Right identification of the substantial energy source in biochemical processes as a necessary prerequisite for coherent development of medical sciences.
Because of essential dependence of medical sciences on basic sciences, eventual misconceptions in basic sciences may exert a profound detrimental effect on medical sciences. One such example relates to a concept taken from chemistry that the reducing agent represents the substantial energy source in the process of oxido-reduction. While the recognition of the substantial source of energy is of little importance in technique, it is of utmost importance in medicine for assessment of results of interactions in vivo of various energetic forms and particularly for appreciation of consequences of energy exchange on dynamics of organismal structure. Three proofs are given here that the oxidizing agent, not the reducing agent, is the source of energy in chemical and biochemical oxido-reductive processes. On the other hand, energy content of organic substances being major organismal constituents is represented mostly by energy stored in chemical bonds between their monomeric units. Circumstantial evidence indicates that energy content of one chemical bond between monomeric units per a weight unit is lower in lipids than in proteins or carbohydrates. Regarding structural disorders, there are principally two opposite, mutually exclusive phenomenons: degeneration resulting from loss of energy on one side, and hypergeneration enabled by excess of energy on the other. Disorders of stress and obesity represent states with relative lack of energy. While stress implies a degenerative process usually resulting from acute loss of energy, obesity represents a chronic disturbance of proportions of constitutive substances of the body in favour of less energy-rich substances and therefore might be regarded as a kind of degeneration. The phenomenon of hypergeneration, being contrary to degeneration usually appears as a local overformation of structure called neoplasia.


Preoperative ultrasound-guided needle biopsy of 63 uterine tumors having high signal intensity upon T2-weighted magnetic resonance imaging.
The differential diagnosis between uterine sarcoma and benign leiomyoma is difficult when made only by magnetic resonance imaging (MRI); it usually requires an additional preoperative diagnostic procedure. We report our results using ultrasound-guided needle biopsy for these types of uterine tumors. Ultrasound-guided needle biopsy was performed on 63 patients with uterine smooth muscle tumors suspected of malignancy by MRI. We compared the results of presurgical biopsy against the postsurgical pathology of the tumor. Among 63 patients with a high signal intensity of the uterine tumor on T2-weighted MRI (1 case was undetermined), 12 cases (19.3%) were diagnosed by the needle biopsy as malignant, and 51 cases (80.6%) were benign. Among the 12 diagnosed as malignant tumors, 11 had surgery performed, and one was treated with chemotherapy. Among the 51 patients diagnosed with a benign tumor, 27 had surgery performed, and 24 were put on a wait-and-see clinical follow-up schedule. One of the 27 surgical patients with a benign tumor had a postsurgical diagnosis of a low-grade endometrial stromal sarcoma. In the 38 cases where surgery was performed, we found the sensitivity, specificity, and the positive and negative predictive values of the needle biopsy were 91.7%, 100%, 100%, and 96.2%, respectively. Ultrasound-guided needle biopsy may be a reliable preoperative diagnostic procedure for uterine tumors with suspected malignancy.


Annual Tuberculosis Preventive Therapy for Persons With HIV Infection : A Randomized Trial.
Tuberculosis preventive therapy for persons with HIV infection is effective, but its durability is uncertain. To compare treatment completion rates of weekly isoniazid-rifapentine for 3 months versus daily isoniazid for 6 months as well as the effectiveness of the 3-month rifapentine-isoniazid regimen given annually for 2 years versus once. Randomized trial. (ClinicalTrials.gov: NCT02980016). South Africa, Ethiopia, and Mozambique. Persons with HIV infection who were receiving antiretroviral therapy, were aged 2 years or older, and did not have active tuberculosis. Participants were randomly assigned to receive weekly rifapentine-isoniazid for 3 months, given either annually for 2 years or once, or daily isoniazid for 6 months. Participants were screened for tuberculosis symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24 using chest radiography and sputum culture. Treatment completion was assessed using pill counts. Tuberculosis incidence was measured over 24 months. Between November 2016 and November 2017, 4027 participants were enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women; all using antiretroviral therapy). Treatment completion in the first year for the combined rifapentine-isoniazid groups (n = 3610) was 90.4% versus 50.5% for the isoniazid group (n = 404) (risk ratio, 1.78 [95% CI, 1.61 to 1.95]). Tuberculosis incidence among participants receiving the rifapentine-isoniazid regimen twice (n = 1808) or once (n = 1802) was similar (hazard ratio, 0.96 [CI, 0.61 to 1.50]). If rifapentine-isoniazid is effective in curing subclinical tuberculosis, then the intensive tuberculosis screening at month 12 may have reduced its effectiveness. Treatment completion was higher with rifapentine-isoniazid for 3 months compared with isoniazid for 6 months. In settings with high tuberculosis transmission, a second round of preventive therapy did not provide additional benefit to persons receiving antiretroviral therapy. The U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.


Fat augmentation following microsurgical removal of the vocal nodules: long-term results.
While the effectiveness of autogenous fat augmentation after microsurgical removal (FAMSR) of the vocal nodules (VN) has been previously shown in patient treatment programs, relatively little information is available regarding the long-term effectiveness of such a procedure. This paper examines, in retrospect, the long-term effectiveness of FAMSR in patients with VN (n = 41) using pre- and post-FAMSR perceptual acoustic and phonatory function data and videolaryngostroboscopic findings for 33 patients. The mean follow-up time was 18 months. Thirty-three (80.4%) patients displayed excellent results; 4 (9.8%) experienced improvement, and 4 (9.8%) postprocedure failure. Patient phonatory functions showed significant improvements in shimmer, harmonic-to-noise ratio, phonation time (p < 0.05), grade, roughness and breathiness (p < 0.001). The videolaryngostroboscopic rating showed significant improvements in vocal fold edge linearity, vocal fold vibration amplitude, and mucosal wave excursion (p < 0.001). Improvements observed through long-term follow-up tended to be less dramatic in patients with recurrent VN than those with nonrecurrent VN. FAMSR is an easy, safe, and fast procedure which should be considered as an option in treating VN patients who either require surgery or do not have the time or perseverance to complete a lengthy program of speech therapy.


Exchange of phospholipids between brain membranes in vitro.
1. When unlabelled mitochondria from guinea-pig brain were incubated with a (32)P-labelled microsomal fraction from brain there was a transfer of phospholipid to the mitochondria, which could not be accounted for by an aggregation of microsomes and mitochondria or an exchange with microsomes contaminating the mitochondria. Under similar circumstances there was a transfer of phospholipid from (32)P-labelled mitochondria to microsomes, indicating that the process was one of exchange. 2. The transfer from microsomes was greatly stimulated by a non-dialysable heat-labile macromolecular component in the brain supernatant fraction but not by the concentration of the particulate fractions. 3. Phospholipid-exchange processes occurred most readily between pH7 and 7.5 and were inhibited by the presence of myelin and on the addition of lysophosphatidylcholine. 4. The rates of transfer of individual phospholipids from brain microsomes to mitochondria were similar. 5. (32)P-labelled microsomes could slowly donate phospholipid to the isolated synaptosomal (nerve-ending) fraction but the phospholipids of the myelin fraction did not exchange. 6. Subfractionation of the synaptosomal fraction after [(32)P]phospholipid transfer showed that the mitochondria were most actively labelled during the incubation. All of the isolated individual synaptosomal membranes were capable of acquiring phospholipid on incubation with a (32)P-labelled brain supernatant fraction although a greater percentage was again exchanged by the mitochondrial fraction.


A General Copper Catalytic System for Suzuki-Miyaura Cross-Coupling of Unactivated Secondary and Primary Alkyl Halides with Arylborons.
Suzuki-Miyaura cross-couplings (SMC) are powerful tools for the construction of carbon-carbon bonds. However, the couplings of sp3-hybridized alkyl halides with arylborons often encounter several problematic issues such as sluggish oxidation addition of alkyl halides and competitive β-hydride elimination side pathways of metal-alkyl species. In precedent reports, copper is mainly utilized for the coupling of sp2-aryl halides, and the cross-couplings with unactivated alkyl halides are far less reported. Herein, we demonstrate that a high-efficiency copper system enabled the coupling of arylborons with various unactivated secondary and primary alkyl halides including bromides, iodides, and even robust chlorides. The present system features broad scope, excellent functionality tolerance, scalability, and practicality. Moreover, the current system could be applied for the late-stage functionalization of complex molecules in moderate to high efficiency.


Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury.
Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI.


Clearance rate of serum-free and total PSA following radical retropubic prostatectomy.
Our objective was to determine the clearance rate of free and total serum PSA following radical retropubic prostatectomy. Sera were obtained from 10 men with localized prostate cancer prior to and 1, 4, 8, 24, 48, and 72 hr after radical prostatectomy. No patient received any postoperative blood transfusion. Free and total PSA were measured using the Hybritech Tandem-R (total PSA) and radioimmunometric free PSA assay. Postsurgery serum-free and total PSA concentrations were modeled using a "two-compartment" pharmacokinetic model. The pharmacokinetic model with an initial constant "infusion" suggests that, following release from the prostate, both free and total PSA are taken up into a second compartment for metabolism. The movement of PSA between these compartments was accurately modeled. Following surgery, there is a shift of both free and total PSA best modeled as a constant infusion into the serum at a rate of 1.97 and 1.60 ng/ml, respectively, for a period of approximately 1 hr. Following this initial constant infusion, the half-life estimations for free and total PSA are initially 1.2 and 0.75 hr, respectively, which then increase to 22 and 33 hr, respectively. Serum free and total PSA are cleared from the circulation following a "two-compartment" model with an initial constant "infusion." The constant "infusion" is most likely a consequence of surgical manipulation. The initial half-life estimates are < 2 hr for both free and total PSA, and later increase to 22 and 33 hr, respectively.


Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.
It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.


Decreased sex ratio following maternal exposure to polychlorinated biphenyls from contaminated Great Lakes sport-caught fish: a retrospective cohort study.
Fish from the Great Lakes are contaminated with polychlorinated biphenyls, which have been found to have several adverse reproductive effects. Several environmental contaminants have been found to alter the sex ratio of offspring at birth, but the evidence of such an effect of polychlorinated biphenyls has been inconsistent. We examined parental serum polychlorinated biphenyl concentration in relation to the sex ratio of 173 children of mothers and 208 children of fathers from the Great Lakes region of the United States between 1970 and 1995. We calculated odds ratios for a male child using logistic regression and generalized estimating equations with adjustment for the year of birth of the child, maternal and paternal age, the mother's parity at the child's birth, and whether the child had an older brother. The adjusted odds ratio for having a male child among mothers in the highest quintile of serum polychlorinated biphenyl concentration was 0.18 (95% CI: 0.06-0.59) compared to mothers in the lowest quintile. Treating exposure as a continuous variable, the adjusted odds ratio for having a male child was 0.54 per unit increase in the natural log of maternal serum polychlorinated biphenyl concentration (95% CI: 0.33-0.89). There was little evidence of an association with paternal exposure. We found no association between either maternal or paternal serum dichlorodiphenyl-dichloroethene concentration and the sex ratio. These findings suggest that maternal exposure to polychlorinated biphenyls may decrease the sex ratio of offspring. These data add to the growing body of evidence that exposure to particular chemicals can alter the sex ratio at birth.


Epidemiology of biopsy proven giant cell arteritis in northwestern Spain: trend over an 18 year period.
In Europe giant cell arteritis (GCA) is more common in Scandinavian countries than in southern regions. Epidemiological studies on GCA in other more distant countries have indicated a progressive increase in incidence. A regular cyclical pattern in incidence of GCA over 20 years has been reported in Olmsted County (Minnesota, USA). In contrast, no cyclical fluctuation has been recently reported in Sweden. To investigate further the epidemiology of GCA in southern Europe the trend in incidence and fluctuations of this vasculitis over 18 years in the Lugo region of northwestern Spain were examined. A retrospective study of biopsy proven GCA diagnosed between 1 January 1981 and 31 December 1998 at a single hospital for a well defined population of almost 250 000 people. Annual incidence was calculated for the whole group of patients and for men and women separately. Monthly variations, annual peaks of incidence, and trend in the incidence of biopsy proven GCA with and without polymyalgia rheumatica (PMR) were also examined. One hundred and sixty one Lugo residents were diagnosed with biopsy proven GCA between 1981 and 1998. The average annual incidence for the population aged 50 and older was 10.24/100 000 (men 11.00/100 000, women 9.57/100 000). A progressive increase in the incidence in both men and women was seen. In men there was an annual increase of 8% (95% CI 4% to 13%; p<0.0001). In women the annual increase was 11% (95% CI 5% to 17%; p<0.0001). The overall annual increase for men and women was 10% (95% CI 6% to 14%; p<0.0001). No seasonal pattern or peaks in the incidence were seen. During the period 1981-94 GCA was more common in men than in women. In contrast, during the last years of study the increase in incidence was higher in women. In women the annual ratio of incidence of GCA with PMR/incidence of GCA without PMR was generally higher than 1. However, in men the annual ratio was initially 1 but decreased gradually, indicating a progressive decrease in the proportion of men with biopsy proven GCA associated with PMR. In northwestern Spain there has been a progressive increase in GCA incidence. As seen in other countries where GCA is more common, during the past few years the increase in incidence has been mainly due to a higher number of new cases in women.


Single-Organelle Quantification Reveals Stoichiometric and Structural Variability of Carboxysomes Dependent on the Environment.
The carboxysome is a complex, proteinaceous organelle that plays essential roles in carbon assimilation in cyanobacteria and chemoautotrophs. It comprises hundreds of protein homologs that self-assemble in space to form an icosahedral structure. Despite its significance in enhancing CO2 fixation and potentials in bioengineering applications, the formation of carboxysomes and their structural composition, stoichiometry, and adaptation to cope with environmental changes remain unclear. Here we use live-cell single-molecule fluorescence microscopy, coupled with confocal and electron microscopy, to decipher the absolute protein stoichiometry and organizational variability of single β-carboxysomes in the model cyanobacterium Synechococcus elongatus PCC7942. We determine the physiological abundance of individual building blocks within the icosahedral carboxysome. We further find that the protein stoichiometry, diameter, localization, and mobility patterns of carboxysomes in cells depend sensitively on the microenvironmental levels of CO2 and light intensity during cell growth, revealing cellular strategies of dynamic regulation. These findings, also applicable to other bacterial microcompartments and macromolecular self-assembling systems, advance our knowledge of the principles that mediate carboxysome formation and structural modulation. It will empower rational design and construction of entire functional metabolic factories in heterologous organisms, for example crop plants, to boost photosynthesis and agricultural productivity.


A Historical Perspective of Healthcare Disparity and Infectious Disease in the Native American Population.
The incidence and severity of COVID-19 infections have been disproportionately high in Native American populations. Native Americans are a high-risk group for COVID-19 because of a variety of healthcare disparities. Historically, these populations suffered excessively during previous epidemics in the United States (US). Several epidemics occurred when disease-naïve indigenous peoples were exposed to European settlers with herd immunity. Native American populations had four times higher mortality in the 1918 Spanish flu epidemic. Deaths from H1N1 infections were higher in Native Americans and most cases and deaths from the Hantavirus pulmonary syndrome (HPS) occurred in Native Americans. Other infectious diseases, including HIV, hepatitis A and hepatitis C are more also common. Diabetes, alcoholism and cardiovascular diseases, all risk factors for severity and mortality in COVID-19 infection, are also more common in this group. Addressing the root causes of enhanced risk in Native American populations will improve outcomes from COVID-19 and future pandemics.


Age related extracellular matrix and interstitial cell phenotype in pulmonary valves.
Heart valve disease is a common manifestation of cardiovascular disease and is a significant cause of cardiovascular morbidity and mortality worldwide. The pulmonary valve (PV) is of primary concern because of its involvement in common congenital heart defects, and the PV is usually the site for prosthetic replacement following a Ross operation. Although effects of age on valve matrix components and mechanical properties for aortic and mitral valves have been studied, very little is known about the age-related alterations that occur in the PV. In this study, we isolated PV leaflets from porcine hearts in different age groups (~ 4-6 months, denoted as young versus ~ 2 years, denoted as adult) and studied the effects of age on PV leaflet thickness, extracellular matrix components, and mechanical properties. We also conducted proteomics and RNA sequencing to investigate the global changes of PV leaflets and passage zero PV interstitial cells in their protein and gene levels. We found that the size, thickness, elastic modulus, and ultimate stress in both the radial and circumferential directions and the collagen of PV leaflets increased from young to adult age, while the ultimate strain and amount of glycosaminoglycans decreased when age increased. Young and adult PV had both similar and distinct protein and gene expression patterns that are related to their inherent physiological properties. These findings are important for us to better understand the physiological microenvironments of PV leaflet and valve cells for correctively engineering age-specific heart valve tissues.


Effect of small doses of deoxycholic acid on bile cholesterol saturation in patients with liver cirrhosis.
To test the hypothesis that the detergent power of each individual bile acid--that is, its separate capacity to solubilize cholesterol and to induce biliary cholesterol secretion, present in the biliary bile acid mixture might be one of the determinant factors of biliary cholesterol saturation, we studied the effect of feeding small doses of deoxycholic acid on biliary cholesterol saturation in patients with liver cirrhosis and low deoxycholic acid pool. Eleven hospitalised patients with cirrhosis of various degree of severity were put on a standard solid diet. Fasting bile rich duodenal fluid was obtained at the beginning of the study, after a three to four weeks treatment with deoxycholic acid (3 mg/kg/day, in two doses) and one month after discontinuing bile acid ingestion. Before treatment the fraction of deoxycholic acid was 5.3 +/- 4.9% (mean +/- SD); after treatment the fraction rose to 43.9 +/- 12.0 of total bile acids, but returned to the basal values after stopping bile acids. Bile cholesterol saturation increased significantly from a mean of 0.92 +/- 0.26 (before treatment) to a mean of 1.34 +/- 0.34 after deoxycholic acid feeding (p less than 0.005). One month after treatment, bile saturation was not significantly different from the basal values (0.91 +/- 0.44). We conclude that feeding low doses of deoxycholic acid to patients with liver cirrhosis induces a significant increase of the fraction of this bile acid in the total pool and this is followed by a sharp increase of bile cholesterol saturation. These data are compatible with the hypothesis that the detergent capacity of individual bile acids is one of the main determinants of bile cholesterol saturation.


Expression and localization of K channels KCNQ2 and KCNQ3 in the mammalian cochlea.
KCNQ1 and KCNQ4 voltage-gated potassium channel subunits play key roles in hearing. Other members of the KCNQ family also encode slow, low voltage-activated K(+) M currents. We have previously reported the presence of M-like K(+) currents in sensory hair cells, and expression of Kcnq family genes in the cochlea. Here, we describe Kcnq2/3 gene expression and distribution of M channel subunits KCNQ2 and 3 in the cochlea. By using RT-PCR, we found expression of Kcnq2 in the modiolus and organ of Corti, while Kcnq3 expression was also detected in the cochlear lateral wall. Five alternative splice variants of the Kcnq2 gene, one of which has not been reported previously, were identified in the rat cochlea. KCNQ2 and KCNQ3 immunoreactivities were observed in spiral ganglion auditory neurons. In addition, the unmyelinated parts of the nerve fibers innervating hair cells and synaptic regions under hair cells showed KCNQ2 immunoreactivity. KCNQ3 immunoreactivity was also prominent in spiral ganglion satellite cells. These findings suggest that cochlear M channels play important roles in regulation of cellular excitability and maintenance of cochlear K(+) homeostasis in the auditory system.


