Analysis of Sleep Macrostructure in Patients Diagnosed with Parkinson's Disease.
Patients diagnosed with Parkinson's disease present sleep disorders with a higher frequency than the general population. The sleep architecture in these patients shows variations with respect to the normal population, so in this work it was decided to investigate the characteristics of the macroarchitecture of sleep in patients diagnosed with Parkinson's disease. A polysomnographic study was carried out on 77 patients diagnosed with Parkinson's disease. All the studies were processed according to the AASM Manual for the Scoring of Sleep and Associated Events v.2.2, and to the criteria of the International Classification of Sleep Disorders 3rd ed. (2014). Processing was carried out using descriptive statistics, as well as non-parametric analysis for comparison between cases and controls. The group of patients showed significant reductions of the N2, N3, and REM sleep stages when compared with a control group, as well as a significant increase in intra-sleep wakefulness. The number of REM⁻NoREM sleep cycles and sleep efficiency showed marked reduction compared to the control group. There was a statistically significant difference in the macroarchitecture of sleep between patients diagnosed with Parkinson's disease and healthy controls.


Trainee Autonomy in Minimally Invasive General Surgery in the United States: Establishing a National Benchmark.
Minimally invasive surgery (MIS) is an integral component of General Surgery training and practice. Yet, little is known about how much autonomy General Surgery residents achieve in MIS procedures, and whether that amount is sufficient. This study aims to establish a contemporary benchmark for trainee autonomy in MIS procedures. We hypothesize that trainees achieve progressive autonomy, but fail to achieve meaningful autonomy in a substantial percentage of MIS procedures prior to graduation. Fifty General Surgery residency programs in the United States, from September 1, 2015 to March 19, 2020. All Categorical General Surgery Residents and Attending Surgeons within these programs were eligible. Data were collected prospectively from attending surgeons and categorical General Surgery residents. Trainee autonomy was assessed using the 4-level Zwisch scale (Show and Tell, Active Help, Passive Help, and Supervision Only) on a smartphone application (SIMPL). MIS procedures included all laparoscopic, thoracoscopic, endoscopic, and endovascular/percutaneous procedures performed by residents during the study. Primary outcomes of interest were "meaningful autonomy" rates (i.e., scores in the top 2 categories of the Zwisch scale) by postgraduate year (PGY), and "progressive autonomy" (i.e., differences in autonomy between PGYs) in MIS procedures, as rated by attending surgeons. Primary outcomes were determined with descriptive statistics, one-way analysis of variance (ANOVA) and Z-tests. Secondary analyses compared (i) progressive autonomy between common MIS procedures, and (ii) progressive autonomy in MIS vs. non-MIS procedures. A total of 106,054 evaluations were performed across 50 General Surgery residency programs, of which 38,985 (37%) were for MIS procedures. Attendings performed 44,842 (42%) of all evaluations, including 16,840 (43%) of MIS evaluations, while residents performed the rest. Overall, meaningful autonomy in MIS procedures increased from 14.1% (PGY1s) to 75.9% (PGY5s), with significant (p < 0.001) increases between each PGY level. Meaningful autonomy rates were higher in the MIS vs. non-MIS group [57.2% vs. 48.0%, p < 0.001], and progressed more rapidly in MIS vs. non-MIS, (p < 0.05). The 7 most common MIS procedures accounted for 83.5% (n = 14,058) of all MIS evaluations. Among PGY5s performing these procedures, meaningful autonomy rates (%) were: laparoscopic appendectomy (95%); laparoscopic cholecystectomy (93%); diagnostic laparoscopy (87%); upper/lower endoscopy (85%); laparoscopic hernia repair (72%); laparoscopic partial colectomy (58%); and laparoscopic sleeve gastrectomy (45%). US General Surgery residents receive progressive autonomy in MIS procedures, and appear to progress more rapidly in MIS versus non-MIS procedures. However, residents fail to achieve meaningful autonomy in nearly 25% of MIS cases in their final year of residency, with higher rates of meaningful autonomy only achieved in a small subset of basic MIS procedures.


The impact of individual creativity, psychological capital, and leadership autonomy support on hospital employees' innovative behaviour.
There is growing interest in and focus on healthcare services research to identify factors associated with innovation in healthcare organizations. However, previous innovation research has concentrated primarily on the organizational level. In contrast, this study focuses on innovation by individual employees. The specific aim is to examine factors with potential impact on individual employee innovation in hospital organizations. Thus, the study significantly deepens and broadens previous research on innovation in the domain of health services. A conceptual model was developed and tested on a sample of hospital employees (n = 1008). Partial least-squares structural equation modelling (PLS-SEM) was used to analyse the data with SmartPLS 3 software in two steps involving a measurement model and a structural model. Mediation analysis was used to test the proposed indirect effects. Hospital employees' individual innovative behaviour is directly and positively associated with individual creativity (β = 0.440), psychological capital (β = 0.34) and leadership autonomy support (β = 0.07). The relationships between leadership autonomy support, psychological capital and individual innovative behaviour are all mediated by employees' creativity. Psychological capital mediates the relationship between leadership autonomy support and individual innovative behaviour. Overall, the proposed model explains 50% of the variance in hospital employees' innovative behaviour. This study reveals a complex pattern of links between innovative behaviour and leadership autonomy support, employees' creativity and employees' psychological capital. However, the findings indicate that leadership autonomy support has an influential and multifaceted impact on hospital employees' innovative behaviour.


Preliminary results of the pioneer venus nephelometer experiment.
Preliminary results of the nephelometer experiments conducted aboard the large sounder, day, north, and night probes of the Pioneer Venus mission are presented. The vertical structures of the Venus clouds observed simultaneously at each of the four locations from altitudes of from 63 kilometers to the surface are compared, and similarities and differences are noted. Tentative results from attempting to use the data from the nephelometer and cloud particle size spectrometer on the sounder probe to identify the indices of refraction of cloud particles in various regions of the Venus clouds are reported. Finally the nephelometer readings for the day probe during impact on the surface of Venus are presented.


Distal radio-ulnar joint instability in children and adolescents after wrist trauma.
This study retrospectively evaluated the medical records and radiographs of patients younger than aged 25 that were referred for a second opinion due to ulnar-sided wrist pain and persistent distal radio-ulnar (DRU) joint instability. We identified 85 patients with a major wrist trauma before the age of 18. Median age at trauma was 14 years. Median time between trauma and diagnosis of DRUJ instability was 3 years. Sixty-seven patients (79%) had sustained a fracture at the initial trauma. The two most common skeletal injuries related to the DRUJ instability were Salter-Harris type II fractures (24%) and distal radius fractures (19%). In 19 patients (22%), the secondary DRUJ instability was caused by malunion or growth arrest. Eighteen patients (21%) had no fracture; in spite of this, they presented with subsequent symptomatic DRUJ instability. Fourteen of these 18 patients had a triangular fibrocartilage complex (TFCC) tear, confirmed by arthroscopy, open surgery, or magnetic resonance imaging. In conclusion, late DRUJ instability due to wrist fractures or isolated TFCC tears was found to be common in children and adolescents. IV.


Overexpression of the OsZIP4 zinc transporter confers disarrangement of zinc distribution in rice plants.
Zinc (Zn), an essential nutrient in cells, plays a vital role in controlling cellular processes such as growth, development, and differentiation. Although the mechanisms of Zn translocation in rice plants (Oryza sativa) are not fully understood, it has recently received increased interest. OsZIP4 is a Zn transporter that localizes to apical cells. Transgenic rice plants overexpressing the OsZIP4 gene under the control of the cauliflower mosaic virus (CaMV) 35S promoter were produced. The Zn concentration in roots of 35S-OsZIP4 transgenic plants was 10 times higher than in those of vector controls, but it was five times lower in shoots. The Zn concentration in seeds of 35S-OsZIP4 plants was four times lower compared with vector controls. Northern blot analysis and quantitative real-time reverse transcription-PCR revealed transcripts of OsZIP4 expression driven by the CaMV 35S promoter in roots and shoots of 35S-OsZIP4 plants, but levels of endogenous OsZIP4 transcripts were low in roots and high in shoots compared with vector controls. Microarray analysis revealed that the genes expressed in shoots of 35S-OsZIP4 plants coincided with those induced in shoots of Zn-deficient plants. These results indicate that constitutive expression of OsZIP4 changes the Zn distribution within rice plants, and that OsZIP4 is a critical Zn transporter that must be strictly regulated.


