Free radical facilitated damage of ungual keratin.
Thioglycolic acid (TA) and urea hydrogen peroxide (urea H(2)O(2)) are thought to disrupt alpha-keratin disulfide links in the nail. However, optimal clinical use of these agents to improve the treatment of nail disorders is currently hindered by a lack of fundamental data to support their mechanism of action. The aim of this study was to investigate how the redox environment of ungual keratin, when manipulated by TA and urea H(2)O(2), influenced the properties of the nail barrier. Potentiometric and voltammetric measurements demonstrated that urea H(2)O(2) obeyed the Nernst equation for a proton coupled one-electron transfer redox process while TA underwent a series of redox reactions that was complicated by electrode adsorption and dimer formation. The functional studies demonstrated that nail permeability, measured through TBF penetration (38.51+/-10.94 microg/cm(2)/h) and nail swelling (244.10+/-14.99% weight increase), was greatest when relatively low concentrations of the thiolate ion were present in the applied solution. Limiting the thiolate ion to low levels in the solution retards thiolate dimerisation and generates thiyl free radicals. It appeared that this free radical generation was fundamental in facilitating the redox-mediated keratin disruption of the ungual membrane.


Carrier transport in high mobility InAs nanowire junctionless transistors.
The ability to understand and model the performance limits of nanowire transistors is the key to the design of next generation devices. Here, we report studies on high-mobility junctionless gate-all-around nanowire field effect transistor with carrier mobility reaching 2000 cm(2)/V·s at room temperature. Temperature-dependent transport measurements reveal activated transport at low temperatures due to surface donors, while at room temperature the transport shows a diffusive behavior. From the conductivity data, the extracted value of sound velocity in InAs nanowires is found to be an order less than the bulk. This low sound velocity is attributed to the extended crystal defects that ubiquitously appear in these nanowires. Analyzing the temperature-dependent mobility data, we identify the key scattering mechanisms limiting the carrier transport in these nanowires. Finally, using these scattering models, we perform drift-diffusion based transport simulations of a nanowire field-effect transistor and compare the device performances with experimental measurements. Our device modeling provides insight into performance limits of InAs nanowire transistors and can be used as a predictive methodology for nanowire-based integrated circuits.


Human Merkel cell polyomavirus: virological background and clinical implications.
The Merkel cell polyomavirus (MCPyV), identified in humans in 2008, is associated with a relatively rare but aggressive neuroendocrine skin cancer, the Merkel cell carcinoma (MCC). MCC incidence is increasing due to the advancing age of the population, the increase in damaging sun exposure and in the number of immunocompromised individuals. MCPyV must be considered as the etiological agent of MCC and thus is the first example of a human oncogenic polyomavirus. MCPyV infection is common, and seroprevalence studies indicate that widespread exposure begins early in life. The majority of adults have anti-MCPyV antibodies and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV suggesting that MCPyV infection persists throughout life. However, the mode of transmission, the host cells, and the latency characteristics of this virus remain to be elucidated. In addition, it is still not clear whether MCPyV is associated with diseases or lesions other than Merkel cell carcinoma. The etiologic role of MCPyV in MCC opens up opportunities to improve the understanding of this cancer and to potentially improve its treatment.


Methods in molecular cardiology: DNA sequencing.
Sequencing is one the major breakthroughs in molecular cardiology. The development of this technique has made it possible to determine the exact order of the nucleotides in DNA. The exact order is relevant for the formation of proteins, through the genetic code. Sequencing is even more important for the identification of genetic variation and disease-causing mutations. The elucidation of the human genome is based on the continuous improvement of this technique, reducing the cost and increasing efficiency. Initially, complex chemical reactions were performed using isotopes to unravel the base sequence in genes. Nowadays, fluorescent capillary-based techniques are available to determine the genetic information. Here, the historical development of the technique is described. In addition, examples are provided on how sequencing is used in clinical medicine.


Recent changes in attack and survival rates of acute myocardial infarction (1975 through 1981). The Worcester Heart Attack Study.
A communitywide study was conducted in all 16 acute general hospitals in the metropolitan Worcester, Mass, area during the calendar years 1975, 1978, and 1981 to examine time trends in the attack and case-fatality rates of patients hospitalized with validated acute myocardial infarction as well as of the occurrence of out-of-hospital coronary heart disease (CHD) deaths. Between 1975 and 1981, there was an increase in the age-adjusted attack rates of initial events of acute myocardial infarction (1975, 254/100,000; 1981, 280/100,000) as well as recurrent events (1975, 133/100,000; 1981, 156/100,000). These overall increases were due to an increase among those 65 years of age and older, with no significant changes observed in those less than 65 years old. The age-adjusted in-hospital case-fatality rates declined from 22.1% in 1975 to 20.3% in 1978 and 17.4% in 1981. In examining long-term prognosis, no significant differences were seen over an eight-year follow-up period between patients discharged in 1975, 1978, and 1981. The age-adjusted mortality rates of out-of-hospital CHD deaths significantly declined between 1975 (229/100,000) and 1981 (147/100,000). The results of this population-based survey suggest that recently observed declines in the mortality rates of CHD may reflect decreases in out-of-hospital coronary deaths and improving trends in the in-hospital survival of patients with acute myocardial infarction.


