 of 124 stock isolates of organisms commonly found in respiratory secretions of CF patients. Cultures were made on PC medium with respiratory secretions of 169 CF patients. P. cepacia was recovered from 35 patients with isolates on PC medium but from only 21 patients with isolates on MacConkey agar. Of 221 other potentially pathogenic isolates found in these specimens, only six (two Pseudomonas aeruginosa isolates, two molds, one yeast, and one Serratia marcescens isolate) grew on PC medium. PC medium should facilitate the recovery of P. cepacia from CF patients.


Diversification of U.S. medical schools via affirmative action implementation.
The diversification of medical school student and faculty bodies via race-conscious affirmative action policy is a societal and legal option for the U.S. Supreme Court has recently ruled its use constitutional. This paper investigates the implications of affirmative action, particularly race-conscious compared to race-blind admissions policy; explains how alternative programs are generally impractical; and provides a brief review of the history and legality of affirmative action in the United States. Selection based solely on academic qualifications such as GPA and MCAT scores does not achieve racial and ethnic diversity in medical school, nor does it adequately predict success as practicing physicians. However, race-conscious preference yields greater practice in underserved and often minority populations, furthers our biomedical research progression, augments health care for minority patients, and fosters an exceptional medical school environment where students are better able to serve an increasingly multicultural society. The implementation of race-conscious affirmative action results in diversity in medicine. Such diversity has shown increased medical practice in underserved areas, thereby providing better health care for the American people.


Stent-assisted Woven EndoBridge device for the treatment of intracranial aneurysms: an international multicenter study.
The Woven EndoBridge (WEB) device is an intrasaccular flow disruptor designed for wide-necked bifurcation aneurysms. These aneurysms may require the use of a concomitant stent. The objective of this study was to determine the clinical and radiological outcomes of patients undergoing stent-assisted WEB treatment. In addition, the authors also sought to determine the predictors of a concomitant stent in aneurysms treated with the WEB device. The data for this study were taken from the WorldWideWEB Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups based on treatment: stent-assisted WEB and WEB device alone. The authors compared clinical and radiological outcomes of both groups. Univariable and multivariable binary logistic regression analyses were performed to determine factors that predispose to stent use. The study included 691 intracranial aneurysms (31 with stents and 660 without stents) treated with the WEB device. The adequate occlusion status did not differ between the two groups at the latest follow-up (83.3% vs 85.6%, p = 0.915). Patients who underwent stenting had more thromboembolic (32.3% vs 6.5%, p < 0.001) and procedural (16.1% vs 3.0%, p < 0.001) complications. Aneurysms treated with a concomitant stent had wider necks, greater heights, and lower dome-to-neck ratios. Increasing neck size was the only significant predictor for stent use. This study demonstrates that there is no difference in the degree of aneurysm occlusion between the two groups; however, complications were more frequent in the stent group. In addition, a wider aneurysm neck predisposes to stent assistance in WEB-treated aneurysms.


Isolation and characterization of microsatellite markers for Cycas debaoensis Y. C. Zhong et C. J. Chen (Cycadaceae).
Cycas debaoensis is one of the critically endangered cycad species endemic to China. In this study, we described the development of six microsatellite markers from the genome of C. debaoensis using the protocol of fast isolation by AFLP of sequences containing repeats (FIASCO) and two microsatellite markers derived from the database of expressed sequence tags (dbEST). Polymorphism of each locus was assessed in 60 adult individuals of the cycad. The average allele number of the microsatellites was 2.6 per locus, ranging from two to five. The observed and expected heterozygosities varied from 0.0833 to 0.7333 and from 0.0805 to 0.7188, respectively. Despite its rarity, only one locus (Y177) deviated from Hardy-Weinberg equilibrium due to the excessive homozygosity. The marker transferability of the eight primer pairs was tested on other four congeneric species that also occur in China.