The characteristics of nuclear membrane fluctuations in stem cells.
We analyse the stem cell nucleus shape fluctuation spectrum obtained from optical confocal microscopy on an hour time scale with 10 s resolution. In particular, we investigate the angular and time dependencies of these fluctuations, define appropriate correlation functions that reveal the fundamentally out of equilibrium nature of the observed fluctuations as well as their global anisotropy. Langevin equations respecting the symmetry of the system allow us to model the damped oscillatory behaviour of the time correlations.


mTORC1/rpS6 regulates blood-testis barrier dynamics and spermatogenetic function in the testis in vivo.
The blood-testis barrier (BTB), conferred by Sertoli cells in the mammalian testis, is an important ultrastructure that supports spermatogenesis. Studies using animal models have shown that a disruption of the BTB leads to meiotic arrest, causing defects in spermatogenesis and male infertility. To better understand the regulation of BTB dynamics, we report findings herein to understand the role of ribosomal protein S6 (rpS6), a downstream signaling protein of mammalian target of rapamycin complex 1 (mTORC1), in promoting BTB disruption in the testis in vivo, making the barrier "leaky." Overexpression of wild-type rpS6 (rpS6-WT, the full-length cDNA cloned into the mammalian expression vector pCI-neo) and a constitutively active quadruple phosphomimetic mutant cloned into pCI-neo (p-rpS6-MT) vs. control (empty pCI-neo vector) was achieved by transfecting adult rat testes with the corresponding plasmid DNA using a Polyplus in vivo-jetPEI transfection reagent. On the basis of an in vivo functional BTB integrity assay, p-rpS6-MT was found to induce BTB disruption better than rpS6-WT did (and no effects in empty vector control), leading to defects in spermatogenesis, including loss of spermatid polarity and failure in the transport of cells (e.g., spermatids) and organelles (e.g., phagosomes), to be followed by germ exfoliation. More important, rpS6-WT and p-rpS6-MT exert their disruptive effects through changes in the organization of actin- and microtubule (MT)-based cytoskeletons, which are mediated by changes in the spatiotemporal expression of actin- and MT-based binding and regulatory proteins. In short, mTORC1/rpS6 signaling complex is a regulator of spermatogenesis and BTB by modulating the organization of the actin- and MT-based cytoskeletons.


Dissociable rate-dependent effects of oral methylphenidate on impulsivity and D2/3 receptor availability in the striatum.
We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [(18)F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [(18)F]fallypride PET scan. Before MPH treatment, we found that D2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3 receptor availability through independent mechanisms.


First case of Zika virus infection in a returning Canadian traveler.
A woman who recently traveled to Thailand came to a local emergency department with a fever and papular rash. She was tested for measles, malaria, and dengue. Positive finding for IgM antibody against dengue and a failure to seroconvert for IgG against dengue for multiple blood samples suggested an alternate flavivirus etiology. Amplification of a conserved region of the non-structural protein 5 gene of the genus Flavivirus yielded a polymerase chain reaction product with a matching sequence of 99% identity with Zika virus. A urine sample and a nasopharygeal swab specimen obtained for the measles investigation were also positive for this virus by reverse transcription polymerase chain reaction. Subsequently, the urine sample yielded a Zika virus isolate in cell culture. This case report describes a number of novel clinical and laboratory findings, the first documentation of this virus in Canada, and the second documentation from this region in Thailand.


12,13-Epoxy-delta 9-trichothecenes as the probable mycotoxins responsible for stachybotryotoxicosis.
Stachybotrys atra cultures grown on oats produced five compounds toxic to brine shrimp; three are the sesquiterpenoid mycotoxins known as 12,13-epoxy-Delta(9)-trichothecenes. One trichothecene is roridin E, a known metabolite of Myrothecium verrucaria. The other two were hydrolyzed to verrucarol, the product of roridin and verrucarin hydrolysis. Spectroscopic data indicate that the two remaining compounds are also 12,13-epoxy-Delta(9)-trichothecenes. These metabolites are probably among those responsible for stachybotryotoxicosis.


Haltere removal alters responses to gravity in standing flies.
Animals detect the force of gravity with multiple sensory organs, from subcutaneous receptors at body joints to specialized sensors like the vertebrate inner ear. The halteres of flies, specialized mechanoreceptive organs derived from hindwings, are known to detect body rotations during flight, and some groups of flies also oscillate their halteres while walking. The dynamics of halteres are such that they could act as gravity detectors for flies standing on substrates, but their utility during non-flight behaviors is not known. We observed the behaviors of intact and haltere-ablated flies during walking and during perturbations in which the acceleration due to gravity suddenly changed. We found that intact halteres are necessary for flies to maintain normal walking speeds on vertical surfaces and to respond to sudden changes in gravity. Our results suggest that halteres can serve multiple sensory purposes during different behaviors, expanding their role beyond their canonical use in flight.


High-frequency jet ventilation in the early management of respiratory distress syndrome is associated with a greater risk for adverse outcomes.
The objective of this investigation was to determine if high-frequency jet ventilation (HFJV) used early in the treatment of premature infants with respiratory distress syndrome was effective in reducing pulmonary morbidity without increasing the occurrence of adverse neurologic outcomes. A total of 73 premature infants who met the inclusion criteria (gestational age of less than 33 weeks, birth weight of more than 500 g, age of less than 24 hours, need for assisted ventilation with peak inspiratory pressure of more than 16 and FIO2 more than 0.30, and roentgenographic evidence of respiratory distress syndrome) were randomized to either conventional (n = 36) or to high-frequency jet (n = 37) ventilation. Our goals were to maintain the infants on the assigned ventilator for at least 7 days unless they could either be extubated or meet crossover criteria. Univariate analyses were initially used to compare the two groups. Stepwise logistic regression was subsequently used to assess whether various factors independently influenced adverse outcomes. The two groups of infants were similar in all obstetrical, perinatal, and neonatal demographic characteristics. The mean birth weight and gestational age in the conventional group were 930 g and 26.6 weeks and in the HFJV group, 961 g and 26.9 weeks. The infants were randomized at similar ages (7.1 and 7.3 hours of life, respectively). Their prerandomization ventilator settings and arterial blood gases were nearly identical. There were no differences in pulmonary outcomes (occurrence of air leaks, need for oxygen or ventilation at 36 weeks postconception), and there were no differences in the mean number of days oxygen was required, number of days ventilated, or length of hospital stay. Infants ventilated with HFJV were significantly more likely to develop cystic periventricular leukomalacia (10 vs 2, P = .022) or to have a poor outcome (grade IV hemorrhage, cystic periventricular leukomalacia, or death) (17 vs 7, P = .016). Logistic regression analysis revealed HFJV to be a significant independent predictor of both cystic periventricular leukomalacia and a poor outcome. The presence of hypocarbia was not an independently significant predictor of adverse outcomes. With the HFJV treatment strategy that we used, use of the high-frequency jet ventilator in the early management of premature infants with respiratory distress syndrome resulted in significantly more adverse outcomes than in those treated with conventional mechanical ventilation.


Tegaserod does not alter fasting or meal-induced biliary tract motility.
Tegaserod is a 5-HT(4) receptor partial agonist that increases peristaltic activity of the intestinal tract. It is approved for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). IBS is a chronic gastrointestinal disorder of function that is reported to be associated with an increased incidence of abdominal surgery including cholecystectomy. The effect of tegaserod on nongut digestive organs, such as the gallbladder and biliary tract, has not been previously investigated. Therefore, this study aimed to evaluate the effects of tegaserod on gallbladder contractility and on functional status of the sphincter of Oddi during both the interdigestive and the digestive periods in healthy female subjects and in female patients with IBS-C. During a 6-wk, double-blind, placebo-controlled crossover study, gallbladder contractility and concomitant change in luminal diameter of the common hepatic duct (CHD) and the common bile duct (CBD, both proximal and distal) in response to a standard liquid meal were quantified using real-time ultrasonography. Changes in luminal diameter of the CHD and the CBD were used as a surrogate marker for sphincter of Oddi function. Ultrasound measurements were conducted every 15 min from 45 min before, to 60 min after the test meal to observe the impact of tegaserod on gallbladder volume and any concomitant change in the diameters of the CHD and the CBD that developed in response to gallbladder contraction. The ultrasound measurements of gallbladder contractility, along with the CHD and the CBD diameters, were repeated after each of the two 2-wk periods of treatment with tegaserod or placebo. The recommended dose of tegaserod (6 mg b.i.d.) for IBS-C patients was used in healthy female subjects (n = 13) and female patients with IBS-C (n = 20). Twice this dose (12 mg b.i.d.) was also evaluated in an additional 20 female patients with IBS-C. Statistical evaluations were conducted using a two-sided analysis of variance (ANOVA). Gallbladder contractility variables including ejection fraction, ejection rate and ejection period, fasting and residual volume, and maximal emptying, were similar after 2 wk of treatment with tegaserod 6 mg b.i.d. and placebo in healthy female subjects and female patients with IBS-C. There were no significant changes in the luminal diameters of the CHD or the CBD after tegaserod compared to placebo in any cohort. Additionally, no significant dilation (> or =7 mm in diameter) of the CHD or CBD was observed during maximal gallbladder emptying. Similar results were also observed when tegaserod was given at 12 mg b.i.d. in patients with IBS-C. Tegaserod treatment had no significant effect on plasma CCK concentration in response to the test meal. No significant abdominal pain or unexpected adverse events were reported during the study. This study showed no significant pharmacodynamic effect of tegaserod on gallbladder contractility or on CBD and CHD diameters as a surrogate marker of sphincter of Oddi function during both the interdigestive (fasting) and the digestive (postprandial) periods in healthy female subjects and female patients with IBS-C.