Diagnostic laparotomy for abdominal trauma. A university hospital experience.
Following the experience of World War II, exploratory laparotomy in all patients with penetrating abdominal trauma was deemed mandatory until 1960 when Shaftan reported his experience with selective laparotomy. In 1973, Nance et al. reported on selective observation of abdominal stab wounds. There seems to be little controversy over mandatory laparotomy for abdominal gunshot wounds. Blunt trauma is generally managed expectantly with the adjunctive use of peritoneal lavage, CT scanning, and serial examinations of the abdomen. Despite the selective approach and the use of adjunctive diagnostic methods, exploratory laparotomy continues to be the most accurate method used to diagnose the presence of intra-abdominal injury. In order to examine our experience with diagnostic laparotomy for trauma, both blunt and penetrating, a retrospective study of 494 consecutive patients undergoing exploratory laparotomy over the past 4 years was undertaken. Abdominal stab wounds were explored under local anesthesia, and, if found to penetrate the posterior fascia, laparotomy was accomplished. All patients with abdominal gunshot wounds underwent exploration. Exploratory laparotomy in patients with blunt abdominal trauma was mandated by clinical signs, positive peritoneal lavage, or positive CT scan. All patients with unexplained shock and/or signs of peritoneal irritation underwent urgent laparotomy. In this series of 494 patients, 99 or 20 per cent of the entire group had a negative exploration (30% for stab wounds, 16% for gunshot wounds, and 19% for blunt abdominal trauma). The morbidity for the negative laparotomy group was limited to five patients with postoperative atelectasis. There were no anesthesia complications, iatrogenic intraoperative injuries, or wound infections. There were five deaths but none were laparotomy-related.(ABSTRACT TRUNCATED AT 250 WORDS)


mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism.
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been shown to benefit myopathic changes following alcohol intake, although the precise mechanism is still unclear. This study was designed to evaluate the role of ALDH2 on chronic alcohol intake-induced myocardial geometric and functional damage with a focus on autophagic signalling. Wild-type friendly virus B (FVB) and transgenic mice overexpressing ALDH2 driven by chicken β-actin promoter were fed a 4% alcohol liquid diet for 12 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate the essential autophagy markers, Akt and AMP-dependent protein kinase (AMPK) as well as their downstream signalling mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3). Alcohol intake altered cardiac geometry and function as demonstrated by lessened LV wall and septal thickness, enlarged end systolic and diastolic diameters, decreased fractional shortening and cell shortening, the effects of which were mitigated by ALDH2 transgene. Chronic alcohol intake triggered myocardial autophagy as shown by LC3B II isoform switch, as well as decreased phosphorylation of mTOR, the effects of which were ablated by ALDH2. Chronic alcohol intake suppressed phosphorylation of Akt and AMPK, which was reconciled by ALDH2. Levels of Notch1 and STAT3 phosphorylation were dampened by chronic alcohol intake in FVB but not ALDH2 myocardium. Moreover, the γ-secretase Notch inhibitor N\xE2\x80\x90[N-(3,5-difluorophenacetyl)-1-alany1]-S-phenyglycine t-butyl ester exacerbated ethanol-induced cardiomyocyte contractile dysfunction, apoptosis and autophagy. In summary, these findings suggested that ALDH2 elicits cardioprotection against chronic alcohol intake-induced cardiac geometric and functional anomalies by inhibition of autophagy possibly via restoring the Akt-mTOR-STAT3-Notch signalling cascade.


A comparison study on creating simulated patient data for individuals suffering from chronic coronary disorders.
An emerging area in data science that has lately gained attention is the virtual population (VP) and synthetic data generation. This field has the potential to significantly affect the healthcare industry by providing a means to augment clinical research databases that have a shortage of subjects. The current study provides a comparative analysis of five distinct approaches for creating virtual data populations from real patient data. The data set utilized for the current analyses involved clinical data collected among patients scheduled for elective coronary artery bypass graft surgery (CABG). To that end, the five computational techniques employed to augment the given dataset were: (i) Tabular Preset, (ii) Gaussian Copula Model (iii) Generative Adversarial Network based (GAN) Deep Learning data synthesizer (CTGAN), (iv) a variation of the CTGAN Model (Copula GAN), and (v) VAE-based Deep Learning data synthesizer (TVAE). The performance of these techniques was assessed against their effectiveness in producing high-quality virtual data. For this purpose, dataset correlation matrices, cosine similarity distance, density histograms, and kernel density estimation are employed to perform a comparative analysis of each attribute and the respective synthetic equivalent. Our findings demonstrate that Gaussian Copula Model prevails in creating virtual data with consistent distributions (Kolmogorov-Smirnov (KS) and Chi-Squared (CS) tests equal to 0.9 and 0.98, respectively) and correlation patterns (average cosine similarity equals to 0.95).Clinical Relevance- It has been shown that the use of a VP can increase the predictive performance of a ML model, i.e., above using a smaller non-augmented population.


Methanol oxidation and assimilation in Hansenula polymorpha. An analysis by 13C n.m.r. in vivo.
The metabolism of methanol was monitored in whole cells of the methylotrophic yeast Hansenula polymorpha by using [13C]methanol and n.m.r. in vivo. The main products observed under normal conditions were trehalose and glycerol, whereas cells that were starved before exposure to [13C]methanol also accumulated glutamate, glutamine and alanine; formate was also more prominent in spectra from starved cells. Cells exposed to high methanol concentration together with high oxygenation oxidized methanol extensively, leading to formaldehyde accumulation; label was not found in any subsequent metabolic products, indicating possible cell inactivation. [13C]Formate was incorporated into metabolic products in glucose-grown cells exposed to 150 mM-methanol for 3 h, but not in cells starved for 3 h, in which it was oxidized. At 21 degrees C such 3 h-starved cells showed a slower metabolism of [13C]methanol compared with those at 37 degrees C, and also converted methanol into formate rather than into assimilation products. The labelling pattern in trehalose from starved cells at 37 degrees C was consistent with methanol assimilation via the pentose phosphate pathway. Lack of appearance of labelled formaldehyde and formate during metabolism under normal conditions suggests that the linear oxidation pathway is not a major contributor to methanol oxidation; their appearance in extreme conditions suggests instead a more likely role in detoxification.