Providers' experiences caring for adolescents who smoke cigarettes.
To describe providers' experiences screening for and counseling adolescent patients who smoke cigarettes. Eight qualitative focus groups were conducted with 51 health care providers in primary care settings. Focus groups were video- and audiotaped; tapes were transcribed for coding by an interdisciplinary team using the constant comparative method. Providers reported experiences screening for and managing adolescent patients who reported smoking cigarettes. Providers expressed confidence in their ability to screen adolescent patients for tobacco use, particularly as part of regularly scheduled preventive and medical visits. Providers reported difficulty balancing screening for smoking with their concern for maintaining rapport with their adolescent patients. In addition, providers reported that adolescent smoking patterns differed from those of adults, and consequently, providers were not certain at what level of smoking an adolescent required intervention. Furthermore, providers were unclear regarding what interventions were recommended for and effective with adolescents. Providers are interested in adolescent evidence-based screening methods and cessation interventions that are supportive of a nonjudgmental and empathic approach to caring for adolescent smokers, particularly those with irregular and situational smoking patterns.


Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.
Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG) was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies.


IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro.
Distinctive properties of stem cells are not autonomously achieved, and recent evidence points to a level of external control from the microenvironment. Here, we demonstrate that self-renewal and pluripotent properties of human embryonic stem (ES) cells depend on a dynamic interplay between human ES cells and autologously derived human ES cell fibroblast-like cells (hdFs). Human ES cells and hdFs are uniquely defined by insulin-like growth factor (IGF)- and fibroblast growth factor (FGF)-dependence. IGF 1 receptor (IGF1R) expression was exclusive to the human ES cells, whereas FGF receptor 1 (FGFR1) expression was restricted to surrounding hdFs. Blocking the IGF-II/IGF1R pathway reduced survival and clonogenicity of human ES cells, whereas inhibition of the FGF pathway indirectly caused differentiation. IGF-II is expressed by hdFs in response to FGF, and alone was sufficient in maintaining human ES cell cultures. Our study demonstrates a direct role of the IGF-II/IGF1R axis on human ES cell physiology and establishes that hdFs produced by human ES cells themselves define the stem cell niche of pluripotent human stem cells.


The science of talk in clinical science: using a conversation analytic approach as a foundation for communication skills training.
This article was migrated. The article was marked as recommended. Communication skills are considered a central part of medical and health professional curricula. The focus for both theoretical knowledge and practical skills in these curricula is often, necessarily, on that which is directly relevant to consultations and other clinical activities. Prior to engaging in this more specific and often experiential learning, it is arguable that the inclusion of foundational learning around how interaction works to adequately scaffold more specific, clinically-contextualised learning, building through the zone of proximal development. In this paper, I describe a conversation analysis-informed curriculum for communication skills in an undergraduate pre-clinical science degree which is designed to enhance the ability to critically and constructively reflect on their own communication.


Clustering of Chromatin Remodeling Enzymes Predicts Prognosis and Clinical Benefit of Therapeutic Strategy in Pancreatic Cancer.
In recent years, translational research and pharmacological targeting of epigenetic modifications have become the focus of personalized therapy for patients with pancreatic cancer. Preclinical and clinical trials targeting post-translational modifications have been evaluated as monotherapy or in combination with standard chemotherapy. In this study, we selected 43 genes from seven families of chromatin-modifying enzymes and investigated the influences of epigenetic modifications and their interactions on pancreatic ductal adenocarcinoma (PDAC) using hierarchical clustering analysis. Our analysis also evaluated their effects on treatment modalities and regimens of chemotherapy for PDAC. RNA-seq data for a total of 177 patients with pancreatic cancer, obtained from The Cancer Genome Atlas database, were analyzed. Our results suggested that high-risk patients of survival significant chromatin remodeling-associated gene cluster (gene cluster 2), composed of histone methyltransferases, histone acetyltransferases, histone deacetylases, histone demethylases, and 10-11 translocation family, demonstrated inferior progression-free survival and overall survival in patients with PDAC, especially in men. Our novel biomarker, survival significant chromatin remodeling-associated gene cluster, showed superior prediction performance compared with the conventional TNM system. Overall, these findings suggest that epigenetic modifications and interactions play an important role in the prognosis and therapeutic response of patients with PDAC.