Experimental and numerical techniques to evaluate coal/biomass fly ash blend characteristics and potentials.
Fossil and renewable fuels are used by industrial units that produce energy-intensive products. Competitive fuel pricing encourages these fuel sources' usage globally, particularly in developing nations, which leads to large volumes of byproducts like fly ash among thermal power plant operators. The elements and compounds found in coal fly ash (CFA) and biomass fly ash (BFA) can be utilized through several engineering applications. This study aims to assess typical CFA and BFA samples quantitatively and qualitatively via techniques such as ultimate analysis (CH-S), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), X-ray fluorescence (XRF) elemental analysis, and ash fusion temperature (AFT), to anticipate the ideal ratios of coal to biomass blends for combustion applications while adhering to environmental regulations. The optimal blend, consisting of 75 % CFA and 25 % BFA, exhibited improved carbon (C%) and hydrogen (H%) percentages, increasing from 2.5 % to 4.67 % and from 0 % to 0.12 %, respectively. These improvements were further confirmed by the observed functional groups in FTIR, indicating a rising trend in both carbon and hydroxyl groups from BFA to CFA. XRF and XRD also confirmed it and TGA also showed optimum mass loss (ML%) behavior of 14.55 % for 75CFA + 25BFA. According to slagging and fouling indices, the values of RB/A, Rs, and Fu indicate a reduction in slagging and fouling issues through the blending of CFA with BFA. Simultaneously, the fusion temperature increased from 1181 °C to 1207 °C. CFA was found to increase the AFT of the BFA from 1197 °C to 1247 °C, mitigating their propensity. This suggests that a blend of 75CFA + 25BFA results in lower to medium range of slagging and fouling. However, AFI and BAI indicate a slightly higher range. AFT analysis further validates the conclusions drawn from the indices. The ternary phase diagram shows that the ash's melting point increases in the optimum blend. This is attributed to a reduced content of K2O (<15 %) and increased proportions of >50 % CaO and SiO2, effectively inhibiting slagging, agglomeration, and deposition. Meanwhile, the blend maintains a medium level of acidity and susceptively to corrosion, as observed in the case of 75CFA + 25BFA. The identification of optimal blend ratios can be anticipated to offer essential solutions for future research, aiming to ensure smooth industrial operations and regulatory compliance in power plants.


Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.
Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.


Professing ethically. On the place of ethics in defining medicine.
Medicine, despite technological advances and societal changes, remains essentially what it has always been, a profession rather than a trade, with its own ends, means, and intrinsic norms of conduct. Being a professional is an ethical matter, entailing devotion to a way of life, in the service of others and of some higher good. The medical profession is devoted to the naturally given end of health and assists the immanent powers of self-healing. It serves the needs as it treats the infirmities of the sick, sensitive to their vulnerability, shame, and exposure and mindful of the meaning of the delicate tension between bodily wholeness and necessary decay. These special characteristics imply specific and inherently medical obligations, both of omission and commission, as well as an appropriately reverential stance of the physician before his chosen profession.


Elevated IL-37 Serum Levels in Patients with Transitional Cell Carcinoma of Bladder.
Interleukin-37 (IL-37) is a recently described cytokine that emerges as a natural inhibitor of inflammatory and immune responses. However, IL-37 has not yet been investigated in bladder cancer, and its biological role is unknown. The purpose of this study was to investigate IL-37 serum levels in patients with bladder cancer and determine whether they were linked to the patients' pathological characteristics. IL-37 serum levels were measured using a commercial ELISA kit in 60 patients with transitional cell carcinoma (TCC) of the bladder (mean age: 64.55±12.93) and 50 healthy controls (mean age: 62.94±12.69). Non-parametric tests were used for statistical comparisons, and the Cohen's d effect size was calculated to evaluate the practical and clinical significance of the results. Our findings indicated an increasing trend in IL-37 serum levels in patients with TCC (42.77±3.36 pg/ml) in comparison with controls (40.51±7.32 pg/ml, p=0.09). However, IL-37 serum levels were found to be significantly higher in male patients (44.72±3.81 pg/ml) and patients aged ≥70 (46.92±6.77 pg/ml) in comparison with male controls (29.96±3.30 pg/ml, p=0.026) and controls aged ≥70 (23.62±4.43 pg/ml, p=0.009). In comparison to similar controls, Cohen's d effect size for patients aged ≥70 years was found to be 0.90. The findings reveal a higher serum level of IL-37 in patients with TCC, which might be clinically associated with immunosuppression and tumor growth. However, this is a preliminary study, and more research on the biological role of IL-37 and its potential therapeutic effects in bladder cancer is required.


A fast globally optimal algorithm for template matching using low-resolution pruning.
Template matching has many applications in signal processing, image processing, pattern recognition, and video compression. This paper proposes a fast coarse-to-fine template matching algorithm for finding the exact best match, i.e., the match that may be found by a full search. This is obtained by pruning the number of candidates in the full search using the results of a coarse search. Experimental results show that speed ups of a couple of orders of magnitude can easily be achieved using this method for typical low-noise cases of two-dimensional (2-D) template matching.


[Eruptive generalized syringomas, milium and atrophoderma vermiculata. Nicolau and Balus' syndrome (author's transl)].
It appears justified to isolate under the term syndrome of Nicolau and Balus', a group of deformities that include eruptive syringomas of the disseminated micropapular type, milium cysts and atrophoderma vermiculata. We present here a highly typical observation of an 11-year-old child whose mother also presented with eruptive syringomas. This syndrome accentuates the semiological value of disseminated syringomas and atrophoderma vermiculata, which often occur in the context of a complex syndrome. In addition, an associated elastopathy was discovered by light- and electron-microscopic observations.


Rotons in a hybrid Bose-Fermi system.
We calculate the spectrum of elementary excitations in a two-dimensional exciton condensate in the vicinity of a two-dimensional electron gas. We show that attraction of excitons due to their scattering with free electrons may lead to formation of a roton minimum. The energy of this minimum may go below the ground state energy which manifests breaking of the superfluidity. The Berezinsky-Kosterlitz-Thouless phase transition temperature decreases due to the exciton-exciton attraction mediated by electrons.


The growth hormone independent insulin-like growth factor-I binding protein BP-28 is associated with serum insulin-like growth factor-I inhibitory bioactivity in adolescent insulin-dependent diabetics.
The relationship between the growth hormone independent insulin-like growth factor binding protein (BP-28) and serum insulin-like growth factor-I (IGF-I) inhibitory bioactivity observed in diabetic serum was investigated in five poorly controlled adolescent type I diabetics. We have measured the in-vitro effects of purified BP-28 from amniotic fluid on serum IGF-I stimulated and basal cartilage sulphation and compared serum IGF-I bioactivity obtained from 24-h serum profiles from each diabetic subject with serum concentrations of BP-28 and IGF-I measured by specific radioimmunoassays. Purified BP-28 inhibited serum IGF-I stimulated and basal cartilage sulphation in vitro, in a dose-dependent manner. Serum IGF-I bioactivity of diabetic sera showed a change in activity over the 24-h period, with peak inhibitory bioactivity observed in each subject between 0800 and 1000 h. BP-28 concentrations in each individual showed a marked circadian rhythm with maximum peak levels occurring at 0800 h. Long-acting insulin administered in the evening in two of the diabetic subjects blunted the maximum peak level attained compared to the three diabetics who had long-acting insulin administered in the morning. IGF-I concentrations did not change over the 24-h period in each individual. The data shows that BP-28 inhibits serum IGF-bioactivity on cartilage in vitro. The changes in inhibitory bioactivity observed in diabetic serum are associated with similar changes in serum concentrations of BP-28. We propose that BP-28 is one of the IGF-I inhibitors observed in diabetic serum and that it may play a role in retarded growth and delayed puberty often seen in the adolescent diabetic.


Eating high-fat chow enhances sensitization to the effects of methamphetamine on locomotion in rats.
Eating high-fat chow can modify the effects of drugs acting directly or indirectly on dopamine systems and repeated intermittent drug administration can markedly increase sensitivity (i.e., sensitization) to the behavioral effects of indirect-acting dopamine receptor agonists (e.g., methamphetamine). This study examined whether eating high-fat chow alters the sensitivity of male Sprague Dawley rats to the locomotor stimulating effects of acute or repeated administration of methamphetamine. The acute effects of methamphetamine on locomotion were not different between rats (n=6/group) eating high-fat or standard chow for 1 or 4 weeks. Sensitivity to the effects of methamphetamine (0.1-10mg/kg, i.p.) increased progressively across 4 once per week tests; this sensitization developed more rapidly and to a greater extent in rats eating high-fat chow as compared with rats eating standard chow. Thus, while eating high-fat chow does not appear to alter sensitivity of rats to acutely-administered methamphetamine, it significantly increases the sensitization that develops to repeated intermittent administration of methamphetamine. These data suggest that eating certain foods influences the development of sensitization to drugs acting on dopamine systems.


Forssman synthetase expression results in diminished shiga toxin susceptibility: a role for glycolipids in determining host-microbe interactions.
Forssman glycolipid (FG), the product of Forssman synthetase (FS), is widely expressed among nonprimate mammalian species. Here, we describe a molecular and genetic relationship between FG expression and Shiga toxin (Stx) susceptibility. We have isolated the FS cDNA from human, canine, and murine cells. Whereas the murine and canine FS genes express a functional enzyme, the human FS cDNA was found to express a protein that lacks FS activity, despite a high degree of sequence identity with the enzymatically active murine and canine FS genes. In order to examine the relationship between FG expression and Stx susceptibility, Vero cells were transfected with the three FS orthologues or a vector control. Complementation with the human FS cDNA had no effect on Stx susceptibility, whereas stable expression of the canine and murine FS resulted in markedly decreased susceptibility to toxin. Among individual cells, an inverse correlation between FG expression and Stx binding was demonstrated. Moreover, only strongly FG-reactive cells were capable of growing in the presence of Stx. These cells were found to have high levels of FG expression and a correspondingly diminished GbO(3) content. We conclude that expression of a functionally active FS modifies Stx receptor glycolipids to FG and results in markedly decreased susceptibility to toxin. We speculate that inactivation of the FS gene during primate evolution may account, at least in part, for the marked susceptibility of human cells to Stx.