Alcohol, stroke and coronary heart disease. Are there anti-oxidants and pro-oxidants in alcoholic beverages that might influence the development of atherosclerotic cardiovascular disease?
Anti-oxidant effects of polyphenolic flavonoid compounds found in alcoholic beverages, especially red wine, have been proposed to mediate, at least in part, protective effects of regular light-to-moderate alcohol use against stroke and coronary artery disease. The proposed mechanism is through the quenching of free radicals decreasing the oxidative modification of low-density lipoprotein cholesterol particles and hence reducing their atherogenicity. In this review, the extent and limitations of the evidence in support of such a hypothesis are outlined. In particular, the paucity of epidemiological evidence linking dietary flavonoids to stroke and coronary artery disease is highlighted. The competing notion that alcohol itself has direct and indirect pro-oxidant and pro-atherogenic effects is canvassed, and the limitations of the in vitro rather than in vivo nature of much of the evidence linking red wine polyphenolics to reduced lipid peroxidation and other relevant biological effects is discussed. Within this framework of current epidemiological evidence together with the results of basic laboratory studies, the conclusion at present is that while we may continue to speculate that there are anti-oxidants and pro-oxidants in alcoholic beverages that influence the development of atherosclerotic cardiovascular disease, this cannot yet be considered as an established scientific fact.


Effects of dietary fumonisin B1-containing culture material, deoxynivalenol-contaminated wheat, or their combination on growing barrows.
To examine the toxic effects of fumonisin B1 (FB1)-containing culture material and deoxynivalenol (DON)-contaminated wheat diets on barrows. 24, 7-week-old crossbred barrows allotted to 4 equal groups of 3 replicates of 2 barrows/replicate. Barrows were fed diets for 28 days that were formulated as follows: no additional FCM or DON/kg of feed (control); 100 mg FB1/kg of feed; 5 mg DON/kg of feed; or 100 mg FB1 plus 5 mg DON/kg of feed. Body weight and feed consumption were monitored weekly. On day 28, blood samples were obtained for serum biochemical, hematologic, and immunologic measurements. On day 29, barrows were euthanatized and necropsies were performed. Analyzed mycotoxin content of diets were: none detected (control); 47 mg of FB1/kg of feed (FB1 diet); 4.5 mg of DON/kg of feed (DON diet); and 56 mg of FB1 and 3.7 mg of DON/kg of feed (FB1 plus DON diet). Differences were detected among groups of barrows for clinical performance, serum biochemical analytes, immunologic response, and histopathologic lesions. Combining FB1-containing material and DON-contaminated wheat in the diets of growing barrows induces a more toxic response than that induced by either toxin singly. For many variables, the response could be described as additive; however, for some variables, responses were interactive in a greater-than-additive manner. Caution should be exercised when formulating swine diets that could contain FB1 and DON, because the condition induced by their combination is more severe than that predicted for each mycotoxin's toxicity.


Isothiocyanates in the chemoprevention of bladder cancer.
Development of effective preventive strategies for bladder cancer is of critical importance. Bladder cancer is among the most common human malignancies and typically recurs after treatment. Many plant-derived isothiocyanates (ITCs) have shown cancer-preventive activity in a variety of rodent organs. They are known to inhibit carcinogen-activating enzymes, and to induce carcinogen-detoxifying enzymes, apoptosis, cell cycle arrest, and differentiation of cancer cells. More importantly, orally ingested ITCs are efficiently absorbed, rapidly and almost exclusively excreted and concentrated in the urine as N-acetylcysteine conjugates (NAC-ITC). NAC-ITCs also possess anticarcinogenic activity, perhaps due largely to their facile dissociation to free ITCs. Storage of urine in the bladder makes the bladder epithelium, which lines the inner surface of the bladder and gives rise to the majority of bladder cancers, the most exposed tissue to ITCs/NAC-ITCs upon their ingestion. Storage of urine in the bladder also will increase the release of ITCs from NAC-ITCs. Consequently, the amount of ITCs needed orally to achieve cancer prevention in the bladder may be much lower than that required for other organs. As a result, potential systemic adverse effects of ITCs may be minimized when using ITCs for chemoprevention of bladder carcinogenesis. Taken together, ITCs may be especially useful for the prevention of bladder cancer.


Efficacy and safety of terazosin to improve voiding in spinal cord injury patients.
A total of 28 male spinal cord injury (SCI) patients were enrolled in an open label study to evaluate the efficacy and safety of terazosin to improve voiding. All patients were started on 1 mg daily dose at bedtime. The dosage was gradually increased to 1-2 mg twice daily, depending upon patient tolerance and a minimum acceptable systolic blood pressure of 90 mm Hg. Urodynamic evaluation was done in 24 patients prior to and one week after a maximum tolerated dose was established for at least 48 hours. The maximum dose varied from 1 to 5 mg daily. Subjective improvement in voiding was noticed in 50 percent of patients. Objective assessment with urodynamics showed a mean drop in maximum voiding pressure of 35 cm H2O (range 9-65 cm H2O) in only 42 percent of patients. Subjective improvement in voiding occurred in 14 of 17 patients with absent detrusor sphincter dyssynergia. The drug was discontinued in three patients with side effects of syncope in one patient, lethargy in another and body rash in the third. Because the tolerance dose of terazosin is variable and the therapeutic response is unpredictable, urodynamic monitoring is recommended to accomplish a useful outcome.


Characterization of HOXB13 expression patterns in localized and metastatic castration-resistant prostate cancer.
HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration-resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher-grade tumors, although no significant association between HOXB13 expression and recurrence or disease-specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor-negative castration-resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non-prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration-resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland.


Automated microchannel alignment using innate opto-signature for microchip electrophoresis.
In laser-induced fluorescence (LIF) detection, optimal alignment is essential in maximizing the fluorescent signal and, hence, detection sensitivity. Micro-total analysis systems (μTAS) involving microchip electrophoresis (ME) are challenged with alignment of the optics to the separation channel each run due to the single-use nature. Furthermore, μTAS devices that are designed to operate autonomously and by non-experts face additional challenges in performing alignment with micrometer resolution without human intervention. As part of the development of a total DNA analysis system, we set out to develop an automated alignment (AA) method to locate a 50-by-50 μm separation channel on a freely rotating microfluidic device in the absence of a fluorescent dye, accomplished without additional hardware. We detail the innate fluorescent signature attainable from laser excitation and the optimization of the algorithm to achieve AA at 84.6% success rate from 26 microchips. This AA method was a key element in realizing complete automation of the DNA analysis process in order to advance our instrument to a technology readiness level of 7. This is the first description of an AA method for ME (and centrifugal ME) with the purpose of providing transparent technical details to bridge the gap from 'fully integrated' to 'fully automated' instruments for point-of-detection, sample in-answer-out use cases. Written in the context of a forensic application, the AA method is adaptable for a wide range of bioanalytical applications involving LIF detection.