[Role of the hypothalamus in regulating liver circulation].
In acute experiments on nembutal anesthetized dogs stimulation of anterior hypothalamus elicited changes in the hepatic artery blood flow, which followed those of arterial pressure; the vascular resistance remaining unchanged. The stimulation of medial and posterior hypothalamus led to decrease in flow and increase in the resistance of the hepatic artery. In most cases of hypothalamic stimulation the portal blood flow diminished, portal pressure and vascular resistance increased. The opposite reactions were observed during stimulation of sympathoinhibitory area, paraventricular and lateral hypothalamic nuclei. The conclusion is made that the hypothalamus participates in integrative and differential control of the hepatic circulation.


Critical air pollutant assessments and health effects attributed to PM2.5 during and after COVID-19 lockdowns in Iran: application of AirQ+ models.
The aim of this study was to evaluate changes in air quality index (AQI) values before, during, and after lockdown, as well as to evaluate the number of hospitalizations due to respiratory and cardiovascular diseases attributed to atmospheric PM2.5 pollution in Semnan, Iran in the period from 2019 to 2021 during the COVID-19 pandemic. Daily air quality records were obtained from the global air quality index project and the US Environmental Protection Administration (EPA). In this research, the AirQ+ model was used to quantify health consequences attributed to particulate matter with an aerodynamic diameter of <2.5 μm (PM2.5). The results of this study showed positive correlations between air pollution levels and reductions in pollutant levels during and after the lockdown. PM2.5 was the critical pollutant for most days of the year, as its AQI was the highest among the four investigated pollutants on most days. Mortality rates from chronic obstructive pulmonary disease (COPD) attributed to PM2.5 in 2019-2021 were 25.18% in 2019, 22.55% in 2020, and 22.12% in 2021. Mortality rates and hospital admissions due to cardiovascular and respiratory diseases decreased during the lockdown. The results showed a significant decrease in the percentage of days with unhealthy air quality in short-term lockdowns in Semnan, Iran with moderate air pollution. Natural mortality (due to all-natural causes) and other mortalities related to COPD, ischemic heart disease (IHD), lung cancer (LC), and stroke attributed to PM2.5 in 2019-2021 decreased. Our results support the general finding that anthropogenic activities cause significant health threats, which were paradoxically revealed during a global health crisis/challenge.


[The jejuno-gastric invaginations after partial gastrectomy. General survey of literature concerning a personal observation (author's transl)].
The authors relate an observation of a postgastrectomic jejuno-gastric invagination. On this occasion they make a general survey of the literature and analyze the 113 cases published up to now. The frequencies of apparition of this complication are much variable, from a few days up to several decades and the clinical symptoms are chronic or acute. They insist on the interest granted by the radiologic and endoscopic examinations for the diagnosis and on the proposed treatment aiming a twofold goal: reduce the invagination and avoid the recurrence.


Morphology of rapidly frozen aortic endothelial cells. Glutaraldehyde fixation increases the number of caveolae.
Using a Polaron E7200 quick freeze unit, we investigated the distribution of vesicles (caveolae) bound to the plasma membrane of aortic endothelial cells from adult Sprague-Dawley rats. Counts of caveolae from replicas of rapidly frozen, unfixed samples were made and compared with counts from both aldehyde-fixed, conventionally frozen, and rapidly frozen aortic samples. Aldehyde-fixed samples prepared for freeze fracture by either of the freezing methods revealed a significantly greater number of caveolae than did unfixed, rapidly frozen samples. These findings suggest that the relative number of caveolae is artifactually increased by exposure to aldehyde fixatives. We conclude that previous estimates of the rates of pinocytotic activity in vascular endothelial cells may contain substantial errors based on overestimates of caveolae and underestimates of subplasmalemmal "free" vesicles.


Bifunctional fluorescent calix[4]arene chemosensor for both a cation and an anion.
[reaction: see text] A new fluorogenic cone calix[4]triazacrown-5 (1) bearing two pyrene amide groups and its structural analogue 2 have been prepared. Excited at 343 nm, 1 and 2 reveal excimer emissions at 448 and 472 nm, respectively. When heavy metal ions such as Pb(2+) and Co(2+) are bound to 1, the fluorescence intensities of both monomer and excimer are quenched whereas H bonding-assisted F(-) binding to 1 gives rise to a quenched monomer emission with little excimer emission change.


Personalised approach in combined treatment of cholangiocarcinoma: a case report of healing from cholangiocellular carcinoma at stage IV.
We describe a rare case of healing from low differentiated cholangiocarcinoma stage T4N1M0 with atypical genetic mutation in gene BRAF V600E for this tumor. A 38-year-old female patient was operated in National Surgery Institute due to cholangiocellular carcinoma (CCA) of left liver lobe with anterior abdominal wall invasion, invasion into diaphragm, pericardium. Left liver resection with lymphatic dissection, pericardial resection was performed. Adjuvant chemotherapy (GEMOX) didn't give any results. Treatment with pembrolizumab also didn't result in any improvement. Next generation sequencing molecular tumor profiling revealed mutation in BRAF V600E gene. Target therapy with dabrafenib and trametinib, a BRAF gene inhibitors was initiated and resulted in a full response. The patient is for 2 years tumor free with no signs of recurrence. To our knowledge our case report is longest in the world for stage IV CCA treated with dabrafenib + trametinib.


Effects of nitrous oxide on coronary perfusion after coronary air embolism.
Coronary air embolism (CAE) can occur after heart surgery whenever air is present in the left heart or proximal aorta. When CAE occurs, its sequelae can range from electrocardiographic changes of ischemia to severe myocardial dysfunction and cardiac arrest. Since N2O has been shown to have detrimental effects in the presence of coronary obstructions, as well as the tendency to enlarge air emboli, the authors tested the hypotheses that N2O would enhance the deleterious effects of CAE, and that discontinuing N2O at the time of CAE would minimize those effects. The effects of ventilation with and without N2O on the cardiac insult due to left anterior descending CAE (0.02 ml.kg-1) were studied in 27 swine. Global cardiovascular changes that occurred after CAE included decreases in cardiac output, systemic arterial and coronary perfusion pressure, and LV dP/dt, as well as increases in LVEDP. These parameters returned towards baseline over time when N2O was discontinued at the time of CAE. Maintenance of N2O in the inspired gas after CAE occurred was uniformly fatal within 2-4 min in this model. Regional myocardial ischemia was significantly greater in animals receiving N2O, as documented by: 1) a greater incidence of elevations of epicardial ST-segments exceeding 3 mm from baseline in embolized and non-embolized coronary artery distributions, 2) a greater incidence of dysrhythmias (greater than 6 PVCs.min-1), 3) longer duration of depression of coronary blood flow, 4) longer duration of post-ischemic coronary hyperemia, and 5) larger decreases with less recovery over time of regional myocardial lactate extraction.(ABSTRACT TRUNCATED AT 250 WORDS)


[Duck hepatitis B virus DNA in multiple primary cancers and metastatic tumors in duck liver].
Duck hepatitis B virus (DHBV) DNA was detected in both multiple primary cancers and intrahepatic metastatic tumors in duck liver by Southern blot technique. Among 7 ducks with multiple primary tumors in the liver, the banding pattern of integrated DHBV DNA in different tumors was identical in 3 animals but different in 2. One duck showed a similar hybridization pattern in different tumor nodules and the remaining one was negative for DHBV DNA. Integrated DHBV DNA was also identified in one duck with metastatic tumor in the lung, in which the hybridization pattern was the same as that of the primary hepatocellular carcinoma. The presence of the same distinct hybridization bands in various tumor nodules indicated that they may arise from the same clone of neoplastically transformed cell. Different hybridization bands showed that tumors may arise from different clones. The results suggest that hybridization pattern of hepatic carcinoma with viral DNA probe could be used as a clone marker of transformed cells to distinguish multiple primary hepatic cancers from intrahepatic metastasis.


Positive pregnancy outcomes in Mexican immigrants: what can we learn?
To provide an integrated review of the literature of potential explanations for better than expected pregnancy outcomes in Mexican immigrants, focusing on socioeconomics, social support, desirability of pregnancy, nutrition, substance use, religion, acculturation, and prenatal care. Computerized searches of MEDLINE and CINAHL databases, as well as reference lists from published articles on low birth weight and prematurity in immigrants and acculturation in immigrants from January 1989 to December 2002. Search terms were Mexican immigrant women, childbearing, and pregnancy outcome, and only English-language articles were reviewed. Literature was selected from refereed publications in the areas of nursing, medicine, public health, family, and sociology. Data were extracted using keywords pertinent to pregnancy outcome in Mexican immigrants. Despite having many of the risk factors for poor pregnancy outcomes, Mexican immigrants have superior birth outcomes when compared to U.S.-born women. Social support, familism, healthy diet, limited use of cigarettes and alcohol, and religion may play a role in improved outcomes. The superior outcomes diminish with the process of acculturation as the individual adapts to her new culture. Low birth weight and prematurity are public health concerns in the United States. Through further study of the factors that lead to superior birth outcomes among Mexican immigrant women, rates of low birth weight and prematurity in the United States may be reduced.