Functional analysis of the human NRAMP family expressed in fission yeast.
The Bcg/Ity/Lsh locus in the mouse genome regulates macrophage activation for antimicrobial activity against intracellular pathogens, and the positional cloning of this locus identified the Nramp1 (natural resistance-associated macrophage protein) gene. Nramp2 was initially isolated as a homologue of Nramp1. Recently, the rat divalent metal transporter DMT1 was identified electrophysiologically, and was found to be an isoform of Nramp2, a mutation which was subsequently identified in rats suffering from hereditary iron-deficiency anaemia. Despite the 64% amino acid sequence identity of Nramp1 and Nramp2, no divalent metal transport activity has yet been detected from Nramp1, and the function of Nramp1 on the molecular level is still unclear. To investigate the divalent metal transport activity of NRAMP molecules, we constructed four chimeric NRAMP genes by swapping the domains of human NRAMP1 and NRAMP2 with each other. The functional characteristics of wild-type NRAMP1, NRAMP2 and their chimeras were determined by expression in the divalent metal transporter-disrupted strain of fission yeast, pdt1Delta, and we analysed the divalent metal transport activity by complementation of the EGTA- and pH-sensitive phenotype of pdt1Delta. Replacement of the N-terminal cytoplasmic domain of NRAMP2 with the NRAMP1 counterpart resulted in inactive chimeras, indicating that the functional difference between NRAMP1 and NRAMP2 is located in this region. However, results obtained with the reverse construct and other chimeras indicated that these regions are not solely responsible for the differences in EGTA- and pH-sensitivity of NRAMP1 and NRAMP2. These findings indicate that NRAMP1 itself cannot represent the divalent metal transport activity in S. pombe and the additional protein segments of the molecules located elsewhere in NRAMP1 are also functionally distinct from their NRAMP2 counterparts.


Muscle mechanoreflex augments arterial baroreflex-mediated dynamic sympathetic response to carotid sinus pressure.
Although the muscle mechanoreflex is one of the pressor reflexes during exercise, its interaction with dynamic characteristics of the arterial baroreflex remains to be quantitatively analyzed. In anesthetized, vagotomized, and aortic-denervated rabbits (n = 7), we randomly perturbed isolated carotid sinus pressure (CSP) using binary white noise while recording renal sympathetic nerve activity (SNA) and arterial pressure (AP). We estimated the transfer functions of the baroreflex neural arc (CSP to SNA) and peripheral arc (SNA to AP) under conditions of control and muscle stretch of the hindlimb (5 kg of tension). The muscle stretch increased the dynamic gain of the neural arc while maintaining the derivative characteristics [gain at 0.01 Hz: 1.0 +/- 0.2 vs. 1.4 +/- 0.6 arbitrary units (au)/mmHg, gain at 1 Hz: 1.7 +/- 0.6 vs. 2.7 +/- 1.4 au/mmHg; P < 0.05, control vs. stretch]. In contrast, muscle stretch did not affect the peripheral arc. In the time domain, muscle stretch augmented the steady-state response at 50 s (-1.1 +/- 0.3 vs. -1.7 +/- 0.7 au; P < 0.05, control vs. stretch) and negative peak response (-2.1 +/- 0.5 vs. -3.1 +/- 1.5 au; P < 0.05, control vs. stretch) in the SNA step response. A simulation experiment using the results indicated that the muscle mechanoreflex would accelerate the closed-loop AP regulation via the arterial baroreflex.


Lipophorin Receptors Genetically Modulate Neurodegeneration Caused by Reduction of Psn Expression in the Aging Drosophila Brain.
Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset familial Alzheimer's disease (FAD). Studies in cell culture, in vitro biochemical systems, and knockin mice showed that PSEN mutations are loss-of-function mutations, impairing γ-secretase activity. Mouse genetic analysis highlighted the importance of Presenilin (PS) in learning and memory, synaptic plasticity and neurotransmitter release, and neuronal survival, and Drosophila studies further demonstrated an evolutionarily conserved role of PS in neuronal survival during aging. However, molecular pathways that interact with PS in neuronal survival remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal survival, we developed a new Drosophila Psn model that exhibits age-dependent neurodegeneration and increases of apoptosis. Following a bioinformatic analysis, we tested top ranked candidate genes by selective knockdown (KD) of each gene in neurons using two independent RNAi lines in Psn KD models. Interestingly, 4 of the 9 genes enhancing neurodegeneration in Psn KD flies are involved in lipid transport and metabolism. Specifically, neuron-specific KD of lipophorin receptors, lpr1 and lpr2, dramatically worsens neurodegeneration in Psn KD flies, and overexpression of lpr1 or lpr2 does not alleviate Psn KD-induced neurodegeneration. Furthermore, lpr1 or lpr2 KD alone also leads to neurodegeneration, increased apoptosis, climbing defects, and shortened lifespan. Lastly, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 or lpr2 similarly lead to age-dependent neurodegeneration and further exacerbate neurodegeneration in Psn KD flies. These findings show that LpRs modulate Psn-dependent neuronal survival and are critically important for neuronal integrity in the aging brain.