Risk of myocardial infarction in young female smokers.
To determine the extent of risk of myocardial infarction from cigarette smoking in young women, and to examine the relation of smoking with other putative risk factors. Community based case control study. England, Scotland, and Wales. Women (n = 448) between 16 and 44 years old with a diagnosis of incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n = 1728) were age and general practice matched women without a diagnosis of myocardial infarction. Odds ratios for risk of myocardial infarction associated with smoking and other risk factors. Odds ratios for myocardial infarction in smokers versus non-smokers showed a strong dose response, from 2.47 (95% confidence interval (CI) 1.12 to 5.45) in smokers of 1-5 cigarettes per day to 74.6 (95% CI 33.0 to 169) in smokers of >/= 40 cigarettes per day. There was no interaction of smoking with use of oral contraceptives, but there were additive risks with other clinical risk factors such as hypertension and diabetes. It is estimated that if all women aged 16-44 years were able to stop smoking, 400 cases of myocardial infarction per annum (of whom 112 would die) would be prevented. In young women the risk of myocardial infarction from smoking was considerable, and heavy smokers with other risk factors were especially at risk.


Systematic Review with Meta-Analysis: Diagnostic Accuracy of Pro-C3 for Hepatic Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.
The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77-0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73-0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD.


[Prescription, assay and interpretation of cardiac troponins tests: guidelines from SFBC-CNBC troponin working group].
Troponin (I or T) has become the gold-standard marker in acute coronary syndromes during the last few years, as confirmed by a national survey realized within french clinical chemists, cardiologists and emergency practitioners. The importance of this marker and the heterogeneousness of circulating forms of troponin after myocardial necrosis fully justify international studies about standardization of this assay, which is a central bulk to reach a global market coherence. Checking analytical problems, although necessary, must be absolutely associated with an informed clinical interpretation. The knowledge of the crucial thresholds of each assay, the kinetic curves and the specificity limits of troponin assays allow the best use of their potential in diagnosis and prognosis together with an optimal patient care in very different clinical settings, in addition to others clinical and technical arguments. The quality improvement through successive generations of assay kits must nowadays persuade the physicians never to ignore a significant and valid troponin increase, which mainly reveals a cardiac injury, whatever its origin.


Identification and nuclear localization of yeast pre-messenger RNA processing components: RNA2 and RNA3 proteins.
Temperature-sensitive mutations in the RNA2 through RNA11 genes of yeast prevent the processing of nuclear pre-mRNAs. We have raised antisera that detect the RNA2 and RNA3 proteins in immunoblots of extracts of yeast containing high copy number RNA2 and RNA3 plasmids. Subcellular fractionation of yeast cells that overproduce the RNA2 and RNA3 proteins has revealed that these proteins are enriched in nuclear fractions. Indirect immunofluorescence results have indicated that these proteins are localized in yeast nuclei. These localization results are consistent with the fact that these genes have a role in processing yeast pre-mRNA.


CO Cleavage and CO2 Functionalization under Mild Conditions by a Multimetallic CsU2 Nitride Complex.
Novel efficient chemical processes involving cheap and widely accessible carbon dioxide or carbon monoxide under mild conditions for the production of valuable chemical products are highly desirable in the current energetic context. Uranium nitride materials act as high activity catalysts in the Haber-Bosch process but the reactivity of molecular nitride compounds remains unexplored. Here we review recent results obtained in our group showing that a multimetallic nitride complex [Cs{[U(OSi(OtBu)3)3]2(μ-N)}] (1) with a CsUIV-N-UIV core, is able to promote N-C bond formation due to its strong nucleophile behaviour. In particular, complex 1, in the presence of excess CO2 leads to a remarkable dicarbamate product. The multimetallic CsUIV-N-UIV nitride also readily cleaves the C≡O bond under mild conditions.


PLGA microsphere/calcium phosphate cement composites for tissue engineering: in vitro release and degradation characteristics.
Bone cements with biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres have already been proven to provide a macroporous calcium phosphate cement (CPC) during in situ microsphere degradation. Furthermore, in vitro/in vivo release studies with these PLGA microsphere/CPC composites (PLGA/CPCs) showed a sustained release of osteo-inductive growth factor when drug was distributed inside/onto the microspheres. The goal of this study was to elucidate the mechanism behind drug release from PLGA/CPC. For this, in vitro release and degradation characteristics of a low-molecular-weight PLGA/CPC (M(w) = 5 kg/mol) were determined using bovine serum albumin (BSA) as a model protein. Two loading mechanisms were applied; BSA was either adsorbed onto the microspheres or incorporated inside the microspheres during double-emulsion. BSA release from PLGA microspheres and CPC was also measured and used as reference. Results show fast degrading polymer microspheres which produced a macroporous scaffold within 4 weeks, but also showed a concomitant release of acidic degradation products. BSA release from the PLGA/CPC was similar to the CPC samples and showed a pattern consisting of a small initial release, followed by a period of almost no sustained release. Separate PLGA microspheres exhibited a high burst release and release efficiency that was higher with the adsorbed samples. Combining degradation and release data we can conclude that for the PLGA/CPC samples BSA re-adsorbed to the cement surface after being released from the microspheres, which was mediated by the pH decrease during microsphere degradation.