The strategic use of closantel and albendazole in controlling naturally acquired gastrointestinal nematodes of sheep in the Kenya highlands.
The strategic use of closantel, a narrow-spectrum salicylanilide anthelmintic against bloodsucking helminths, and of albendazole, a broad-spectrum benzimidazole anthelmintic, in the control of gastrointestinal nematodes of sheep was investigated on a farm in Nyandarua District in the highlands of Kenya. Thirty Corriedale female lambs aged between 9 and 12 months were assigned to three treatment groups of 10 lambs each. The three groups were set stocked on separate paddocks for 12 months. Lambs in group 1 (strategic treatment group) were treated with closantel and albendazole at the beginning and towards the end of the long rains (April and June, respectively) and towards the end of the short rains. (December). During the intervening dry season, the lambs were treated with albendazole. Lambs in group 2 (suppressive treatment group) were kept 'worm free' by regular deworming with albendazole at 3-weekly intervals for 12 months. The third group of lambs remained untreated (control group). Gastrointestinal nematode infections and pasture infectivity were well controlled in the case of the strategic treatment group. This resulted in higher weight gains, wool production, packed cell volume, and serum albumin and protein concentrations compared with the untreated control lambs. These parameters were comparable between the strategic treatment and the suppressive treatment groups of lambs. It was concluded that worm control strategies based on the epidemiology of the parasites and the sustained anthelmintic action of closantel in combination with broad-spectrum anthelmintics can provide effective control of gastrointestinal nematodes of sheep in the study area.


Noble metal-free SERS: mechanisms and applications.
Surface-enhanced Raman scattering (SERS) is a very important tool in vibrational spectroscopy. The coupling of nanomaterials induces local surface plasmon resonance (LSPR), which contributes greatly to SERS. Due to its remarkable sensitivity in trace detection, SERS has gained prominence in the fields of catalysis, biosensors, drug tracking, and optoelectronic devices. SERS activity is believed to be closely related to the LSPR and charge transfer (CT) of the material. Noble metal nanostructures have been commonly used as SERS-active substrates due to their strong local electric fields and relatively mature preparation, application, and enhancement mechanisms. In recent years, SERS research based on semiconductor materials has attracted significant attention because semiconductor materials have advantages such as repeatable preparation, simple pretreatment, stable SERS spectra and superior biocompatibility, stability, and reproducibility. Semiconductor-based SERS has the potential to enrich SERS theory and applications. Thus, the development of semiconductor materials will introduce a new epoch for SERS-based research. In this review, we outline the two main kinds of semiconductor SERS-active substrates: inorganic and organic semiconductor SERS-active substrates. We also provide an overview of the SERS mechanism for different kinds of materials and SERS-based applications.


Comparison of parametrization methods of the collimator scatter correction factor for open rectangular fields of 6-25 MV photon beams.
To facilitate the use of the collimator scatter correction factor, Sc, parametrization methods that relate Sc to the field size by fitting were investigated. Sc was measured with a mini-phantom for five types of dual photon energy accelerators with energies varying between 6 and 25 MV. Using these Sc-data six methods of parametrizing Sc for square fields were compared, including a third-order polynomial of the natural logarithm of the field size normalized to the field size of 10 cm2. Also five methods of determining Sc for rectangular fields were considered, including one which determines the equivalent field size by extending Sterling's method. The deviations between measured and calculated Sc-values were determined for all photon beams and methods investigated in this study. The resulting deviations of the most accurate method varied between 0.07 and 0.42% for square fields and between 0.26 and 0.79% for rectangular fields. A recommendation is given as to how to limit the number of fields for which Sc should be measured in order to be able to accurately predict it for an arbitrary field size.


Mutations of PTEN/MMAC1 in primary prostate cancers from Chinese patients.
PTEN/MMAC1 is a putative tumor suppressor gene located on 10q23, one of the most frequently deleted chromosomal regions in human prostate cancer. Although mutations of PTEN have often been detected in metastases of prostate cancer, localized tumors have shown lower rates of mutation, which have varied from 0 to 20% among different studies. It is unknown whether the rate of PTEN mutations is different in prostate cancer from Asian men compared with Western men. To further clarify the role of PTEN in prostate cancer and to examine the gene for mutations in Asian men, we analyzed 32 cases of primary prostate cancers from Chinese patients, each of whom was not diagnosed by screening with serum prostate-specific antigen, for PTEN mutations using the methods of tissue microdissection, single-strand conformational polymorphism, and direct DNA sequencing. Seventy % of the tumors were Gleason scores 8-10, whereas the remainder were Gleason score 7. Six metastases of prostate cancer from American patients were also analyzed. Five of 32 (16%) primary prostate cancers from Chinese men and two of six metastases from American men showed mutations in a total of 10 codons of PTEN, which involved exons 1, 2, 5, 8, and 9. Two of the mutations were truncation type, whereas the rest were missense mutations. The mutation frequency in these cases from Asian patients was higher than that in our previous study of cases in radical prostatectomy specimens from American men, in which the 40 primary tumors were lower grade and had been detected by serum prostate-specific antigen test. We conclude that mutation of PTEN occurs more often in primary prostate cancers of Chinese men, whose tumors are high grade and reflective of an unscreened population.


Selection in the making: a worldwide survey of haplotypic diversity around a causative mutation in porcine IGF2.
Domestic species allow us to study dramatic evolutionary changes at an accelerated rate due to the effectiveness of modern breeding techniques and the availability of breeds that have undergone distinct selection pressures. We present a worldwide survey of haplotype variability around a known causative mutation in porcine gene IGF2, which increases lean content. We genotyped 34 SNPs spanning 27 kb in 237 domestic pigs and 162 wild boars. Although the selective process had wiped out variability for at least 27 kb in the haplotypes carrying the mutation, there was no indication of an overall reduction in genetic variability of international vs. European local breeds; there was also no evidence of a reduction in variability caused by domestication. The haplotype structure and a plot of Tajima's D against the frequency of the causative mutation across breeds suggested a temporal pattern, where each breed corresponded to a different selective stage. This was observed comparing the haplotype neighbor-joining (NJ) trees of breeds that have undergone increasing selection pressures for leanness, e.g., European local breeds vs. Pietrain. These results anticipate that comparing current domestic breeds will decisively help to recover the genetic history of domestication and contemporary selective processes.


Change in blood levels of eicosapentaenoic acid and posttraumatic stress symptom: A secondary analysis of data from a placebo-controlled trial of omega3 supplements.
Eicosapentaenoic acid (EPA) is suggested to be protective against posttraumatic stress disorder (PTSD) from two observational studies. We previously conducted a randomized controlled trial and found no effect of docosahexaenoic acid (DHA) for prevention of PTSD. This secondary analysis aimed to determine whether change in blood levels of EPA is associated with PTSD symptoms. The percentages of EPA, DHA, and arachidonic acid (AA) were measured in erythrocyte membranes at baseline and posttreatment in 110 participants with severe physical injury who were randomly assigned to receive either a daily dose of 1,470mg DHA and 147mg EPA or of placebo for 12 weeks. Associations between change in erythrocyte fatty acid levels during the trial controlling for each baseline level and PTSD severity at 12 weeks were analyzed by treatment arm. In the omega3 supplements arm, changes in EPA+DHA (p=.023) and EPA (p=.001) as well as the EPA:AA ratio (p=.000) and EPA: DHA ratio (p=.013) were inversely correlated with PTSD severity. Change in AA was positively correlated with PTSD severity (p=.001). This trial was conducted at a single-center in Japan and PTSD symptoms in most participants were not serious. Increased erythrocyte level of EPA during the trial was associated with low severity of PTSD symptoms in patients receiving omega3 supplements.


Impact of training dementia caregivers in sensitivity to nonverbal emotion signals.
Ninety-one mid- to late-stage dementia patients residing in nursing homes, along with their staff caregivers, participated in a study designed to assess whether training caregivers in sensitivity to nonverbal communication could enhance mood and reduce symptoms in patients and improve psychological well-being in caregivers. Patients and staff at three nursing homes comprised three groups that were randomly assigned to either a nonverbal sensitivity group, a behavioral placebo group that received instruction in the cognitive and behavioral aspects of dementia, and a wait-list control. Training consisted of 10 one-hour sessions taught by a clinical psychologist using prepared materials. Patient measures, which were taken at baseline and at 4 three-week intervals, included patient symptomatology (depression, agitation, behavioral symptoms), as reported by the staff caregivers, and positive and negative facial expressions of emotion elicited during a face-to-face interview and coded by trained research staff. Results indicated that positive affect increased sharply during the first 6 weeks after intervention in the nonverbal group, with the placebo and wait-list controls showing no change. There was also a decline in negative affect across time for all groups. Effects with respect to patient symptomatology did not reach significance. Caregivers in both training groups showed a decline in symptomatology, whereas the wait-list control group did not.


Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release.
The nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI). Hydrogen treatment was recently associated with down-regulation of the expression of HMGB1 and pro-inflammatory cytokines during sepsis and myocardial IRI, but it is not known whether hydrogen has an effect on HMGB1 in liver IRI. A rat model of 60 minutes 70% partial liver ischemia reperfusion injury was used. Hydrogen enriched saline (2.5, 5 or 10 ml/kg) was injected intraperitoneally 10 minutes before hepatic reperfusion. Liver injury was assessed by serum alanine aminotransferase (ALT) enzyme levels and histological changes. We also measured malondialdehyde (MDA), hydroxynonenal (HNE) and 8-hydroxy-guanosine (8-OH-G) levels as markers of the peroxidation injury induced by reactive oxygen species (ROS). In addition, pro-inflammatory cytokines including TNF-α and IL-6, and high mobility group box B1 protein (HMGB1) were measured as markers of post ischemia-reperfusion inflammation. Hydrogen enriched saline treatment significantly attenuated the severity of liver injury induced by ischemia-reperfusion. The treatment group showed reduced serum ALT activity and markers of lipid peroxidation and post ischemia reperfusion histological changes were reduced. Hydrogen enriched saline treatment inhibited HMGB1 expression and release, reflecting a reduced local and systemic inflammatory response to hepatic ischemia reperfusion. These results suggest that, in our model, hydrogen enriched saline treatment is protective against liver ischemia-reperfusion injury. This effect may be mediated by both the anti-oxidative and anti-inflammatory effects of the solution.