Betanin protects against bleomycin-induced pulmonary fibrosis by regulating the NLRP3/IL-1β/TGF-β1 pathway-mediated epithelial-to-mesenchymal transition.
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease that leads to dyspnea and progressive loss of lung function. This study aimed to investigate the protective effect of betanin (BET), the major pigment in red beetroot, on pulmonary fibrosis induced by bleomycin (BLM) in rats and to assess the underlying mechanisms. In this view, total and differential cell counts and LDH activity in bronchoalveolar lavage fluid were estimated. Furthermore, MDA and GSH contents in the lungs were colorimetrically measured, while hydroxyproline, NLRP3, ASC, caspase-1, TGF-β1, and vimentin levels in lung tissue were evaluated using the ELISA technique. Moreover, IL-1β, E-cadherin, and α-SMA expressions were analyzed by immunostaining of lung specimens. BET treatment protects against pulmonary fibrosis as indicated by the reduction in total and differential cell counts, LDH activity, hydroxyproline, NLRP3, ASC, caspase-1, IL-1β, and TGF-β1 levels. MDA content was also decreased following BET administration, while GSH content was elevated. Additionally, BET suppressed the EMT process as evidenced by an increase in E-cadherin expression besides the reduction in vimentin and α-SMA expressions. To conclude, these results revealed the protective effect of BET against pulmonary fibrosis that might be attributed to the attenuation of the NLRP3/IL-1β/TGF-β1 signaling pathway and EMT process.


The mistress, the midwife, and the medical doctor: pregnancy and childbirth on the plantations of the antebellum American South, 1800-1860.
This article represents a step towards examining the relationship between three key figures in the antebellum American South: the plantation mistress, the slave-midwife, and the professional male physician. It elucidates how the experiences of pregnancy and childbirth, which brought women close to death, formed the basis of a deeper, positive relationship between the black and white women of the antebellum South, and assesses the ways in which the professionalization of medicine affected this reproductive bond. Evaluating such a complicated network of relationships necessitates dissecting numerous layers of social interaction, including black and white women's shared cultural experiences and solidarity as reproductive beings; the role, power, and significance of slave-midwives and other enslaved caretakers in white plantation births; the cooperation between pregnant bondswomen and plantation mistresses; and the impact that the burgeoning profession of medicine had on the procreative union between antebellum black and white women.


Studies on the mechanisms of allergen-induced activation of the classical and lectin pathways of complement.
Allergen extracts are efficient activators of the complement system trough the classical pathway. Involvement of the lectin pathway was not previously studied. To further examine the mechanism of complement activation by allergens, in vitro experiments, which covered early steps both of classical and lectin pathways, were performed. Two types of allergens used in these studies: parietaria (PA) and house dust (HD) mite extracts. These allergen extracts bound to the globular head of C1q and interacted with purified mannan-binding lectin (MBL) as measured by solid-phase ELISA. None of the allergen extracts was able to activate human C1 in vitro, as measured by the determination of the split products of C1s in a reconstituted precursor C1 preparation. Neither the HD nor the PA extracts induced C4d generation above background in the serum of three subjects with hypogammaglobulinaemia but normal complement haemolytic activity. After reconstitution to normal level with purified human IgG, allergen extracts induced C4d formation above control at a level comparable to that measured in normal serum incubated with the same amounts of the extracts. HD-induced C4d generation was about the same comparable in MBL-depleted serum and in normal sera. In contrast PA induced no C4d formation in the MBL-depleted serum, whereas reconstitution with purified MBL restored C4d generation. These in vitro findings indicate that although the allergen extracts can bind purified C1q and MBL, they require IgG for efficient complement activation. Depending on the allergens, this activation may be initiated through C1, MBL, or both.