[Mining Polo-Box domain of Polo-like kinase 1 as a new therapeutic target for cancer].
Polo-like kinase 1 (Plk1) is widely regarded as one of the most promising targets for cancer therapy due to its essential role in cell division and tumor cell survival. At present, most Plk1 inhibitors have been developed based on kinase domain, some of which are in clinical trial. However, inhibitors targeting kinase domain face off-target effect and drug resistance owing to the conserved nature and the frequent mutations in the ATP-binding pocket. In addition to a highly conserved kinase domain, Plk1 also contains a unique Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. Inhibitors targeting Plk1 PBD show stronger selectivity and less drug resistance for cancer therapy. Therefore, Plk1 PBD is an attractive target for the development of anti-cancer agents. In this review, we will summarize the up-to date drug discovery for targeting Plk1 PBD, including the molecular structure and cellular functions of Plk1 PBD. Small-molecule inhibitors targeting Plk1 PBD not only provide an opportunity to specifically inhibit Plk1 activity for cancer treatment, but also unveil novel biological basis regarding the molecular recognition of Plk1 and its substrates.


Identification of Genetic Interaction with Risk Factors Using a Time-To-Event Model.
Certain diseases can occur with and without a trigger. We use Venous Thromboembolism (VTE) as our example to identify genetic interaction with pregnancy in women with VTE during pre- or postpartum. Pregnancy is one of the major risk factors for VTE as it accounts for 10% of maternal deaths. We performed a whole genome association analysis using the Cox Proportional Hazard (CoxPH) model adjusted for covariates to identify genetic variants associated with the time-to-event of VTE related to pre- or postpartum during the childbearing age of 18-45 years using a case-only design in a cohort of women with VTE. Women with a VTE event after 45 years of age were censored and contributed only follow-up time. We identified two intragenic single nucleotide polymorphisms (SNPs) at genome-wide significance in the PURB gene located on chromosome 7, and two additional intragenic SNPs, one in the LINGO2 gene on chromosome 9 and one in RDXP2 on chromosome X. We showed that the time-to-event model is a useful approach for identifying potential hazard-modification of the genetic variants when the event of interest (VTE) occurs due to a risk factor (pre- or post-partum).


Chromosomes in Hodgkin's disease.
Chromosome studies in lymph nodes from patients with Hodgkin's disease have been limited by the low yield of dividing cells. Of 25 consecutive involved lymph nodes, 12 had no mitotic cells, three had only normal cells, seven had a mixture of normal and abnormal cells, and three had only abnormal cells. Correlating histology with the karyotype, 66% of unsuccessful samples were of the nodular sclerosing type. The majority (58%) of samples with no dividing cells were from previously treated patients. Distinct clones were obtained in samples from only four of ten patients with abnormal cells. Samples from the other six patients had single abnormal cells with bizarre marker chromosomes; these single cells probably represent the only dividing malignant cell. The high failure rate and the low number of clear-cut aneuploid clones in Hodgkin's disease contrast markedly with other lymphomas in which 80% of the samples yield mitotic cells that represent an aneuploid clone in virtually every instance.


The rheology of aqueous solutions of ethyl hydroxy-ethyl cellulose (EHEC) and its hydrophobically modified analogue (hmEHEC): extensional flow response in capillary break-up, jetting (ROJER) and in a cross-slot extensional rheometer.
Cellulose derivatives containing associating hydrophobic groups along their hydrophilic backbone are used as rheology modifiers in the formulation of water-based spray paints, medicinal sprays, cosmetics and printable inks. Jetting and spraying applications of these materials involve progressive thinning and break-up of a fluid column or sheet into drops. Strong extensional kinematics develop in the thinning fluid neck. In viscous Newtonian fluids, inertial and viscous stresses oppose the surface tension-driven instability. In aqueous solutions of polymers such as Ethyl Hydroxy-Ethyl Cellulose (EHEC), chain elongation provides additional elastic stresses that can delay the capillary-driven pinch-off, influencing the sprayability or jettability of the complex fluid. In this study, we quantify the transient response of thinning filaments of cellulose ether solutions to extensional flows in a Capillary Break-up Extensional Rheometer (CaBER) and in a forced jet undergoing break-up using Rayleigh Ohnesorge Jetting Extensional Rheometry (ROJER). We also characterize the steady state molecular deformations using measurements of the flow-induced birefringence and excess pressure drop in an extensional stagnation point flow using a Cross-Slot Extensional Rheometer (CSER). We show that under the high extension rates encountered in jetting and spraying, the semi-dilute solutions of hydrophobically modified ethyl hydroxy-ethyl cellulose (hmEHEC) exhibit extensional thinning, while the unmodified bare chains of EHEC display an increase in extensional viscosity, up to a plateau value. For both EHEC and hmEHEC dispersions, the low extensibility of the cellulose derivatives limits the Trouton ratio observed at the highest extension rates attained (close to 10(5) s(-1)) to around 10-20. The reduction in extensional viscosity with increasing extension rate for the hydrophobically modified cellulose ether is primarily caused by the disruption of a transient elastic network that is initially formed by intermolecular association of hydrophobic stickers. This extensional thinning behavior, in conjunction with the low extensibility of the hydrophobically modified cellulose ether additives, makes these rheology modifiers ideal for controlling the extensional rheology in formulations that require jetting or spraying, with minimal residual stringiness or stranding.


Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats.
The spontaneously hypertensive stroke-prone rat (SHRSP) is a potential animal model of human lacunar stroke, but there is little information on SHRSP small vessel pathology, especially in young rats. We investigated the structural changes that occur in cortical and subcortical vessels and adjacent tissue in SHRSP before, during and after the onset of hypertension. We examined brains from SHRSP and Wistar Kyoto rats (WKY) at 5, 16 and 21 weeks of age. Structural changes in small arterioles and adjacent tissue were studied using antibodies to investigate different components of the neurovascular unit. We quantified staining in three standard regions, at two coronal levels. Immunostaining for claudin-5, a marker of endothelial tight junctions, was reduced in SHRSP at all ages compared to age-matched WKY controls. Smooth muscle actin, glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 were increased in SHRSP vs. WKY by 16 weeks. Additionally, 21-week-old WKY and SHRSP rats fed a high-salt diet showed differences in claudin-5, glial fibrillary acidic protein and matrix metalloproteinase 9 staining compared to those fed a normal diet. Endothelial tight junction alterations of SHRSP rats from the earliest ages point towards increased susceptibility to blood-brain barrier dysfunction and stroke, which is exacerbated by salt loading. Salt loading may also damage the neurovascular unit in WKY controls.