Evaluation of acid-base balance in ST-elevation myocardial infarction in the early phase: a prognostic tool?
Metabolic acidosis has been described after myocardial infarction, but little data are available on the acid-base imbalance in ST-elevation myocardial infarction (STEMI) submitted to mechanical revascularization, and earlier studies on this topic differ with respect to patients' selection criteria, treatment and evaluated parameters. We assessed admission base excess, anion gap, and lactate in 445 consecutive patients with STEMI submitted to primary percutaneous coronary intervention and whether its evaluation could help in identifying patients at a higher risk for in-hospital mortality and complications (acute pulmonary edema and arrhythmias). At backward stepwise logistic regression analysis, the following variables were independently associated with intra-ICCU mortality: age [odds ratio (OR) 1.05; 95% confidence interval (CI) 1.02-1.10; P = 0.006], estimated glumerular filtration rate (OR 0.98; 95% CI 0.96-0.99; P= 0.010), Tn I (OR 1.006; 95% CI 1.004-1.008; P <0.001), and base excess (OR 0.90; 95% CI 0.82-0.99; P = 0.038); Hosmer-Lemeshow v2: 5.69, P = 0.681. At backward stepwise logistic regression analysis, the following variables were independently associated with intra-ICCU complications: left ventricular ejection fraction (OR 0.95; 95% CI 0.91-0.98; P = 0.005) and lactic acid (OR 1.31; 95% CI 1.10-1.57; P =0.003); Hosmer-Lemeshow v2: 4.11, P = 0.847. According to our findings, the evaluation of base excess and lactate in the early phase of STEMI provides the bedside clinicians with useful tools for early risk stratification. In fact, base excess proved to be an independent predictor for intra-ICCU mortality, whereas lactate represented an independent marker for intra-ICCU complications.


High-Fat-Diet-Evoked Disruption of the Rat Dorsomedial Hypothalamic Clock Can Be Prevented by Restricted Nighttime Feeding.
Obesity is a growing health problem for modern society; therefore, it has become extremely important to study not only its negative implications but also its developmental mechanism. Its links to disrupted circadian rhythmicity are indisputable but are still not well studied on the cellular level. Circadian food intake and metabolism are controlled by a set of brain structures referred to as the food-entrainable oscillator, among which the dorsomedial hypothalamus (DMH) seems to be especially heavily affected by diet-induced obesity. In this study, we evaluated the effects of a short-term high-fat diet (HFD) on the physiology of the male rat DMH, with special attention to its day/night changes. Using immunofluorescence and electrophysiology we found that both cFos immunoreactivity and electrical activity rhythms become disrupted after as few as 4 weeks of HFD consumption, so before the onset of excessive weight gain. This indicates that the DMH impairment is a possible factor in obesity development. The DMH cellular activity under an HFD became increased during the non-active daytime, which coincides with a disrupted rhythm in food intake. In order to explore the relationship between them, a separate group of rats underwent time-restricted feeding with access to food only during the nighttime. Such an approach completely abolished the disruptive effects of the HFD on the DMH clock, confirming its dependence on the feeding schedule of the animal. The presented data highlight the importance of a temporally regulated feeding pattern on the physiology of the hypothalamic center for food intake and metabolism regulation, and propose time-restricted feeding as a possible prevention of the circadian dysregulation observed under an HFD.


Surface proteins of gram-positive bacteria and mechanisms of their targeting to the cell wall envelope.
The cell wall envelope of gram-positive bacteria is a macromolecular, exoskeletal organelle that is assembled and turned over at designated sites. The cell wall also functions as a surface organelle that allows gram-positive pathogens to interact with their environment, in particular the tissues of the infected host. All of these functions require that surface proteins and enzymes be properly targeted to the cell wall envelope. Two basic mechanisms, cell wall sorting and targeting, have been identified. Cell well sorting is the covalent attachment of surface proteins to the peptidoglycan via a C-terminal sorting signal that contains a consensus LPXTG sequence. More than 100 proteins that possess cell wall-sorting signals, including the M proteins of Streptococcus pyogenes, protein A of Staphylococcus aureus, and several internalins of Listeria monocytogenes, have been identified. Cell wall targeting involves the noncovalent attachment of proteins to the cell surface via specialized binding domains. Several of these wall-binding domains appear to interact with secondary wall polymers that are associated with the peptidoglycan, for example teichoic acids and polysaccharides. Proteins that are targeted to the cell surface include muralytic enzymes such as autolysins, lysostaphin, and phage lytic enzymes. Other examples for targeted proteins are the surface S-layer proteins of bacilli and clostridia, as well as virulence factors required for the pathogenesis of L. monocytogenes (internalin B) and Streptococcus pneumoniae (PspA) infections. In this review we describe the mechanisms for both sorting and targeting of proteins to the envelope of gram-positive bacteria and review the functions of known surface proteins.


STAACS3: Simulation Tool for AAC with Single-Switch Scanning.
Communication for people with motor impairments is a difficult, yet necessary, task in daily activities. To do so, soft keyboards, digital counterpart of physical keyboards, are used. Depending on their features, several designs can be considered, however their thoughtful evaluation in real-life is not feasible. Therefore, it becomes necessary to filter the possible configurations wisely, taking advantage of simulation tools. This paper presents STAACS3, a Simulation Tool for AAC with Single-Switch scanning, that allows to model and simulate the performance of any type of scanning keyboard regardless of its keys configuration, scanning strategy or prediction systems.


[Rare Vascular Complication after ACL Reconstruction].
The anterior cruciate ligament reconstruction is currently one of the most commonly performed arthroscopic procedures of knee joint. Overall, it is a reliable and sophisticated procedure associated with a relatively low complication rate. In the available literature, less severe complications are reported in 3-7% of cases. The most frequent complications are intractable pain not manageable using analgesic therapy (6.7%), hemarthrosis requiring puncture (4.4%), fever (3.2%) and other complications related in particular to immobilisation (1.2%). The percentage of severe complications is very low (less than 1%). These include deep vein thrombosis (0.6%), cellulitis (0.6%) and infectious complications requiring arthroscopic or surgical revision (0.3%). Vascular injuries around the knee joint are rare and are described in case studies only. The authors present a patient with reduced mobility of the knee and significant pain, haematoma and swelling in the calf, which developed within a short time span after the reconstruction of anterior cruciate ligament. It was caused by bleeding into the medial gastrocnemius muscle. This rare vascular complication was diagnosed angiographically and coiling was used to stop the arterial bleeding, once deep vein thrombosis, congenital haemostasis, gonitis and compartment syndrome were excluded. Key words: ACL reconstruction, angiography, anterior cruciate ligament, arthroscopy, inferior medial genicular artery, vascular complications.


Eukaryotic elongation factor 2 kinase inhibitor, A484954 induced diuresis via nitric oxide production in spontaneously hypertensive rats.
Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is a protein kinase that inactivates eEF2, a protein that mediates a peptidyl-tRNA translocation during an elongation step of protein synthesis. We have previously shown that eEF2K was involved in pathogenesis of essential and pulmonary hypertension. A484954 (7-amino-1-cyclopropyl-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carboxamide), a selective eEF2K inhibitor, is a membrane permeable small molecule. We have previously shown that A484954 lowered blood pressure and induced diuretic effects in spontaneously hypertensive rats (SHR) due to an increase in renal blood flow. Here we aimed to reveal mechanisms underlying the diuretic effects of A484954 in SHR. A484954-induced diuresis and increase in urinary Na+ excretion were inhibited by N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor. A484954 increased mRNA expression of angiotensin type 2 receptor (AT2R) and nuclear factor-erythroid 2-related factor 2 (Nrf2). In summary, we for the first time revealed that A484954 induces diuresis in SHR at least partly via the activation of NO/Nrf2/AT2R pathway.


[The 'paper-based' preoperative evaluation: non-optimal health care].
A nationwide preoperative assessment guideline was introduced in the Netherlands in 1997 at the advice of the Health Council of the Netherlands. The preoperative assessment should entail an appropriate interview, a physical examination, additional tests, risk assessment and informing the patient. Dutch and several international guidelines recommend a complete assessment under the responsibility of the anaesthesiologist. In addition, Dutch law states that patients should be clearly informed about any medical procedure that is to be performed, including the possible risks and alternatives. All of the above is not possible with a paper-based assessment. A complete assessment may reduce health care costs by reducing the number of consultations by other specialists, additional tests, cancellations and length of stay. The assessment also reduces patient anxiety and improves patient satisfaction. In conclusion, a complete preoperative assessment is required by guidelines and law and does offer many advantages.


δ18O in the tropical conifer Agathis robusta records ENSO-related precipitation variations.
Long-lived trees from tropical Australasia are a potential source of information about internal variability of the El Niño-Southern Oscillation (ENSO), because they occur in a region where precipitation variability is closely associated with ENSO activity. We measured tree-ring width and oxygen isotopic composition (δ18O) of α-cellulose from Agathis robusta (Queensland Kauri) samples collected in the Atherton Tablelands, Queensland, Australia. Standard ring-width chronologies yielded low internal consistency due to the frequent presence of false ring-like anatomical features. However, in a detailed examination of the most recent 15 years of growth (1995-2010), we found significant correlation between δ18O and local precipitation, the latter associated with ENSO activity. The results are consistent with process-based forward modeling of the oxygen isotopic composition of α-cellulose. The δ18O record also enabled us to confirm the presence of a false growth ring in one of the three samples in the composite record, and to determine that it occurred as a consequence of anomalously low rainfall in the middle of the 2004/5 rainy season. The combination of incremental growth and isotopic measures may be a powerful approach to development of long-term (150+ year) ENSO reconstructions from the terrestrial tropics of Australasia.