A proposal of new diagnostic pathway for fatal familial insomnia.
In absence of a positive family history, the diagnosis of fatal familial insomnia (FFI) might be difficult because of atypical clinical features and low sensitivity of diagnostic tests. FFI patients usually do not fulfil the established classification criteria for Creutzfeldt-Jakob disease (CJD); therefore, a prion disease is not always suspected. To propose an update of diagnostic pathway for the identification of patients for the analysis of D178-M129 mutation. Data on 41 German FFI patients were analysed. Clinical symptoms and signs, MRI, PET, SPECT, polysomnography, EEG and cerebrospinal fluid biomarkers were studied. An algorithm was developed which correctly identified at least 81% of patients with the FFI diagnosis during early disease stages. It is based on the detection of organic sleep disturbances, either verified clinically or by a polysomnography, and a combination of vegetative and focal neurological signs and symptoms. Specificity of the approach was tested on three cohorts of patients (MM1 sporadic CJD patients, non-selected sporadic CJD and other neurodegenerative diseases). The proposed scheme may help to improve the clinical diagnosis of FFI. As the sensitivity of all diagnostic tests investigated but polysomnography is low in FFI, detailed clinical investigation is of special importance.


Intrahemispheric Perfusion in Chronic Stroke-Induced Aphasia.
Stroke-induced alterations in cerebral blood flow (perfusion) may contribute to functional language impairments and recovery in chronic aphasia. Using MRI, we examined perfusion in the right and left hemispheres of 35 aphasic and 16 healthy control participants. Across 76 regions (38 per hemisphere), no significant between-subjects differences were found in the left, whereas blood flow in the right was increased in the aphasic compared to the control participants. Region-of-interest (ROI) analyses showed a varied pattern of hypo- and hyperperfused regions across hemispheres in the aphasic participants; however, there were no significant correlations between perfusion values and language abilities in these regions. These patterns may reflect autoregulatory changes in blood flow following stroke and/or increases in general cognitive effort, rather than maladaptive language processing. We also examined blood flow in perilesional tissue, finding the greatest hypoperfusion close to the lesion (within 0-6 mm), with greater hypoperfusion in this region compared to more distal regions. In addition, hypoperfusion in this region was significantly correlated with language impairment. These findings underscore the need to consider cerebral perfusion as a factor contributing to language deficits in chronic aphasia as well as recovery of language function.


Resolution evaluation of MR images reconstructed by iterative thresholding algorithms for compressed sensing.
Magnetic resonance imaging systems usually feature linear and shift-invariant (stationary) transform characteristics. The point spread function or equivalently the modulation transfer function may thus be used for an objective quality assessment of imaging modalities. The recently introduced theory of compressed sensing, however, incorporates nonlinear and nonstationary reconstruction algorithms into the magnetic resonance imaging process which prohibits the usage of the classical point spread function and therefore the according evaluation. In this work, a local point spread function concept was applied to assess the quality of magnetic resonance images which were reconstructed by an iterative soft thresholding algorithm for compressed sensing. The width of the main lobe of the local point spread function was used to perform studies on the spatial and temporal resolution properties of both numerical phantom and in vivo images. The impact of k-space sampling patterns as well as additional sparsifying transforms on the local spatial image resolution was investigated. In addition, the local temporal resolution of image series, which were reconstructed by exploiting spatiotemporal sparsity, was determined. Finally, the dependency of the local resolution on the thresholding parameter of the algorithm was examined. The sampling patterns as well as the additional sparsifying transform showed a distinct impact on the local image resolution of the phantom image. The reconstructions, which were using x-f-space as a sparse transform domain showed slight temporal blurring for dynamic parts of the imaged object. The local image resolution had a dependence on the thresholding parameter, which allowed for optimizing the reconstruction. Local point spread functions enable the evaluation of the local spatial and temporal resolution of images reconstructed with the nonlinear and nonstationary iterative soft thresholding algorithm. By determining the influence of thresholding parameter and sampling pattern chosen on this model-based reconstruction, the method allows selecting appropriate acquisition parameters and thus improving the results.


Bioengineered Cystinotic Kidney Tubules Recapitulate a Nephropathic Phenotype.
Nephropathic cystinosis is a rare and severe disease caused by disruptions in the CTNS gene. Cystinosis is characterized by lysosomal cystine accumulation, vesicle trafficking impairment, oxidative stress, and apoptosis. Additionally, cystinotic patients exhibit weakening and leakage of the proximal tubular segment of the nephrons, leading to renal Fanconi syndrome and kidney failure early in life. Current in vitro cystinotic models cannot recapitulate all clinical features of the disease which limits their translational value. Therefore, the development of novel, complex in vitro models that better mimic the disease and exhibit characteristics not compatible with 2-dimensional cell culture is of crucial importance for novel therapies development. In this study, we developed a 3-dimensional bioengineered model of nephropathic cystinosis by culturing conditionally immortalized proximal tubule epithelial cells (ciPTECs) on hollow fiber membranes (HFM). Cystinotic kidney tubules showed lysosomal cystine accumulation, increased autophagy and vesicle trafficking deterioration, the impairment of several metabolic pathways, and the disruption of the epithelial monolayer tightness as compared to control kidney tubules. In particular, the loss of monolayer organization and leakage could be mimicked with the use of the cystinotic kidney tubules, which has not been possible before, using the standard 2-dimensional cell culture. Overall, bioengineered cystinotic kidney tubules recapitulate better the nephropathic phenotype at a molecular, structural, and functional proximal tubule level compared to 2-dimensional cell cultures.


Cryptococcus neoformans var. gattii in Australia.
An examination of 45 clinical isolates of Cryptococcus neoformans revealed an unusually high incidence of C. neoformans var. gattii in South Australia (65%) and in the Northern Territory (95%). In assessing all the available data from Australian isolates of C. neoformans, there appeared to be an endemic focus for the incidence of C. neoformans var. gattii in the rural aboriginal population of the Northern Territory.


A second survey of high explosives traces in public places.
This survey was carried out as a follow-up to a 1994 survey carried out by this laboratory (1) in order to determine the background levels of explosives traces in public places. The first survey concentrated on transport areas and police stations in and around London. This second study examines levels in four of the United Kingdom's major cities: Birmingham, Cardiff, Glasgow, and Manchester. Samples were taken at various transport sites and from hotels, private houses, private vehicles, and clothing. The survey showed that traces of the high explosives nitroglycerine (NG), trinitrotoluene (TNT), pentaerythritol tetranitrate (PETN), and cyclotrimethylene trinitramine (RDX) are rare within the general public environment. Only one low-level trace of RDX was detected. NG, possibly associated with the use of firearms, was detected at low levels in two samples and 2,4-DNT was detected in a separate sample. No PETN was detected in any of the samples. The results of the survey indicate that it is unlikely that persons visiting public areas could become significantly contaminated with explosives. The analytical procedures employed would also have detected ethylene glycol dinitrate (EGDN) if present at levels greater than 2 ng, nitrobenzene (NB) if present at levels greater than 50 ng, mononitrotoluenes if present at levels greater than 50 ng, and the other common isomers of dinitrotoluene if these had been present at levels in excess of 10 ng. None of these were detected. The relatively high volatility of EGDN, NB, and the mononitrotoluenes would, however, cause traces of these compounds to disperse rapidly. A proportion of the samples (approximately 7%) were analyzed for the presence of HMX. No HMX was detected.


Systematic development and refinement of a contextually relevant strategy for undergraduate medical ethics education: a qualitative study.
Delivery of medical ethics education is complex due to various reasons, compounded by the context-dependent nature of the content. The scarcity of relevant resources in the contexts of some developing countries adds a further layer of difficulty to ethics education in these contexts. We used a consultative approach with students, teachers and external experts to develop a practical approach to medical ethics education. This study aimed to develop and refine a contextually relevant approach to ethics education in the region of Saudi Arabia. The study utilised an explorative qualitative methodology to seek views of students and faculty of Rabigh Faculty of Medicine, Saudi Arabia, and international experts in the field of ethics and education to review and enhance a new ethics learning strategy which included a workbook-based tool. Three focus groups with 12 students, in-depth interviews with four faculty members and qualitative feedback from eleven external experts enabled the study participants to objectively critique the WBEL and provide feedback to enhance its quality. Thematic content analysis of the data was done to draw inferences which were used to refine the educational strategy. The analysis generated twenty-one sub-themes within four main themes: design features, content, teaching methods and assessment. These findings helped to design the educational strategy to improve its effectiveness in the given context. The study drew on the views of students, faculty and external experts to systematically develop a novel approach to ethics education for countries like Saudi Arabia. It also demonstrated the use of the consultative approach for informing a culturally relevant educational strategy in the Middle East context.