Adenosine-induced bronchoconstriction: comparison between nedocromil sodium and sodium cromoglycate.
The purpose of this study was to compare the protective effect of nedocromil sodium with that of sodium cromoglycate against adenosine-induced bronchoconstriction in 15 asymptomatic asthmatic patients. Airways response was evaluated as FEV1 and adenosine was administered as an aerosol diluted in 0.9% saline to produce a concentration range of 0.03-4.00 mg/ml. When FEV1 was decreased by 20% of the post-saline value, inhalation was discontinued and the PD20 adenosine calculated. Patients were studied on four separate days. On the first day the adenosine challenge was performed and on subsequent days patients were pretreated with either placebo or test drug in a randomized double-blind manner. In this study both sodium cromoglycate and nedocromil sodium showed a significant protective effect against adenosine in comparison with placebo. Their activity was not related to a bronchodilator action. Nedocromil sodium showed a greater protective effect against adenosine challenge which may be indicative of a broader spectrum of activity against nonantigenic stimuli.


A checklist for trauma quality improvement meetings: A process improvement study.
Each year approximately five million people die from injuries. In countries where systems of trauma care have been introduced, death and disability have decreased. A major component of developed trauma systems is a trauma quality improvement (TQI) program and trauma quality improvement meeting (TQIM). Effective TQIMs improve trauma care by identifying and fixing problems. But globally, TQIMs are absent or unstructured in most hospitals providing trauma care. The aim of this study was to implement and evaluate a checklist for a structured TQIM. This project was conducted as a prospective before-and-after study in four major trauma centres in India. The intervention was the introduction of a structured TQIM using a checklist, introduced with a workshop. This workshop was based on the World Health Organization (WHO) TQI Programs short course and resources, plus the developed TQIM checklist. Pre- and post-intervention data collection occurred at all meetings in which cases of trauma death were discussed. The primary outcome was TQIM Checklist compliance, defined by the discussion of, and agreement upon each of the following: preventability of death, identification of opportunities to improve care and corrective actions and a plan for closing the loop. There were 34 meetings in each phase, with 99 cases brought to the pre-intervention phase and 125 cases brought to the post-intervention phase. There was an increase in the proportion of cases brought to the meeting for which preventability of death was discussed (from 94% to 100%, p = 0.007) and agreed (from 7 to 19%, OR 3.7; 95% CI:1.4-9.4, p = 0.004) and for which a plan for closing the loop was discussed (from 2% to 18%, OR 10.9; 95% CI:2.5-47.6, p < 0.001) and agreed (from 2% to 18%, OR 10.9; 95% CI:2.5-47.6, p < 0.001). This study developed, implemented and evaluated a TQIM Checklist for improving TQIM processes. The introduction of a TQIM Checklist, with training, into four Indian trauma centres, led to more structured TQIMs, including increased discussion and agreement on preventability of death and plans for loop closure. A TQIM Checklist should be considered for all centres managing trauma patients.


Plasma membrane Ca-ATPases: Targets of oxidative stress in brain aging and neurodegeneration.
The plasma membrane Ca(2+)-ATPase (PMCA) pumps play an important role in the maintenance of precise levels of intracellular Ca(2+) [Ca(2+)](i), essential to the functioning of neurons. In this article, we review evidence showing age-related changes of the PMCAs in synaptic plasma membranes (SPMs). PMCA activity and protein levels in SPMs diminish progressively with increasing age. The PMCAs are very sensitive to oxidative stress and undergo functional and structural changes when exposed to oxidants of physiological relevance. The major signatures of oxidative modification in the PMCAs are rapid inactivation, conformational changes, aggregation, internalization from the plasma membrane and proteolytic degradation. PMCA proteolysis appears to be mediated by both calpains and caspases. The predominance of one proteolytic pathway vs the other, the ensuing pattern of PMCA degradation and its consequence on pump activity depends largely on the type of insult, its intensity and duration. Experimental reduction of PMCA expression not only alters the dynamics of cellular Ca(2+) handling but also has a myriad of downstream consequences on various aspects of cell function, indicating a broad role of these pumps. Age- and oxidation-related down-regulation of the PMCAs may play an important role in compromised neuronal function in the aging brain and its several-fold increased susceptibility to neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and stroke. Therapeutic approaches that protect the PMCAs and stabilize [Ca(2+)](i) homeostasis may be capable of slowing and/or preventing neuronal degeneration. The PMCAs are therefore emerging as a new class of drug targets for therapeutic interventions in various chronic degenerative disorders.


Circadian rhythm of fever induced by interferon-alpha in mice.
The influence of dosing time on the fever induced by interferon-alpha (IFN-alpha) was investigated in ICR male mice under light-dark cycle. There was a significant circadian rhythm in rectal temperature, as an index of fever, at 1 hr after IFN-alpha (10 MIU/kg, i.v.) injection. The rhythmic pattern resembled overall the rhythm occurring in the nondrugged state. IFN-alpha increased rectal temperature during the light phase, but not during the dark phase. The fever induced by IFN-alpha was blocked by indomethacin (10 mg/kg, i.p.) pretreatment. There was no significant difference of plasma IFN-alpha concentrations at 0.167, 0.5 and 1 hr after IFN-alpha injection. Therefore the dosing time dependent difference of fever induced by IFN-alpha may be caused via that of PGE2 level elevated by IFN-alpha. The choice of the most appropriate time of day for drug administration may help to achieve rational chronotherapeutics of IFN-alpha.