Effect of Antihypertensive and Statin Medication Use on Muscle Performance in Community-Dwelling Older Adults Performing Strength Training.
Antihypertensive drugs (AHTD) and statins have been shown to have effects beyond their primarily designed purpose; here we investigate their possible effect on muscle performance and strength in older adults following a physical exercise programme. The Senior PRoject INtensive Training (SPRINT) study is a randomised, controlled clinical trial designed to evaluate the effects of physical exercise on the immune system and muscle performance in older adults. In this secondary analysis, we included 179 independent participants (aged 65 years and above). We applied further categorisation based on medication use: AHTD (including, angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARB], β-blockers, and other AHTD) and statins. Participants were allocated randomly to one of the three exercise protocols: intensive strength training 3 times/week (3 × 10 repetitions at 80% of one-repetition maximum), strength endurance training (2 × 30 repetitions at 40% of one-repetition maximum), or control (passive stretching exercise) for 6 weeks. The change in maximal hand grip strength (GS), muscle fatigue resistance (FR), Muscle Strength Index (MSI), the 6-min walk test (6MWT), and Timed Up and Go Test (TUG) were assessed before and after 6 weeks of training. After 6 weeks, muscle strength (MSI and TUG) improved significantly in all training groups compared to baseline, independently of AHTD use. Moreover, AHTD had no effect on exercise improvements, with no significant differences between medication groups, except for TUG in ARB users, which exhibited a significantly lower performance. On the other hand, statin users presented a significantly longer FR time, indicating better performance compared to non-users. Finally, medication did not affect the participants' commitment to the training programme. Our study showed that statins and ARB usage might affect participant's response to strength training. Nevertheless, 6 weeks of training significantly improved muscle strength and performance irrespective of AHTD or statin use.


Type I hypersensitivity to rubber.
Seven patients with type I hypersensitivity reactions to rubber are reported. Radioallergosorbent testing with crude latex antigen was positive in 6/7 patients. Five patients had coexisting spina bifida, and all had undergone surgery before the development of rubber allergy. Rubber allergy is a new phenomenon that should be in the differential diagnosis of idiopathic anaphylaxis and urticaria.


Phytophthora capsici genome assembly for two isolates using long-read Oxford Nanopore Technology sequencing.
The oomycete Phytophthora capsici is a common pathogen of the Solanaceae and Cucurbitaceae families. An improved assembly for the reference isolate LT1534 was constructed using Oxford Nanopore Technologies and Illumina data. Additionally, an unpolished assembly was produced for the European isolate Pc285 collected on chili pepper using Oxford Nanopore reads.


Childhood adversity and the risk of gestational diabetes: A population-based cohort study of nulliparous pregnant women.
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications, and though it may be linked to childhood adversity, the effect of different types of adversity remains unclear. Childhood adversity is linked to a younger maternal age, which may hide the overall impact of adversity on GDM risk. We therefore aimed to explore the association between different types of childhood adversity and GDM while accounting for the potential impact of maternal age. We used Danish nation-wide register data, including 208,207 women giving birth for the first time from 2004 to 2018. Five adversity groups were used to examine the effect of childhood adversity on GDM risk: (1) low (referent group), (2) early life material deprivation, (3) persistent deprivation, (4) loss or threat of loss within the family and (5) high adversity. 5375 women were diagnosed with GDM in the study population (2.6% absolute risk). Compared to women who experienced low adversity, the other adversity groups had a higher GDM risk (absolute difference [%]) directly; early material deprivation (0.64% [95% CI 0.44; 0.84]), persistent deprivation (0.63% [0.41; 0.86]), loss or threat of loss (0.73% [0.42; 1.05]) and high adversity (0.80% [0.32; 1.27]). The indirect effect of maternal age attenuated the total effect of childhood adversity on GDM by an absolute difference of 0.25%-0.46%. Experiencing childhood adversity to any extent is associated with a higher risk of GDM. Interventions aimed at preventing childhood adversity may have a positive effect in reducing GDM burden and the associated health risks.


Replication timing networks reveal a link between transcription regulatory circuits and replication timing control.
DNA replication occurs in a defined temporal order known as the replication timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. However, transcription and RT are not sufficiently coordinated to predict each other, suggesting an indirect relationship. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create highly complex RT networks composed of thousands of interactions that form specific functional subnetwork communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages, and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and transcriptional regulatory networks (TRNs) by combining them into more complex circuitries of composite and bipartite networks. Results identified novel trans interactions linking transcription factors that are core to the regulatory circuitry of each cell type to RT changes occurring in those cell types. These core transcription factors were found to bind cooperatively to sites in the affected replication domains, providing provocative evidence that they constitute biologically significant directional interactions. Our findings suggest a regulatory link between the establishment of cell-type-specific TRNs and RT control during lineage specification.


[The prevalence and distribution of intestinal parasites detected by the Uludag University Medical School].
In this study, patients (outpatients and in-patients) with various gastrointestinal system complaints presenting at various clinics of the Uludag University Medical Faculty, Bursa, from January 2001-December 2004 were investigated for intestinal parasites. The prevalence of intestinal parasites was evaluated according to age, gender and the months in which cases were seen. Saline and iodine preparations from 8,351 stool samples before and after formal-ethyl acetate concentration were examined under 100x and 400x magnification. Also, trichrome stained preparations in ambiguous cases and modified Erlich Ziehl Nielsen stained preparations for Cryptosporidium spp. were examined by oil-immersion lens (total magnification 1000x). One or more pathogenic parasites were found in 298 of the 8,381 stool samples. Enterobius vermicularis was detected in 227 of 3,758 cellophane tape preparations. The predominant parasite was E. vermicularis (prevalence of 1.56%), followed by Giardia intestinalis (1.03%) and Blastocystis hominis (0.96%). The overall prevalence of intestinal parasitic infection rate was 4.27%. Of these, 40.4% were female and 59.6%, male. The results indicated that 94.9% of the subjects had one parasite and 5.1%, co-infection with two parasites. The rate of intestinal parasites in the 0-9 age group was higher than that of other groups. The incidence of parasitic diseases was lower in this study as compared to results previously reported in our hospital. Although different infection rates were found in these studies, there were no statistically significant differences in our study.


Clinical varieties of carnitine and carnitine palmitoyltransferase deficiency.
Several clinical entities are associated with disorders of fatty acid oxidation or transfer across the inner mitochondrial membrane. Over 40 cases of the primary carnitine deficiency syndrome have been reported to date and various subtypes have been characterized. This represents a large clinical spectrum. The deficiency of carnitine in muscle is at the basis of a syndrome characterized by muscle weakness and lipid storage myopathy. The systemic form of carnitine deficiency is more generalized and includes recurrent episodes of hepatic encephalopathy as well as lipid storage in muscle, liver and heart. In one subtype, hypoglycemia upon fasting and cardiomyopathy are found. There are also several causes of secondary carnitine deficiency states which are either acquired or associated with inborn errors of metabolism (organic acidurias, defects of acyl-CoA dehydrogenases). Clinically, Carnitine palmitoyltransferase (CPT) deficiency is a rather homogeneous syndrome presenting with recurrent episodes of myoglobinuria provoked by fasting or prolonged exercise. The only exception is an infantile variety associated with severe hypoglycemia and hepatic CPT deficiency. Using malonyl-CoA, a specific inhibitor of CPT-I, we had suggestions in five adult patients with myoglobinuria that CPT-II is lacking in muscle, liver and platelets while CPT-I is above the control level. The enzyme abnormality seems partial and limited to CPT-II or to its binding to the inner mitochondrial membrane.


Prevalence of depression among Iranian patients with myasthenia gravis during 2017-2018.
Background: Myasthenia gravis (MG) is a chronic neuromuscular disease, which physically and mentally affects the patient's life, with depression being one of the most important psychological complications in these patients. This study aims to investigate the prevalence of depression and its associated factors in a group of Iranian patients with MG. Methods: This was a cross-sectional study in which consecutive patients diagnosed with MG who referred to two referral neuromuscular clinics affiliated to the Tehran University of Medical Sciences, Tehran, Iran, were evaluated for eligibility. Patients with a previously known psychiatric disorder and those with a family history of mental disorders were excluded. Eligible patients were interviewed and screened for depression through the administration of the Hamilton Depression Rating Scale (HDRS) and the Iranian version of Beck Depression Inventory-II (BDI-II). Results: A total of 62 patients participated in this study. The total prevalence of depression according to the HDRS and BDI-II scores was 64.5% and 53.2%, respectively. The mild depression was the most frequent level of depression based on the HDRS (33.9%) and BDI-II (22.6%) scores. None of the variables, including age, sex, duration of the disease, and dosages of prednisolone, pyridostigmine, and azathioprine, were correlated with the severity of depression. The number of academic years was the only variable associated with the lower HDRS score (P = 0.037). Conclusion: Based on the current findings, depression was common among Iranian patients with MG. The severity of depressive symptoms was unrelated to age, sex, marital status, duration of the disease, the daily dosage of medications, and thymectomy status. Further investigations are needed to reveal the exact burden of depression in patients with MG and address the importance of preventive interventions for improving the quality of life (QOL) in these patients.