Trends in female breast cancer incidence, mortality, and survival in Austria, with focus on age, stage, and birth cohorts (1983-2017).
Breast cancer (BC) is the most commonly diagnosed malignant disease and the leading cause of cancer death in women in Austria. We investigated overall and subgroup-specific female breast cancer rates to provide a comprehensive analysis of trends over several decades. Incidence, mortality, and survival, as well as age-, stage-, and birth cohort-specific incidence were analysed using nationwide cancer registry data on 163,694 cases of female breast cancer in Austria (1983-2017). Annual percentage changes were estimated using joinpoint regression. BC incidence underwent linear increases until 1997 and reversed with statistically non-significant declines until 2017. After initial increases in BC-specific mortality, rates were stable from 1989 through 1995 and started declining thereafter, although statistically non-significantly after 2011. Overall BC-specific survivals, as well as survivals according to the calendar period of diagnosis, increased throughout the observation period. Incidence in younger women (aged 44 and lower) showed linear increases, whereas for women aged 45 and higher mostly stable or decreasing rates were observed. Localised BC incidence increased markedly and started declining only in 2012. Distant disease-BC incidence decreased through the whole observation period and incidence of regionalised BC started declining in 2000. Birth cohort-specific incidence peaked in women born between 1935 and 1949 (ages 45-74). In conclusion, the incidence of BC in younger women is increasing, while overall female BC incidence and mortality are stable with non-significant declines. Further, increases in the incidence of early-stage BC (localised) seem disproportionately high in comparison to more modest decreases in late-stage BC incidence (regionalised and distant disease).


Acaricidal Activity and Synergistic Effect of Thyme Oil Constituents against Carmine Spider Mite (Tetranychus Cinnabarinus (Boisduval)).
Studies examining the use of essential oils as replacements for synthetic insecticides require an understanding of the contribution of each constituent present, interactions among these components, and how they relate to overall toxicity. In the present study, the chemical composition of commercial thyme oil was identified by gas chromatography-mass spectrometry. Thyme oil and blends of its major constituents were tested for their acaricidal activitities against carmine spider mites (Tetranychus cinnabarinus (Boisduval)) using a slide-dip bioassay. Natural thyme oil showed greater toxicity than any single constituent or blend of constituents. Thymol was the most abundant component (34.4%), and also possessed the strongest acaricidal activity compared with other single constituents. When tested individually, four constituents (linalool, terpinene, p-cymene and carvacrol) also had activity, while α-pinene, benzoic acid and ethyl gallate had almost no activity. The toxicity of blends of selected constituents indicated a synergistic effect among the putatively active and inactive constituents, with the presence of all constituents necessary to reach the highest toxicity. The results indicated that thyme oil and some of its major constituents have the potential to be developed into botanical acaricides.


[Aspects of risk stratification in acute coronary syndrome (Part II): Prognostic value of evaluation of exercise-induced myocardial ischemia according to the data of pharmacological stress echocardiography].
To define the prognostic value of evaluation exercise-induced myocardial ischemia according to the data of pharmacological (dobutamine or dipyridamole) stress echocardiography (EchoCG) in patients with acute coronary syndrome (ACS). The results of examinations were analyzed in a total of 91 patients with ACS. An analysis of events in the established follow-up period (mean 14.3 +/- 0.7 months) took into consideration outcomes, such as death from cardiac diseases, a recurrent acute coronary episode (nonfatal myocardial infarction (MI), unstable angina (UA). Pharmacological stress EchoCG showed a positive result in 40 (44%) patients (Group 1) and a negative one in 51 (56%) patients (Group 2). Thus, the sensitivity and specificity of the pharmacological test in determining the risk for cardiac events were 89.3 and 76.2%, respectively; the prognostic value of positive and negative results was 62.5 and 94.1%, respectively. Analysis of EchoCG parameters used to identify poor prognostic factors in patients with ACS has indicated that the most important predictors of death and major cardiac events (cardiac death, acute MI, UA) are resting impaired segmental contractility index (ISCI), number of asynergic segments, and total ejection fraction (TEF) at baseline; TEF, ISCI, deltaISCI (as compared to the baseline data), and the number of segments with a negative response after low-dose drug infusion; a positive or negative result, TEF, deltaTEF (as compared to the baseline data), and ISCL at the test peak. Pharmacological stress EchoCG is a safe noninvasive diagnostic method in a group of patients with ACS. When the latter is diagnosed, it may be performed in the earliest periods (on day 4 after onset of the disease) to estimate its prognosis and to decide whether aggressive treatments should be used.