Cost of illness in patients with multiple myeloma in Italy: the CoMiM study.
Multiple myeloma is the second most common hematological cancer. Although it accounts for only a relatively small percentage of all cancer types, the costs associated with managing multiple myeloma are considerable. Available studies are mainly focused on health care costs. The Costo del Mieloma Multiplo (Cost of MM, CoMiM) study investigated the cost of illness of multiple myeloma in Italy during one year of disease management. CoMiM is a retrospective, prevalence-based, multi-center, cross-sectional study based on a stratified sample of patients seen during normal clinical practice (asymptomatic; symptomatic on drugs; symptomatic receiving autologous stem cell transplantation; plateau/remission). Demographics, clinical history, health care and non-health care resource consumption data were collected. Costs were evaluated from the societal viewpoint and expressed in Euro 2008. Data on 236 patients were analyzed (39 asymptomatic, 17%; 29 symptomatic receiving autologous stem-cell transplantation, 12%; 105 symptomatic receiving drugs, 44%; 63 plateau/remission, 27%). The total cost of illness reached € 19,267.1 ± 25,078.6 (asymptomatic, € 959.3 ± 1091.6; symptomatic receiving drugs, € 21,707.8 ± 21,785.3; symptomatic receiving autologous stem-cell transplantation, € 59,243.7 ± 24,214.0; plateau/remission, € 8130.7 ± 15,092.5). The main cost drivers of total cost of illness were drugs and hospital admissions (46.1% and 29.4%, respectively). Antineoplastics and immunomodulators drove the cost of drugs (21.6% and 21.1% of the total cost of illness). Cost of antineoplastics was led by bortezomib (97.4%), whereas the cost driver for immunomodulators was lenalidomide (99.4%). Cost of hospitalization funded by the Italian National Health Service was strongly influenced by transplantation (94.6%), whereas chemotherapy and skeletal fractures did not exceed 1% and 2%, respectively. Despite some limitations, the CoMiM study provides Italian health care decision-makers with an insight into the stratified cost of illness of multiple myeloma patients.


Transepidermal water loss does not correlate with skin barrier function in vitro.
The purpose of this study was to investigate the relationship between transepidermal water loss and skin permeability to tritiated water (3H2O) and the lipophilic penetrant sulfur mustard in vitro. No correlation was found between basal transepidermal water loss rates and the permeability of human epidermal membranes to 3H2O (p = 0.72) or sulfur mustard (p = 0.74). Similarly, there was no correlation between transepidermal water loss rates and the 3H2O permeability of full-thickness pig skin (p = 0.68). There was no correlation between transepidermal water loss rate and 3H2O permeability following up to 15 tape strips (p = 0.64) or up to four needle-stick punctures (p = 0.13). These data indicate that transepidermal water loss cannot be unconditionally ascribed to be a measure of skin barrier function. It is clear that further work should be conducted to interpret the significance of measuring transepidermal water loss by evaporimetry.


Calcium channels resistant to organic calcium entry blockers in a rabbit vein.
We compared the effects of calcium entry blockers on myogenic tone with the effects of these compounds on agonist- and depolarization-induced mechanical responses in isolated rings of the rabbit facial vein. The development of intrinsic tone in response to distension of the vessel wall and its potentiation by increasing the ambient temperature were antagonized by MnCl2 (0.5 mM) but not verapamil, diltiazem, or nifedipine. Similarly, the contractile response to histamine was blocked by MnCl2 but was unaffected by moderate concentrations of the organic calcium entry blockers. The histamine contractile response elicited at 34 degrees C (a condition which abolishes intrinsic tone) was also refractory to verapamil (10(-6) M). Verapamil, diltiazem, and nifedipine antagonized the contractile response to calcium in depolarized facial vein rings. Thus both extrinsic and intrinsic contractile responses in the rabbit facial vein depend on an extracellular source of calcium. The distension-operated channels are unique in exhibiting a marked temperature sensitivity. However, receptor- and distension-operated calcium channels can be distinguished from the voltage-operated channels in their insensitivity to the organic calcium entry blockers.


Acinar cells in the neonatal pancreas grow by self-duplication and not by neogenesis from duct cells.
Pancreatic acinar cells secrete digestive enzymes necessary for nutrient digestion in the intestine. They are considered the initiating cell type of pancreatic cancer and are endowed with differentiation plasticity that has been harnessed to regenerate endocrine beta cells. However, there is still uncertainty about the mechanisms of acinar cell formation during the dynamic period of early postnatal development. To unravel cellular contributions in the exocrine acinar development we studied two reporter mouse strains to trace the fate of acinar and duct cells during the first 4 weeks of life. In the acinar reporter mice, the labelling index of acinar cells remained unchanged during the neonatal pancreas growth period, evidencing that acinar cells are formed by self-duplication. In line with this, duct cell tracing did not show significant increase in acinar cell labelling, excluding duct-to-acinar cell contribution during neonatal development. Immunohistochemical analysis confirms massive levels of acinar cell proliferation in this early period of life. Further, also increase in acinar cell size contributes to the growth of pancreatic mass.We conclude that the growth of acinar cells during physiological neonatal pancreas development is by self-duplication (and hypertrophy) rather than neogenesis from progenitor cells as was suggested before.


Long-term LPS systemic administration leads to memory impairment and disturbance in astrocytic homeostasis.
Dementia is the most prevalent neurodegenerative disorder, characterized by progressive loss of memory and cognitive function. Inflammation is a major aspect in the progression of brain disorders, and inflammatory events have been associated with accelerated deterioration of cognitive function. In the present work, we investigated the impact of low-grade repeated inflammation stimuli induced by lipopolysaccharide (LPS) in hippocampal function and spatial memory. Adult male Wistar rats received a weekly injection of LPS (500 ug/kg) for sixteen weeks, eliciting systemic inflammation. Animals submitted to LPS presented impaired spatial memory and neuroinflammation. While neuronal synaptic markers such as synaptophysin and PSD-95 were unaltered, critical aspects of astrocyte homeostatic functions, such as glutamate uptake and glutathione content, were reduced. Also, glucose uptake and astrocyte lactate transporters were altered, suggesting a disturbance in the astrocyte-neuron coupling. Our present work demonstrates that long-term repeated systemic inflammation can lead to memory impairment and hippocampal metabolic disorders, especially regarding astrocyte function.