Modulating functionally-distinct vagus nerve fibers using microelectrodes and kilohertz frequency electrical stimulation.
Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα- and Aβ-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B- and C-) indicated a stronger dependency.Clinical Relevance- Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects.


Associations of metabolic syndrome and diabetes mellitus with 16-year survival after CABG.
The associations of metabolic syndrome (MetS) or diabetes mellitus (DM) on long-term survival after coronary artery bypass grafting (CABG) have not been extensively evaluated. The aim of the present study was to assess the impact of MetS and DM on the 16-year survival after CABG. Diabetic and metabolic status together with relevant cardiovascular data was established in 910 CABG patients operated in 1993-94. They were divided in three groups as follows: neither DM nor MetS (375 patients), MetS alone (279 patients) and DM with or without MetS (256 patients). The 16-year follow-up of patient survival was carried out using national health databases. The relative survival rates were analyzed using the Life Table method comparing the observed survival rates of three patient groups to the rates based on age-, sex- and time-specific life tables for the whole population in Finland. To study the independent significance of MetS and DM for clinical outcome, multivariate analysis was made using an optimizing stepwise procedure based on the Bayesian approach. Bayesian multivariate analysis revealed together six variables to predict clinical outcome (2 months to 16 years) in relation to the national background population, i.e. age, diabetes, left ventricular ejection fraction, BMI, perfusion time during the CABG and peripheral arterial disease. Our principal finding was that after postoperative period the 16-year prognosis of patients with neither DM nor MetS was better than that of the age-, sex-and time-matched background population (relative survival against background population 1.037, p < 0.0001). The overall survival of MetS patients resembled that of the matched background population (relative survival 0.998, NS). DM was associated with significantly increased mortality (relative survival 0.86, p < 0.0001). Additionally, mortality was even higher in patients receiving insulin treatment than in those without. Excess death rate of DM patients was predominantly caused by cardiovascular causes. In this long-term follow-up study patient groups without diabetes had at least equal 16 years' survival after CABG than their matched background populations. Survival of DM patients started to deteriorate already few years after the operation.


Isolation of small interfering RNAs using viral suppressors of RNA interference.
The tombusvirus P19 VSR (viral suppressor of RNA interference) binds siRNAs with high affinity, whereas the Flockhouse Virus (FHV) B2 VSR binds both long double-stranded RNA (dsRNA) and small interfering RNAs (siRNAs). Both VSRs are small proteins and function in plant and animal cells. Fusing a Nuclear Localization Signal (NLS) to the N-terminus shifts the localization of the VSR from cytoplasmic to nuclear, allowing researchers to specifically probe the subcellular distribution of siRNAs, and to investigate the function of nuclear and cytoplasmic siRNAs. This chapter provides a detailed protocol for the immunoprecipitation of siRNAs bound to epitope-tagged VSR and subsequent analysis by 3'-end-labeling using cytidine-3',5'-bis phosphate ([5'-(32)P]pCp) and northern blotting.


Tamsulosin hydrochloride vs placebo for management of distal ureteral stones: a multicentric, randomized, double-blind trial.
α-Blockers induce selective relaxation of ureteral smooth muscle with subsequent inhibition of ureteral spasms and dilatation of the ureteral lumen. The aim of the study was to evaluate the efficacy and safety of the α-blocker tamsulosin hydrochloride in patients with ureteral colic owing to a distal ureteral stone. This was a multicenter, placebo-controlled, randomized, double-blind study. Patients with emergency admission for ureteral colic with a 2- to 7-mm-diameter radio-opaque distal ureteral stone were included in the study. They received tamsulosin (0.4 mg/d) or matching placebo until stone expulsion or day 42, whichever came first. The main end point was time to stone expulsion between inclusion and day 42. Sequential statistical analysis was performed using the triangular test. A total of 129 patients with acute renal colic were recruited from emergency wards between February 1, 2002, and December 8, 2006, in 6 French hospitals. Of these 129 randomized patients (placebo, 63; tamsulosin, 66), 7 were excluded from analyses: 5 for major deviations from inclusion criteria, 1 for stone expulsion before the first treatment administration, and 1 for consent withdrawal. At inclusion, mean (SD) stone diameters were 3.2 (1.2) and 2.9 (1.0) mm in the placebo and tamsulosin groups, respectively (P = .23). Expulsion delay distributions during 42 days did not show any difference (P = .30). The numbers of patients who spontaneously expelled their stone within 42 days were 43 of 61 (70.5%) and 47 of 61 (77.0%) in the placebo and tamsulosin groups, respectively (P = .41). Corresponding delays were 10.1 (10.0) and 9.6 (9.8) days (P = .82). Other secondary end points and tolerance were not different between groups. Although well tolerated, a daily administration of 0.4 mg of tamsulosin did not accelerate the expulsion of distal ureteral stones in patients with ureteral colic. clinicaltrials.gov Identifier: NCT00151567.


Transcatheter mitral valve implantation via transapical approach: an early experience.
As many as 50% of patients with severe symptomatic mitral valve regurgitation are denied surgical valve replacement or repair due to high operative risk. We describe an early series of cases of transcatheter implantation with a CardiAQ™ mitral valve via a transapical approach. Three consecutive patients with an Society of Thoracic Surgeons (STS) mortality score of >22% were selected for transcatheter mitral valve implantation (TMVI) on compassionate grounds. All patients were elderly, had severe mitral regurgitation (MR), were in Class IV heart failure and deemed unsuitable for the MitraClip. Two of the patients had functional MR in the setting of ischaemic cardiomyopathy with left ventricular ejection fraction (LVEF) <40%, deemed while the remaining patient had chordal rupture with extensive anterior leaflet flail (preserved LVEF). Comorbidities included previous coronary artery bypass surgery (n = 2), severe pulmonary hypertension (n = 1) and moderate to severe chronic renal failure (n = 3). A CardiAQ mitral valve was implanted using fluoroscopy and transoesophageal (TEE) guidance via a standard transapical approach. Accurate prosthesis positioning and deployment with immediate elimination of the MR was achieved in all 3 cases. Two patients made full clinical recovery and were discharged home. Post-procedural TEE performed on Days 1, 30 and 60 days showed good valve function, stable valve position and minimal LVOT gradient. One patient expired on the postoperative day 9 due to pneumonia. TMVI using the CardiAQ™ device via a transapical approach is feasible and effective.


Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients.
The study was undertaken to evaluate the frequency of inherited medullary thyroid carcinoma (MTC) among patients with apparent sporadic disease. A stepwise algorithm was used depending on clinical indices and the age of patient at MTC diagnosis. One hundred sixteen patients with MTC verified by postoperative pathologic examination were subjected to genetic analysis of RET exons 10, 11, 13, 14, and 16 by means of polymerase chain reaction, restriction endonuclease digestion, and DNA sequencing. Among 116 apparent sporadic MTC patients, we identified eleven (9.5%) RET germline mutation carriers. Seven of these (6.0%) were found by routine analysis (exons 10 and 11). The frequency of inherited disease among patients younger than 45 years at diagnosis was 10.2% by analysis of typical mutations in exons 10 and 11. Extended genetic analysis (sequencing of exons 11, 13, 14, and 16) yielded 6.1% additional diagnoses, giving a risk of 16.3% in this age group. One previously unreported mutation in exon 11 affected codon 649 (TCG>TTG, Ser>Leu). In the true sporadic MTC patients younger than 30 years at diagnosis, frequencies of 36% and 4.5% in polymorphic variants L769L and S836S, respectively, were observed. The frequency for L769L was higher than in older patients (P <.05). The frequency of inherited disease among apparent sporadic medullary thyroid carcinoma patients is close to 10% in the Polish population of MTC patients. The extended analysis of all known RET proto-oncogene mutation sites is obligatory in patients younger than 45 years at diagnosis, but we also see the need to analyze the impact of rarer mutations in older patients.


Stability, surface features, and atom leaching of palladium nanoparticles: toward prediction of catalytic functionality.
Surfactant-stabilized metal nanoparticles have shown promise as catalysts although specific surface features and their influence on catalytic performance have not been well understood. We quantify the thermodynamic stability, the facet composition of the surface, and distinct atom types that affect rates of atom leaching for a series of twenty near-spherical Pd nanoparticles of 1.8 to 3.1 nm size using computational models. Cohesive energies indicate higher stability of certain particles that feature an approximate 60/20/20 ratio of {111}, {100}, and {110} facets while less stable particles exhibit widely variable facet composition. Unique patterns of atom types on the surface cause apparent differences in binding energies and changes in reactivity. Estimates of the relative rate of atom leaching as a function of particle size were obtained by the summation of Boltzmann-weighted binding energies over all surface atoms. Computed leaching rates are in good qualitative correlation with the measured catalytic activity of peptide-stabilized Pd nanoparticles of the same shape and size in Stille coupling reactions. The agreement supports rate-controlling contributions by atom leaching in the presence of reactive substrates. The computational approach provides a pathway to estimate the catalytic activity of metal nanostructures of engineered shape and size, and possible further refinements are described.