Surgical psycho-ophthalmology and contracted sockets.
Surgical psycho-ophthalmology is the integration of ophthalmic surgery and medicine with basics in psychiatry and psychology, lest the psyche be forgotten amid the spectacular leaps in techniques and technology, or our judgment be veiled by our related psychodynamics [1]. Its scope encompasses a much broader spectrum than the conventional psychosomatic eye diseases. Besides due consideration of the psychological and physical conditions of patients, it increases the awareness of the surgeons' psychodynamics that reflect on our continuing judgment before, during, and after surgery. Further, surgical psycho-ophthalmology impacts on the indications, timing, planning, and performance of each individual operation and/or reoperation. It equally emphasizes both the psychologic priming of patients and attuning of the surgical team. In establishing and maintaining rapport with the patient, surgical psycho-ophthalmology helps to curb the growing problems of malpractice, iatrogenicity, and noncompliance. It also stresses careful weighing of the risk/benefit ratio in adherence to the surgical axiom: "primum non nocere". Despite all advances and ingenuity in contracted socket surgery, the challenge still remains. However, with the proper evaluation and management in the perspective of psycho-ophthalmology we may achieve success, not only in esthetics, but also in sight preservation, and even in life salvage.


[Morphology of the lymphoid tissue of the bronchus in healthy persons of various ages, and the effect of smoking].
Bronchoassociated lymphoid tissue (BALT) is studied histologically and morphometrically in 49 autopsy cases of persons of various ages after violent death. Lymphoepithelial follicles typical for BALT of small laboratory animals were not observed in human lungs of healthy persons. BALT structural components are represented by interepithelial lymphocytes, diffusely scattered lymphocytes in the mucous membrane tunica propria, lymphoid agglomerations (focal loose agglomerations in the mucous membrane tunica propria, focal periglandular and dense periductal, dense peribronchial and peribronchiolar agglomerations). According to the morphometrical study, there is BALT hyperplasia at young and adolescent ages and involutive changes at advanced age. Reduction of periglandular lymphoid agglomerations and an increase of the alveolar macrophages number were observed in adult persons who smoked for many years.


Phase II prospective study with sorafenib in advanced soft tissue sarcomas after anthracycline-based therapy.
We investigated the activity and safety of sorafenib, a multitargeted tyrosine-kinase inhibitor, in patients with advanced soft tissue sarcomas (STS). An open-label nonrandomised multicentre phase II study was conducted in advanced STS patients pre-treated with anthracycline-based chemotherapy. Patients received sorafenib 400 mg twice daily for 28 days. The primary end point was the progression-free survival (PFS) rate at 6 months. Toxicity was assessed. Clinical outcomes were evaluated in all histologies and in leiomyosarcoma (L) and angiovascular sarcomas (A). Between November 2006 and January 2010, 101 patients (36 L, 19 A, and 46 others) were enrolled; 76 patients per-protocol (PP) and 100 per intention-to-treat (ITT) were assessable for the primary end point. In the PP analysis, 11 (14.5%) achieved partial response and 25 (32.9%) stable disease; 6-month PFS rates were all histologies, 34.5%; L, 38.4%; and A, 56.3%. In the ITT analysis, 6-month PFS results were 27.1, 35, and 35.5% in all histologies, L, and A, respectively. When stratified by histology, we observed a better PFS favouring leiomyosarcoma versus other histologies (P = 0.033). Treatment was well tolerated. Sorafenib appears to be a promising option in leiomyosarcoma patients. This finding warrants further evaluation in histology-driven trials.


Anti-heat shock protein autoantibody profiling in breast cancer using customized protein microarray.
Heat shock proteins (HSPs) are over-expressed in a wide range of human cancers. It results in the stimulation of the immune system and consequently in elevated concentration of anti-HSP autoantibodies. Elevated anti-HSP autoantibodies were found in breast cancer patients, and they are associated with tumor metastasis. Therefore, screening these autoantibodies could be of diagnostic and prognostic values. Protein microarrays have already demonstrated their great potential as a diagnostic tool. However, protein diversity requires optimization of the microarray fabrication to achieve high sensitivity and specificity. In this study, seven HSPs were immobilized on six different surface chemistries. After evaluation and optimization with purified antibodies of the six surface chemistries, two surfaces were selected to detect anti-HSP autoantibodies in breast cancer sera. Multiplex detection of anti-HSP autoantibodies allowed discrimination of breast cancer patients (50) from healthy controls (26) with a sensitivity of 86% and a specificity of 100%.