Correlation between binding affinity and necrosis-inducing activity of mutant AVR9 peptide elicitors.
The race-specific peptide elicitor AVR9 of the fungus Cladosporium fulvum induces a hypersensitive response only in tomato (Lycopersicon esculentum) plants carrying the complementary resistance gene Cf-9 (MoneyMaker-Cf9). A binding site for AVR9 is present on the plasma membranes of both resistant and susceptible tomato genotypes. We used mutant AVR9 peptides to determine the relationship between elicitor activity of these peptides and their affinity to the binding site in the membranes of tomato. Mutant AVR9 peptides were purified from tobacco (Nicotiana clevelandii) inoculated with recombinant potato virus X expressing the corresponding avirulence gene Avr9. In addition, several AVR9 peptides were synthesized chemically. Physicochemical techniques revealed that the peptides were correctly folded. Most mutant AVR9 peptides purified from potato virus X::Avr9-infected tobacco contain a single N-acetylglucosamine. These glycosylated AVR9 peptides showed a lower affinity to the binding site than the nonglycosylated AVR9 peptides, whereas their necrosis-inducing activity was hardly changed. For both the nonglycosylated and the glycosylated mutant AVR9 peptides, a positive correlation between their affinity to the membrane-localized binding site and their necrosis-inducing activity in MoneyMaker-Cf9 tomato was found. The perception of AVR9 in resistant and susceptible plants is discussed.


Incongruences Between Facial Expression and Self-Reported Emotional Reactivity in Frontotemporal Dementia and Related Disorders.
Emotional reactivity normally involves a synchronized coordination of subjective experience and facial expression. These aspects of emotional reactivity can be uncoupled by neurological illness and produce adverse consequences for patient and caregiver quality of life because of misunderstandings regarding the patient's presumed internal state. Frontotemporal dementia (FTD) is often associated with altered social and emotional functioning. FTD is a heterogeneous disease, and socioemotional changes in patients could result from altered internal experience, altered facial expressive ability, altered language skills, or other factors. The authors investigated how individuals with FTD subtypes differ from a healthy control group regarding the extent to which their facial expressivity aligns with their self-reported emotional experience. Using a compound measure of emotional reactivity to assess reactions to three emotionally provocative videos, the authors explored potential explanations for differences in alignment of facial expressivity with emotional experience, including parkinsonism, physiological reactivity, and nontarget verbal responses. Participants with the three main subtypes of FTD all tended to express less emotion on their faces than they did through self-report. Exploratory analyses suggest that reasons for this incongruence likely differ not only between but also within diagnostic subgroups.


Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship.
Transient receptor potential melastatin-8 (TRPM8) is an ion channel expressed extensively in sensory nerves, human prostate and overexpressed in a variety of cancers including prostate, breast, lung, colon and skin melanomas. It is activated by innoxious cooling and chemical stimuli. TRPM8 activation by cooling or chemical agonists is reported to induce profound analgesia in neuropathic pain conditions. Known TRPM8 agonists like menthol and icilin cross-activate other thermo-TRP channels like TRPV3 and TRPA1 and mutually inhibit TRPM8. This limits the usefulness of menthol and icilin as TRPM8 ligands. Consequently, the identification of selective and potent ligands for TRPM8 is of high relevance both in basic research and for therapeutic applications. In the present investigation, a group of menthol derivates was characterized. These ligands are selective and potent agonists of TRPM8. Interestingly they do not activate other thermo-TRPs like TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4. These ion channels are also nociceptors and target of many inflammatory mediators. Investigations were performed in a recombinant system: Xenopus oocytes microinjected with cRNA of gene of interest were superfused with the test substances after initial responses of known standard agonists. Evoked currents were measured by two-electrode voltage clamp technique. The newly characterized ligands possess an up to six-fold higher potency (EC50 in low microM) and an up to two-fold increase in efficacy compared to the parent compound menthol. In addition, it is found that chemical derivatives of menthol like CPS-368, CPS-369, CPS-125, WS-5 and WS-12 are the most selective ligands for TRPM8. The enhanced activity and selectivity seems to be conferred by hexacyclic ring structure present in all ligands as substances like WS-23 which lack this functional group activate TRPM8 with much lower potency (EC50 in mM) and those with pentacyclcic ring structure (furanone compounds) are totally inactive. The new substances activate TRPM8 with a higher potency, efficacy and specificity than menthol and will thus be of importance for the development of pharmacological agents suitable for treatment and diagnosis of certain cancers and as analgesics. STATEMENT OF NOVELTY: The new compounds have an unmatched specificity for TRPM8 ion channels with additional display of high potency and efficacy. Thus these substances are better pharmacological tools for TRPM8 characterization then known compounds and it is suggested that these menthol-derivates may serve as model substances for the development of TRPM8 ligands.


Lack of correlation between antibody titers to fibrinogen-binding protein of Streptococcus equi and persistent carriers of strangles.
Previously published studies have neither used nor reported the results of an indirect enzyme-linked immunosorbent assay (iELISA) to measure serologic responses in natural outbreaks of strangles. The concept of using serologic responses to identify persistent carriers of Streptococcus equi has been proposed but not scientifically evaluated. The specific aims of the current study were to determine the duration and level of truncated fibrinogen-binding protein-specific (SeM allele 1) antibody production in ponies involved in a natural outbreak of strangles and to determine if test results from this serologic iELISA could predict persistent carrier status. Serologic samples were obtained before and after an outbreak of naturally occurring strangles infection. Persistent carriers of S. equi were identified via culture and polymerase chain reaction (PCR) testing of lavage fluid collected from the guttural pouches and nasopharynx or swabs of the nasopharynx after recovery from acute disease and at postmortem examination. Logistic regression analysis was used to determine if an association existed between serologic response and persistent carrier state. The ELISA reported in the current study definitively confirmed a recent exposure to S. equi. However, the measured serologic response did not predict carrier status in this strangles outbreak. Therefore, a guttural-pouch endoscopy with subsequent culture or PCR testing to detect S. equi remains the most accurate method available for the identification of persistent carriers.


On the mechanism of rapid plasma membrane and chloroplast envelope expansion in Dunaliella salina exposed to hypoosmotic shock.
Dunaliella salina cells rapidly diluted from their normal 1.71 M NaCl-containing growth medium into medium containing 0.86 M NaCl swelled within 2--4 min to an average volume 1.76 X larger and a surface area 1.53 X larger than found in control cells. Morphometric analysis of thin section electron micrographs revealed that certain organelles, including the chloroplast, nucleus, and some types of vacuoles, also expanded in surface area as much or more than did the entire cell. It is likely that glycerol, the most important osmotically active intracellular solute, was present in high concentration within these organelles as well as in the cytoplasm itself. Thin section and freeze-fracture electron microscopy were utilized to trace the origin of membrane material whose addition permitted the large increase in plasma membrane surface area and the equally large growth of the chloroplast outer envelope. The findings indicated that the plasma membrane's expansion resulted from its selective fusion with numerous small (less than or equal to 0.25 micron diam) vesicles prevalent throughout the cytoplasm. In contrast, new membrane added to the chloroplast outer envelope was drawn from an entirely different source, namely, elements of the endoplasmic reticulum.


Gender and laterality differences in thermosensation throughout the perceptible range.
Several studies suggest that females exhibit greater sensitivity to experimentally induced thermal pain than males. These investigations have focused mainly on the sensory-discriminative rather than the affective aspect of pain. Moreover, potential gender differences for the affective components of innocuous thermal sensations have yet to be examined. The primary aim of the present study was to evaluate gender differences in the sensory and the affective dimensions of the entire thermosensory system, including warmth, coolness, heat pain and cold pain. The secondary aim was to evaluate laterality differences in these same perceptual dimensions and ranges. Twenty healthy females and 20 healthy males immersed their hands in water baths maintained at temperatures ranging from 10 to 47 degrees C, and rated their perceived thermal intensity, (un)pleasantness, and pain intensity. There was a progressive growth in the thermal intensity ratings as bath temperatures either increased or decreased from the adapting temperature of 33 degrees C. No gender differences emerged for these thermal intensity ratings. However, a significant sex effect emerged for the pain intensity ratings (P<0.01), and a significant sex x temperature interaction for the affective ratings (P<0.01). Females provided higher unpleasantness and pain intensity ratings for the more extreme temperatures (10, 15 and 47 degrees C), compared to males. Moreover, women perceived the milder temperature baths as more pleasant than men did. For a given painful temperature, unpleasantness ratings were higher than pain intensity ratings. This relationship between unpleasantness ratings and pain ratings was not significantly different between the sexes. No laterality differences emerged for the thermal intensity ratings. However, perceived pain intensity was significantly higher for the left as compared to the right hand (P<0.01). Ratings of unpleasantness also tended to be higher for the left vs. right hand, but this difference fell just short of statistical significance (P=0.06). These findings indicate that sex differences in thermosensory perception are not general, but occur only for the painful and affective components. Of particular note is the sex difference for affective but not intensive ratings of innocuous temperatures, revealing sex differences in thermal perception outside the nociceptive system.


Liberal versus restrictive fluid management in knee arthroplasty: a randomized, double-blind study.
There are few data describing the relationship between amount of perioperative fluid and organ function. In this study we investigated the effects of two levels of intravascular fluid administration ("liberal" versus "restrictive") in knee arthroplasty on physiological recovery as the primary outcome variable. In a double-blind study, 48 ASA I-III patients undergoing fast-track elective knee arthroplasty were randomized to restrictive or liberal perioperative intravascular fluid administration. Patients received a fixed rate infusion of Ringer's lactate solution with a standardized volume of colloid. All other aspects of perioperative management (including anesthesia, preoperative fluid status, and postoperative management) were standardized. Primary outcome variables included pulmonary function (spirometry), exercise capacity ("timed up and go" test), coagulation (Thrombelastograph), postoperative hypoxemia (nocturnal pulse oximetry), postoperative ileus (defecation), and subjective patient recovery (visual analog scales). Hospital stay and complications were also noted. Fluid guidelines were followed strictly in all patients. Liberal (median 4250 mL, range 3150-5200 mL) compared with restrictive (median 1740 mL, range 1100-2165 mL) intravascular fluid administration led to improved pulmonary function 6 h postoperatively, significant hypercoagulability 24-48 h postoperatively, and reduced incidence of vomiting. There were no overall differences in the other assessed perioperative physiological recovery variables (postoperative hypoxemia, exercise capacity or subjective patient recovery variables). No difference was found in hospital stay (median 4 days in both groups, not significant). A liberal compared to a restrictive intravascular fluid regimen may lead to significant hypercoagulability and a reduction in vomiting, but without differences in other recovery variables or hospital stay after fast-track knee arthroplasty.


CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation.
CD97 is a receptor that spans the membrane seven times, a defining feature of G protein-coupled receptors. CD97 is predominantly expressed in leukocytes, but the function and accurate protein structure of this receptor have not been described. We show here that CD97 has the novel property among G protein-coupled receptors characterized to date of being processed intracellularly in either the endoplasmic reticulum or early Golgi from a proprotein into a noncovalently associated two-subunit structure that becomes expressed on the cell surface and is composed of a large extracellular protein (CD97alpha) and a seven-membrane spanning protein (CD97beta). CD97beta is part of an evolutionarily conserved subfamily of four proteins, including two Caenorhabditis elegans proteins of as yet unknown function, which is distinct from but most closely related to the glucagon receptor family. CD97alpha exists in three alternatively spliced isoforms that contain between three and five epidermal growth factor (EGF)-like repeats that are related to the calcium binding EGF-like repeats in the microfibril protein fibrillin. Leukocytes strongly positive for CD97 are concentrated at sites of inflammation relative to CD97 expression in normal lymphoid tissues. Soluble CD97alpha was found in body fluids from inflamed tissues, suggesting that a functional consequence of the CD97 heterodimeric structure is the stable existence of CD97alpha in a cellfree form. CD97 appears to be a multifunctional protein that may play a signal transduction role associated with the establishment or development of an inflammatory process.


Older Adults Experiences of Learning to Use Tablet Computers: A Mixed Methods Study.
Background: We wanted to understand older adults' experiences of learning how to use a tablet computer in the context of an intervention trial, including what they found helpful or unhelpful about the tablet training, to guide future intervention studies. Methods: Mixed methods study using questionnaire and focus group approaches. Forty-three participants aged between 65 and 76 years old from the "Tablet for Healthy Ageing" study (comprising 22 in the intervention group and 21 controls) completed a post-intervention tablet experience questionnaire. Those who completed the tablet training intervention were invited to share their experiences of engaging with new technology in post-intervention focus groups. We conducted three separate focus groups with 14 healthy older adults (10 females). Results: Questionnaire data suggested that the overall experience of the 22 participants who participated in the tablet training intervention was positive. The majority of participants said that it was likely or very likely they would use a tablet in the future. The focus group themes that emerged were related to the perception of tablet training, the experience of using tablets, and suggestions for future studies. Participants mentioned that their confidence was increased, that they enjoyed being part of a social group and downloading applications, but they also felt challenged at times. Advantages of using tablets included the ability to keep in touch with family and friends, a motivation to contribute to the community, and the potential for tablets to improve mental abilities and overall health and wellbeing. Participants made suggestions that would enable tablet usage, including improvement of features, and suggestions that would improve future tablet training studies, including smaller classes. Conclusion: Our findings have implications for the development of interventions utilizing new technologies that might promote the health and wellbeing of older adults.


Distribution-wide effects of climate on population densities of a declining migratory landbird.
1. Increases in global temperatures have created concern about effects of climatic variability on populations, and climate has been shown to affect population dynamics in an increasing number of species. Testing for effects of climate on population densities across a species' distribution allows for elucidation of effects of climate that would not be apparent at smaller spatial scales. 2. Using autoregressive population models, we tested for effects of the North Atlantic Oscillation (NAO) and the El Niño Southern Oscillation (ENSO) on annual population densities of a North American migratory landbird, the yellow-billed cuckoo Coccyzus americanus, across the species' breeding distribution over a 37-year period (1966-2002). 3. Our results indicate that both the NAO and ENSO have affected population densities of C. americanus across much of the species' breeding range, with the strongest effects of climate in regions in which these climate systems have the strongest effects on local temperatures. Analyses also indicate that the strength of the effect of local temperatures on C. americanus populations was predictive of long-term population decline, with populations that were more negatively affected by warm temperatures experiencing steeper declines. 4. Results of this study highlight the importance of distribution-wide analyses of climatic effects and demonstrate that increases in global temperatures have the potential to lead to additional population declines.


Autonomic Dysfunction in Cardiology: Pathophysiology, Investigation, and Management.
Presyncope and syncope are common medical findings, with a > 40% estimated lifetime prevalence. These conditions are often elicited by postural stress and can be recurrent and accompanied by debilitating symptoms of cerebral hypoperfusion. Therefore, it is critical for physicians to become familiar with the diagnosis and treatment of common underlying causes of presyncope and syncope. In some patients, altered postural hemodynamic responses result from a failure of compensatory autonomic nervous system reflex mechanisms. The most common presentations of presyncope and syncope secondary to this autonomic dysfunction include vasovagal syncope, neurogenic orthostatic hypotension, and postural tachycardia syndrome. The most sensitive method for diagnosis is a detailed initial evaluation with medical history, physical examination, and resting electrocardiogram to rule out cardiac syncope. Physical examination should include measurement of supine and standing blood pressure and heart rate to identify the pattern of hemodynamic regulation during orthostatic stress. Additional testing may be required in patients without a clear diagnosis after the initial evaluation. Management of patients should focus on improving symptoms and functional status and not targeting arbitrary hemodynamic values. An individualized structured and stepwise approach should be taken for treatment, starting with patient education, lifestyle modifications, and use of physical counter-pressure manoeuvres and devices to improve venous return. Pharmacologic interventions should be added only when conservative approaches are insufficient to improve symptoms. There are no gold standard approaches for pharmacologic treatment in these conditions, with medications often used off label and with limited long-term data for effectiveness.


Comparative outcomes and cost-utility after surgical treatment of focal lumbar spinal stenosis compared with osteoarthritis of the hip or knee--part 1: long-term change in health-related quality of life.
It is well accepted that total hip and knee arthroplasty (THA/TKA) for osteoarthritis (OA) is associated with reliable and sustained improvements in postoperative health-related quality of life (HRQoL). Although several studies have demonstrated comparable outcomes with THA/TKA after surgical intervention for lumbar spinal stenosis (LSS), the sustainability of the outcome after LSS surgery compared with THA/TKA remains uncertain. The primary purpose of this study is to assess whether improvements in HRQoL after surgical management of focal lumbar spinal stenosis (FLSS) with or without spondylolisthesis are sustainable over the long term compared with that of THA/TKA for OA. Single-center, retrospective, longitudinal matched cohort study of prospectively collected outcomes, with a minimum of 5-year follow-up (FU). Patients who had primary one- to two-level spinal decompression with or without instrumented fusion for FLSS and THA/TKA for primary OA. Postoperative change from baseline to last FU in Short-Form 36 physical component summary (PCS) and mental component summary (MCS) scores among groups was used as the primary outcome measure. An age, sex-matched inception cohort of primary one- to two-level spinal decompression with or without instrumented fusion for FLSS (n=99) was compared with a cohort of primary THA (n=99) and TKA (n=99) for OA and followed for a minimum of 5 years. Linear regression was used for the primary analysis. Mean (percent) FUs in months were 80.5+16.04 (79%), 94.6+16.62 (92%), and 80.6+16.84 (85%) for the FLSS, THA, and TKA cohorts, respectively, with a range of 5 to 10 years for all three cohorts. The number of patients who have undergone revision including those lost to FU for the FLSS, THA, and TKA cohorts were n=20 (20.2%, same site [n=7] and adjacent segment [n=13]) requiring 27 operations, n=3 (3%, same site) requiring 5 operations, and n=8 (8.1%, same site) requiring 12 operations, respectively (p<.01). The average time to first revision was 56/65/43 months, respectively. Mean postoperative PCS (p<.0001) and MCS (p<.02) scores improved significantly and were durable for all groups at the last FU. The mean changes from baseline PCS/MCS scores to last FU were 8.5/6.4, 12.3/7.0, and 8.3/4.9 for FLSS, THA, and TKA, respectively. Adjusting for baseline age, sex, body mass index, PCS score, and MCS score, there was a strong trend in favor of greater sustained change in the PCS score of THA over FLSS (p=.07) and TKA (p=.08). No difference was noted for change in PCS score between FLSS and TKA (p=.95). No differences were noted for change in MCS score among all three cohorts (p>.1). Significant improvements in HRQoL after surgical treatment of FLSS with or without spondylolisthesis and hip and knee OA are sustained for a mean of 7 to 8 years, with a minimum of 5-year FU. Despite a higher revision rate, patients undergoing surgery for FLSS can expect a comparable long-term average improvement in HRQoL from baseline compared with their peers undergoing TKA and to a lesser extent THA.


[Remodelling of peripheral vessels in cardiovascular diseases: pathogenesis and treatment with telmisartan].
The authors present remodelling mechanisms of distal peripheral vessels in vibration disease, caused by endothelium functions disorder (lower NO, increased endothelin-1 and Villebrandt factor), stressed oxidative metabolism in neutrophils, intensified lipid peroxidation, depressed antioxidant defence, activated anti-inflammatory cytokines (TNF-alpha, IL-1beta) and hyperhomocysteinemia. Degree of the changes increases with combination of vibration disease and arterial hypertension. The data justify application of Telmisartan improving functional state of endothelium.