High-resolution peripheral quantitative computed tomography and finite element analysis of bone strength at the distal radius in ovariectomized adult rhesus monkey demonstrate efficacy of odanacatib and differentiation from alendronate.
Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 μg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs.


Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae.
Opacity (Opa) protein variation in Neisseria gonorrhoeae is implicated in the pathogenesis of gonorrhea, possibly by mediating adherence and entry of the bacteria into human tissues. One particular Opa protein mediates adherence to epithelial cells through cell surface proteoglycans. Recently, two other eukaryotic cell receptors for Opa proteins have been reported. These receptors are members of a subgroup of the carcinoembryonic (CEA) gene family that express CD66 antigens. CEA family members vary in their distribution in human tissues. In order to understand whether interactions between Opa and CEA-like molecules play any role in pathogenesis, we must investigate which CEA family members are able to serve as Opa receptors and which Opa proteins recognize CEA-like molecules. We therefore studied HeLa cells that were stably transfected with five different members of the CEA family, i.e., CEA, CEA gene family member 1a (CGM1a), CGM6, nonspecific cross-reacting antigen (NCA), and biliary glycoprotein a (BGPa). We infected these transfectants with all possible 11 Opa variants of gonococcal strain MS11 and determined the numbers of bacteria that were bound and internalized. To account for proteoglycan-mediated adherence, infection assays were also performed in the presence of heparin. Our results show that of the 11 Opa variants of MS11, the same 4 recognized CGM1a and NCA. CGM6, however, was not recognized by any Opa variant of MS11. CEA was recognized by at least 9 of 11 Opa variants, and the BGP transfectants specifically bound and internalized 10 of 11 Opa variants and also bound Opa-negative gonococci. Immunofluorescence experiments showed that clustering of CEA-like molecules occurred upon infection of HeLa transfectants with those Opa variants that interacted specifically with the CEA family member. Together these data show that CEA family members are differentially recognized by gonococcal Opa variants, suggesting that this phenomenon may contribute to cell tropism displayed by gonococci.


Weighted least-squares phase unwrapping algorithm based on a non-interfering image of an object.
Conventional quality maps for weighted least-squares phase unwrapping are not appropriate in regions of abnormal fringes. In this paper, the use of a non-interfering image of an object for a reliability map is proposed for robust phase unwrapping. First, the conventional weighted least-squares algorithm is applied, and the unreliable region is detected. Then, the unreliable region is unwrapped iteratively using the non-interfering image of the object. Finally, both phase maps are combined and smoothed by a continuity operation. Experimental results show that the proposed algorithm is appropriate for unwrapping phase maps of abnormal fringes.


Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment.
Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.


Nuclear and mitochondrial DNA analysis of a 2,000-year-old necropolis in the Egyin Gol Valley of Mongolia.
DNA was extracted from the skeletal remains of 62 specimens excavated from the Egyin Gol necropolis, in northern Mongolia. This burial site is linked to the Xiongnu period and was used from the 3rd century b.c. to the 2nd century a.d. Three types of genetic markers were used to determine the genetic relationships between individuals buried in the Egyin Gol necropolis. Results from analyses of autosomal and Y chromosome short tandem repeats, as well as mitochondrial DNA, showed close relationships between several specimens and provided additional background information on the social organization within the necropolis as well as the funeral practices of the Xiongnu people. To the best of our knowledge, this is the first study using biparental, paternal, and maternal genetic systems to reconstruct partial genealogies in a protohistoric necropolis.


Extremely 54Cr- and 50Ti-rich presolar oxide grains in a primitive meteorite: Formation in rare types of supernovae and implications for the astrophysical context of solar system birth.
We report the identification of 19 presolar oxide grains from the Orgueil CI meteorite with substantial enrichments in 54Cr, with 54Cr/52Cr ratios ranging from 1.2 to 56 times the solar value. The most enriched grains also exhibit enrichments at mass 50, most likely due in part to 50Ti, but close-to-normal or depleted 53Cr/52Cr ratios. There is a strong inverse relationship between 54Cr enrichment and grain size; the most extreme grains are all <80 nm in diameter. Comparison of the isotopic data with predictions of nucleosynthesis calculations indicate that these grains most likely originated in either rare, high-density Type Ia supernovae (SNIa), or in electron-capture supernovae (ECSN) which may occur as the end stage of evolution for stars of mass 8-10 M ⊙. This is the first evidence for preserved presolar grains from either type of supernova. An ECSN origin is attractive since these likely occur much more frequently than high-density SNIa, and their evolutionary timescales (~20 Myr) are comparable to those of molecular clouds. Self-pollution of the Sun's parent cloud from an ECSN may explain the heterogeneous distribution of n-rich isotopic anomalies in planetary materials, including a recently reported dichotomy in Mo isotopes in the solar system. The stellar origins of three grains with solar 54Cr/52Cr, but anomalies in 50Cr or 53Cr, as well as of a grain enriched in 57Fe, are unclear.


Cardiovascular outcome studies in type 2 diabetes: Comparison between SGLT2 inhibitors and GLP-1 receptor agonists.
Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are two pharmacological classes that have proven their efficacy to reduce major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease in large prospective cardiovascular outcome trials (CVOTs): EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), LEADER (liraglutide) and SUSTAIN 6 (semaglutide). Some heterogeneity appears to exist between the various agents within the two pharmacological classes. Whether these positive results could be extrapolated to patients without cardiovascular disease is still unknown. The underlying mechanisms remain a matter of debate but appear to differ between SGLT2is and GLP-1RAs. One crucial question is which patient's characteristics should be taken into account to guide the choice between a SGLT2i or a GLP-1RA according to a personalized approach. Heart failure should encourage the use of a SGLT2i whereas moderate to severe chronic kidney disease should favour the prescription of a GLP-1RA. Despite the results of recent CVOTs, numerous patients who are good candidates for benefiting of these agents do not receive them in clinical practice. Currently, there is a paradigm shift in T2DM management, moving from a primary objective of glucose control to a cardiovascular and renal protection.


Welfare reform and older immigrants' health insurance coverage.
I examined changes in older immigrants' health insurance coverage after welfare reform in the United States to determine whether the reform measures achieved their goal of saving money by reducing Medicaid participation without increasing the number of uninsured people. Data were obtained from older adults who participated in the Current Population Survey's Annual Social and Economic Supplement from 1994 to 1996 and 2001 to 2005. I used logistic regression to estimate changes in the sample's Medicaid and health insurance coverage after welfare reform, paying special attention to noncitizens and recent immigrants. Older immigrants' health insurance status was associated with their citizenship status and length of stay in the United States. Medicaid participation significantly decreased among noncitizens and recent immigrants but increased among naturalized citizens. Private health insurance and employer-sponsored insurance coverage significantly increased among recent immigrants but decreased among established immigrants and naturalized citizens. The probability of being uninsured did not significantly change among any group of immigrants. Given increases in postreform Medicaid participation among some immigrant groups, my findings suggest that the long-term cost-saving effectiveness of the current restrictive Medicaid eligibility policy is doubtful.


Physiological mechanisms contributing to the QTL-combination effects on improved performance of IR64 rice NILs under drought.
Characterizing the physiological mechanisms behind major-effect drought-yield quantitative trait loci (QTLs) can provide an understanding of the function of the QTLs-as well as plant responses to drought in general. In this study, we characterized rice (Oryza sativa L.) genotypes with QTLs derived from drought-tolerant traditional variety AdaySel that were introgressed into drought-susceptible high-yielding variety IR64, one of the most popular megavarieties in South Asian rainfed lowland systems. Of the different combinations of the four QTLs evaluated, genotypes with two QTLs (qDTY 2.2 + qDTY 4.1 ) showed the greatest degree of improvement under drought compared with IR64 in terms of yield, canopy temperature, and normalized difference vegetation index (NDVI). Furthermore, qDTY 2.2 and qDTY 4.1 showed a potential for complementarity in that they were each most effective under different severities of drought stress. Multiple drought-response mechanisms were observed to be conferred in the genotypes with the two-QTL combination: higher root hydraulic conductivity and in some cases greater root growth at depth. As evidenced by multiple leaf water status and plant growth indicators, these traits affected transpiration but not transpiration efficiency or harvest index. The results from this study highlight the complex interactions among major-effect drought-yield QTLs and the drought-response traits they confer, and the need to evaluate the optimal combinations of QTLs that complement each other when present in a common genetic background.


Somatosensory feedback modulates the respiratory motor program of crystallized birdsong.
Birdsong, like human speech, involves rapid, repetitive, or episodic motor patterns requiring precise coordination between respiratory, vocal organ, and vocal tract muscles. The song units or syllables of most adult songbirds exhibit a high degree of acoustic stereotypy that persists for days or months after the elimination of auditory feedback by deafening. Adult song is assumed to depend on central motor programs operating independently from immediate sensory feedback. Nothing is known, however, about the possible role of mechanoreceptive or other somatosensory feedback in the motor control of birdsong. Even in the case of human speech, the question of "how and when sensory information is used in normal speaking conditions...remains unanswered" and controversial [Smith, A. (1992) Crit. Rev. Oral Biol. Med. 3, 233-267]. We report here evidence for somatosensory modulation of ongoing song motor patterns. These patterns include the respiratory muscles that, in both birdsong and speech, provide the power for vocalization. Perturbing respiratory pressure by a brief, irregularly timed injection of air into the cranial thoracic air sac during song elicited a compensatory reduction in the electrical activity of the abdominal expiratory muscles, both in hearing and deafened adult northern cardinals (Cardinalis cardinalis). This muscle response was absent or reduced during quiet respiration, suggesting it is specifically linked to phonation. Our findings indicate that somatosensory feedback to expiratory muscles elicits compensatory adjustments that help stabilize, in real time, the subsyringeal pressure against fluctuations caused by changes in posture or physical activity.


[Gas radionuclide myelography in assessing patency of the subarachnoid space of the spinal cord].
CSF dynamic tests and gas radionuclide myelography were conducted in 184 patients with arachnoiditis, arachnomyelitis, and tumors of the spinal cord and spine. From the findings of myelography, differentiated degrees of retention of the gas radiopharmaceutical (RP) in obstruction of the CSF channels of the spinal cord were distinguished. The relationship between the distinguished degrees of retention of the gas RP and the degrees of CSF dynamics disorder was determined and each method was correlated with the exact diagnosis of the diseases. It was found that to gain a fuller idea of the patency of the CSF channels, the findings of gas radionuclide myelography must be compared with the results of tests for CSF dynamics.


H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis.
Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-κB and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C-C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment.


Characterization of Dysregulated lncRNA-Associated ceRNA Network Reveals Novel lncRNAs With ceRNA Activity as Epigenetic Diagnostic Biomarkers for Osteoporosis Risk.
The altered expression of long non-coding RNAs (lncRNAs) has been implicated in the development and human diseases. However, functional roles and regulatory mechanisms of lncRNA as competing endogenous RNAs (ceRNAs) in osteoporosis and their potential clinical implication for osteoporosis risk are largely unexplored. In this study, we performed integrated analysis for paired expression profiles and regulatory relationships of dysregulated lncRNAs, mRNAs, and miRNAs based on "ceRNA hypothesis," and constructed an osteoporosis-related dysregulated miRNA-mediated lncRNA-mRNA ceRNA network (DysCeNet) composed of 105 nodes (including eight miRNAs, 24 mRNAs, and 73 lncRNAs) and 515 edges. Functional analysis suggested that the DysCeNet was involved in known osteoporosis or bone metabolism-related biological processes and pathways. Then, we performed random forest-based feature selection for 73 lncRNAs with ceRNA activity and identified 25 of 73 lncRNAs as potential diagnostic biomarkers. A random forest-based classifier composed of 25 lncRNA biomarkers (RF-25lncRNA) was developed for predicting osteoporosis risk. Performance evaluation with the leave-one-out cross-validation (LOOCV) procedure showed that the RF-25lncRNA achieved a good performance in distinguishing high- and low-bone mineral density (BMD) subjects in different osteoporosis datasets. Our study for the first time revealed a global view of lncRNA-associated ceRNA regulation in osteoporosis and provided novel lncRNAs with ceRNA activity as candidate epigenetic diagnostic biomarkers for early detection of osteoporosis risk.


Efficacy of pefloxacin in the treatment of postoperative sepsis in gynaecology.
Twenty four women with postoperative sepsis following gynaecological surgery were recruited into a study designed to determine the efficacy of Pefloxacin. With the standard oral dose of Pefloxacin, clinical cure or improvement occurred in 98% of the patients. In-vitro, 90% of bacterial isolates were sensitive to Pefloxacin. No adverse effect was encountered in any of the patients. We concluded that Pefloxacin is effective in the treatment of postoperative bacterial infections following gynaecological surgery.


Sparse decompositions for exploratory pattern analysis.
We define and verify the utility of a pattern analysis procedure called sparse decomposition. This technique involves sequentially ``peeling'' sparse subsets of patterns from a pattern set, where sparse subsets are sets of patterns which possess a certain degree of regularity or compactness as measured by a compactness measure c. If this is repeated until all patterns are deleted, then the sequence of decomposition ``layers'' derived by this procedure provides a wealth of information from which inferences about the original pattern set may be made. A statistic P is derived from this information and is shown to be powerful in detecting clustering tendency for data in reasonably compact sampling windows. The test is applied to both synthetic and real data.


Role of smooth muscle alpha 1-receptors in nonspecific bronchial responsiveness in asthma.
It has been postulated that the wide range of bronchial hyperresponsiveness to nonspecific stimuli, such as methacholine, found in asthmatics could be due to increased alpha-adrenergic receptor activity in the airways. We examined alpha 1- receptor responsiveness by comparing the responses obtained after inhaling the alpha 1-agonist phenylephrine (2 to 32 mg/ml) with the responses obtained after inhaling buffered saline in 10 asthmatics in whom the provocation concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (FEV1) ranged from 0.13 to 9.19 mg/ml. Subjects were pretreated with inhaled atropine (3 mg nebulized during tidal breathing) and inhaled propranolol (3 mg nebulized during tidal breathing) to exclude cholinergic and beta receptor activity influencing bronchial smooth muscle responsiveness. After pretreatment drugs, the mean value for FEV1 before phenylephrine inhalations did not differ significantly from that before the control inhalations of saline. There was no significant change in FEV1 after phenylephrine compared with that after saline, suggesting that bronchial smooth muscle alpha 1-adrenergic receptor activity was not present. We conclude that increased bronchial smooth muscle alpha 1-receptor activity is not the primary abnormality producing the variability between asthmatics in nonspecific bronchial hyperresponsiveness.


[Effect of nucleoside triphosphates on cyclic nucleotide phosphodiesterase: role of protein modulators].
The effects of nucleoside triphosphates (ATP and GTP) on phosphodiesterase (PDE) of brain and outer segments of the retina enriched or devoid of protein modulators were studied. In the case of retinal outer segment PDE the enzyme activity was considerably inhibited by both nucleosides only when the enzyme was separated from the inhibitor. In case of brain PDE, on the contrary, the effect of the nucleosides was much more pronounced in the enzyme preparation coupled with the protein activator, calmodulin. The latter when added to brain PDE devoid of the activator in the presence of ATP and GTP considerably reduced the enzyme activity. An addition of the inhibitor simultaneously with GTP to the purified PDE of outer segments increased the PDE activity. The constants for the inhibition of brain PDE coupled with calmodulin and retinal outer segment PDE separated from the inhibitor by ATP and GTP were determined.


Can meristematic activity determine variation in leaf size and elongation rate among four Poa species? A kinematic study.
We studied inherent variation in final leaf size among four Poa spp. that live at different elevations. The average final length of leaf 7 of the main stem of the smallest species (Poa alpina) was only one-half that of the largest species (Poa trivialis); it was correlated with leaf elongation rate, but not with the duration of leaf elongation. A faster rate of leaf elongation rate was associated with (a) larger size of the zone of cell expansion, and (b) faster rates of cell production (per cell file) in the meristem, which in turn were due to greater numbers of dividing cells, whereas average cell division rates were very similar for all species (except Poa annua). Also we found that the proliferative fraction equaled 1 throughout the meristem in all species. It was remarkable that rates of cell expansion tended to be somewhat higher in the species with slower growing leaves. We discuss the results by comparing the spatial and material viewpoints, which lead to different interpretations of the role of cell division. Although the presented data do not strictly prove it, they strongly suggest a regulatory role for cell division in determining differences in growth rate among the present four Poa spp.


Heme oxygenase-1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow.
Recruiting polymorphonuclear neutrophil granulocytes (PMNs) from circulation and bone marrow to the site of inflammation is one of the pivotal mechanisms of the innate immune system. During inflammation, the enzyme heme oxygenase 1 (HO-1) has been shown to reduce PMN migration. Although these effects have been described in various models, underlying mechanisms remain elusive. Recent studies revealed an influence of HO-1 on different cells of the bone marrow. We investigated the particular role of the bone marrow in terms of HO-1-dependent pulmonary inflammation. In a murine model of LPS inhalation, stimulation of HO-1 by cobalt (III) protoporphyrin-IX-chloride (CoPP) resulted in reduced segmented PMN migration into the alveolar space. In the CoPP group, segmented PMNs were also decreased intravascularly, and concordantly, mature and immature PMN populations were higher in the bone marrow. Inhibition of the enzyme by tin protoporphyrin-IX increased segmented and banded PMN migration into the bronchoalveolar lavage fluid with enhanced PMN release from the bone marrow and aggravated parameters of tissue inflammation. Oxidative burst activity was significantly higher in immature compared with mature PMNs. The chemokine stromal-derived factor-1 (SDF-1), which mediates homing of leukocytes into the bone marrow and is decreased in inflammation, was increased by CoPP. When SDF-1 was blocked by the specific antagonist AMD3100, HO-1 activation was no longer effective in curbing PMN trafficking to the inflamed lungs. In conclusion, we show evidence that the anti-inflammatory effects of HO-1 are largely mediated by inhibiting the release of segmented PMNs from the bone marrow rather than direct effects within the lung.


Children with autism respond differently to spontaneous, elicited and deferred imitation.
Imitation, a key vehicle for both cognitive and social development, is often regarded as more difficult for children with autism spectrum disorders (ASD) than for children with Down syndrome (DS) or typically developing (TD) children. The current study investigates similarities and differences in observed elicited, spontaneous and deferred imitation using both actions with objects and gestures as imitation tasks in these groups. Imitation among 19 children with autism was compared with 20 children with DS and 23 TD children matched for mental and language age. Elicited imitation resulted in significantly lower scores for the ASD group compared with the other two groups, an effect mainly carried by a low level of gesture imitation among ASD children. We observed no differences among the groups for spontaneous imitation. However, children with ASD or DS displayed less deferred imitation than the TD group. Proneness to imitate also differed among groups: only 10 (53%) of the children with autism responded in the elicited imitation condition compared with all children with DS and almost all TD children (87%). These findings add to our understanding of the kind of imitation difficulties children with ASD might have. They also point to the necessity of not equating various imitation measures because these may capture different processes and be differently motivating for children with autism.


Filicidal ring-Y chromosomes in D. melanogaster.
Ring-Y chromosomes are recovered infrequently from crosses of ring-Y-bearing males to females of certain strains (OSTER 1964). Experiments described here have unveiled a diverse class of genes that exert a maternal effect on the behavior during cleavage of these "filicidal" ring chromosomes. Cytological observations of inviable embryos have revealed that the ring-Y chromosome causes gross disorganization of the cleavage nuclei. This inviability may be equivalent to the "dominant lethality" attributed to unstable ring-X chromosomes (HINTON 1955; PASZTOR 1971). Mapping studies indicate that no single region of the normal Y is solely responsible for the unusual behavior of ring-Y chromosomes.


Tumor control probability reduction in gated radiotherapy of non-small cell lung cancers: a feasibility study.
We studied the feasibility of evaluating tumor control probability (TCP) reductions for tumor motion beyond planned gated radiotherapy margins. Tumor motion was determined from cone-beam CT projections acquired for patient setup, intrafraction respiratory traces, and 4D CTs for five non-small cell lung cancer (NSCLC) patients treated with gated radiotherapy. Tumors were subdivided into 1 mm sections whose positions and doses were determined for each beam-on time point. (The dose calculation model was verified with motion phantom measurements.) The calculated dose distributions were used to generate the treatment TCPs for each patient. The plan TCPs were calculated from the treatment planning dose distributions. The treatment TCPs were compared to the plan TCPs for various models and parameters. Calculated doses matched phantom measurements within 0.3% for up to 3 cm of motion. TCP reductions for excess motion greater than 5mm ranged from 1.7% to 11.9%, depending on model parameters, and were as high as 48.6% for model parameters that simulated an individual patient. Repeating the worst case motion for all fractions increased TCP reductions by a factor of 2 to 3, while hypofractionation decreased these reductions by as much as a factor of 3. Treatment motion exceeding gating margins by more than 5 mm can lead to considerable TCP reductions. Appropriate margins for excess motion are recommended, unless applying daily tumor motion verification and adjusting thegating window.


Sound production in female Trichopsis schalleri (Labyrinth fishes): comparison to males and evolutionary considerations.
Croaking gouramis (genus Trichopsis, Anabantoidei) generate series of two-pulsed bursts (croaks) during agonistic interactions. Sex-specific differences are minor in T. vittata which raises the question whether sexes differ in the other two species. The current study analyses sounds recorded in female T. schalleri, compares the sound characteristics to those of males investigated earlier and correlates these characteristics to female body size. Sex-specific differences were found in three out of six sound characteristics. In females, sounds were lower in burst number, burst period and SPL. Pulse period, dominant frequency and peak-to-peak amplitude ratios of pulses did not differ between sexes. Burst period and SPL increased significantly with female body weight, whereas dominant frequency decreased. The present acoustic data indicate the sex-specific differences are more pronounced in T. schalleri than T. vittata. The results also demonstrate that both sexes are vocal, which remains to be shown for females of the third species, T. pumila, which have poorly developed sonic organs. The evolution of the pectoral sound-producing mechanism in Trichopsis is most likely based on an exaptation process during which acoustic signals are generated by fin tendons initially related to other functions as is evident in closely related genera lacking this organ.


Impact of Fiber Structure on the Material Stability and Rupture Mechanisms of Coronary Atherosclerotic Plaques.
The rupture of an atherosclerotic plaque in the coronary circulation remains the main cause of heart attack. As a fiber-oriented structure, the fiber structure, in particular in the fibrous cap (FC), may affect both loading and material strength in the plaque. However, the role of fiber orientation and dispersion in plaque rupture is unclear. Local orientation and dispersion of fibers were calculated for the shoulder regions, mid FC, and regions with intimal thickening (IT) from histological images of 16 human coronary atherosclerotic lesions. Finite element analysis was performed to assess the effect of these properties on mechanical conditions. Fibers in shoulder regions had markedly reduced alignment (Median [interquartile range] 12.9° [6.6, 18.0], p < 0.05) compared with those in mid FC (6.1° [5.5, 9.0]) and IT regions (6.7° [5.1, 8.6]). Fiber dispersion was highest in shoulders (0.150 [0.121, 0.192]), intermediate in IT (0.119 [0.103, 0.144]), and lowest in mid FC regions (0.093 [0.081, 0.105], p < 0.05). When anisotropic properties were considered, stresses were significantly higher for the mid FC (p = 0.030) and IT regions (p = 0.002) and no difference was found for the shoulder or global regions. Shear (sliding) stress between fibers in each region and their proportion of maximum principal stress were: shoulder (25.8 kPa [17.1, 41.2], 12.4%), mid FC (13.9 kPa [5.8, 29.6], 13.8%), and IT (36.5 kPa [25.9, 47.3], 15.5%). Fiber structure within the FC has a marked effect on principal stresses, resulting in considerable shear stress between fibers. Fiber structure including orientation and dispersion may determine mechanical strength and thus rupture of atherosclerotic plaques.


Complex Glycerol Kinase Deficiency and Adrenocortical Insufficiency in Two Neonates.
Contiguous gene deletions of chromosome Xp21 can lead to glycerol kinase deficiency and severe adrenocortical insufficiency (AI) in a male newborn among other problems. We describe our experience with two such patients who presented with dysmorphic facies, AI, and pseudo-hypertriglyceridemia. Both infants had normal serum 17-hidroxyprogesterone levels, and adrenal glands could not be observed with ultrasonography. Creatine kinase and triglyceride levels were measured to elucidate the etiology of adrenal hypoplasia and were above normal limits in both cases. Both patients required steroid and salt supplementation. They were both found to have Xp21.2 deletions (DMD, NR0B1, GK, IL1RAPL1). We conclude that AI in the context of other genetic abnormalities should prompt chromosomal investigations in the absence of another unifying explanation.


Adaptation to the most abundant host genotype in an agricultural plant-pathogen system--potato late blight.
This study investigated local adaptation of Phytophthora infestans populations, the causal agent of potato late blight, to two susceptible potato cultivars, each grown for a number of years and over large areas in separate French regions. We measured aggressiveness (quantitative pathogenicity) of each pathogen population to sympatric and allopatric hosts in a reciprocal cross-inoculation experiment. There was no evidence for specific host adaptation in this pathosystem. At both local and regional scales, the distribution of aggressiveness fits a pattern of adaptation to the most common host genotype. Our observations support the theoretical predictions that large pathogen dispersal rates and genetic drift, revealed by the comparisons of the genotypic structures of the populations tested, can lead to a local adaptation pattern detectable only at a large spatial scale. The unravelling of adaptive patterns at different spatial scales can be used for a more efficient management of the disease.


Hepatitis B antigen and polymyositis.
Concomitant polymyositis diagnosed by muscle biopsy developed in a 51-year-old man with hepatitis B surface antigen (HBsAg) hepatitis. Findings from immunofluorescent studies showed deposits of gamma-globulins and complement in both muscle and liver. The HBsAg and HBsAg-antibody complexes were detected in the liver by immunofluorescence using fluorescein-labeled antibody to hepatitis Bs.


Renal fibrosis in cyclosporin A-treated renal allograft recipients: morphological findings in relation to renal hemodynamics.
Nineteen nondiabetic kidney graft patients treated with cyclosporin A for 2 years underwent percutaneous renal allograft biopsy as well as renal hemodynamic examination. Renal allograft fibrosis was quantitatively evaluated as the relative volume of the renal cortical interstitium (VV %) and as the interstitium/tubuli ratio (I/T ratio). The histological changes were then classified into four groups, depending on the degree of interstitial fibrosis. The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and fractional clearance of sodium, potassium, phosphate, chloride, osmoles, and free water clearance were determined in all patients and in 13 healthy controls. Kidney graft recipients had significantly lower GFR, lower RPF, and lower RBF than the healthy controls (P < 0.001 for all comparisons) while FF was similar in patients and controls. Transplant recipients had a significantly higher fractional excretion of sodium, potassium, chloride, and phosphate than controls. All except one patient had clearly increased VV values, indicating increased interstitial fibrosis. The mean VV in renal allograft patients was 35% +/- 10% (normal < 16% +/- 5%) and the I/T ratio was 1.07 +/- 0.60 (normal < 0.24 +/- 0.08). No correlation was found between the quantitative or semiquantitative biopsy analysis and any renal hemodynamic parameter measured. We conclude that renal function is significantly decreased in kidney graft recipients, but that adaptive tubular changes occur in the graft. Interstitial renal fibrosis was common but did not correlate to any renal functional parameter.