Fourth-grade students' motivational changes in an elementary physical education running program.
Achievement goal theory and the expectancy-value model of achievement choice were used to examine fourth-grade students' motivational changes in an elementary physical education running program. In fall and spring of the school year, participants (N = 113; 66 boys, 47 girls) completed questionnaires assessing achievement goals, expectancy beliefs, subjective task values, and intention for future running participation. They also completed a timed 1-mile (1.6 km) run. The number of laps they ran/walked during the school year was used to assess students' persistence/effort. Results indicated the students improved their run but became less motivated about running while participating in a year-long running program. Children's beliefs about how good they were in the running program (i.e., expectancy beliefs) and their perceptions of how interesting and fun it was (i.e., interest) emerged as the strongest positive predictors of their motivation for running over time. These findings provide strong empirical evidence that expectancy beliefs and interest are essential to children's motivation in elementary physical education.


T cell-dependent hapten-specific and polyclonal B cell responses require release of interleukin 5.
CD4+ T cells in the mouse have recently been subdivided into two major subpopulations which differ in their functional activities and in the lymphokines they produce. Although cloned T cells lines representative of both sets will activate B cells in polyclonal responses, only the subset producing interleukin 4 (IL-4) will activate antigen-specific B cells in linked recognition assays. This suggested that IL-4 was essential for such responses. In the present experiments, the requirements were compared for B cell activation in specific as opposed to polyclonal antibody responses by T cell clones of the helper (IL-4 producing) subset. It was found that specific responses involve primarily small B cells, whereas polyclonal responses activate exclusively the large B cells. Second, polyclonal B cell responses can proceed in the absence of T:B contact, whereas specific responses require physical interaction of the two cells. Third, it was found that interleukin 5 (IL-5, formerly known as T cell replacing factor/B cell growth factor II) is essential for these polyclonal responses by inhibition of such responses with monoclonal anti-IL-5 antibody. Anti-IL-5 also inhibits specific antibody responses involving direct T:B interaction. Thus, IL-5 is clearly a critical mediator of differentiation to immunoglobulin secretion of activated B cells, whether such B cells are obtained as large B cells from freshly isolated spleen cells or are initially activated in an IL-4-dependent fashion by cognate interaction by a helper T cell clone.


S-Nitrosation destabilizes glutathione transferase P1-1.
Protein S-nitrosation is a post-translational modification that regulates the function of more than 500 human proteins. Despite its apparent physiological significance, S-nitrosation is poorly understood at a molecular level. Here, we investigated the effect of S-nitrosation on the activity, structure, stability, and dynamics of human glutathione transferase P1-1 (GSTP1-1), an important detoxification enzyme ubiquitous in aerobes. S-Nitrosation at Cys47 and Cys101 reduces the activity of the enzyme by 94%. Circular dichroism spectroscopy, acrylamide quenching, and amide hydrogen-deuterium exchange mass spectrometry experiments indicate that the loss of activity is caused by the introduction of local disorder at the active site of GSTP1-1. Furthermore, the modification destabilizes domain 1 of GSTP1-1 against denaturation, smoothing the unfolding energy landscape of the protein and introducing a refolding defect. In contrast, S-nitrosation at Cys101 alone introduces a refolding defect in domain 1 but compensates by stabilizing the domain kinetically. These data elucidate the physical basis for the regulation of GSTP1-1 by S-nitrosation and provide general insight into the consequences of S-nitrosation on protein stability and dynamics.


Top-down enhancement and suppression of activity in category-selective extrastriate cortex from an act of reflective attention.
Recent research has demonstrated top-down attentional modulation of activity in extrastriate category-selective visual areas while stimuli are in view (perceptual attention) and after they are removed from view (reflective attention). Perceptual attention is capable of both enhancing and suppressing activity in category-selective areas relative to a passive viewing baseline. In this study, we demonstrate that a brief, simple act of reflective attention ("refreshing") is also capable of both enhancing and suppressing activity in some scene-selective areas (the parahippocampal place area [PPA]) but not others (refreshing resulted in enhancement but not in suppression in the middle occipital gyrus [MOG]). This suggests that different category-selective extrastriate areas preferring the same class of stimuli may contribute differentially to reflective processing of one's internal representations of such stimuli.


Systemic treatment with ubiquitin carboxy terminal hydrolase L1 TAT protein ameliorates axonal injury and reduces functional deficits after traumatic brain injury in mice.
Traumatic brain injury (TBI) is often associated with axonal injury that leads to significant motor and cognitive deficits. Ubiquitin carboxy terminal hydrolase L1 (UCHL1) is highly expressed in neurons and loss of its activity plays an important role in the pathogenesis of TBI. Fusion protein was constructed containing wild type (WT) UCHL1 and the HIV trans-activator of transcription capsid protein transduction domain (TAT-UCHL1) that facilitates transport of the protein into neurons after systemic administration. Additional mutant proteins bearing cysteine to alanine UCHL1 mutations at cysteine 152 (C152A TAT-UCHL1) that prevents nitric oxide and reactive lipid binding of C152, and at cysteine 220 (C220A TAT-UCHL1) that inhibits farnesylation of the C220 site were also constructed. WT, C152A, and C220A TAT-UCHL1 proteins administered to mice systemically after controlled cortical impact (CCI) were detectable in brain at 1 h, 4 h and 24 h after CCI by immunoblot. Mice treated with C152A or WT TAT-UCHL1 decreased axonal injury detected by NF200 immunohistochemistry 24 h after CCI, but C220A TAT-UCHL1 treatment had no significant effect. Further study indicated that WT TAT-UCHL1 treatment administered 24 h after CCI alleviated axonal injury as detected by SMI32 immunoreactivity 7 d after CCI, improved motor and cognitive deficits, reduced accumulation of total and K48-linked poly-Ub proteins, and attenuated the increase of the autophagy marker Beclin-1. These results suggest that UCHL1 activity contributes to the pathogenesis of white matter injury, and that restoration of UCHL1 activity by systemic treatment with WT TAT-UCHL1 after CCI may improve motor and cognitive deficits. These results also suggest that farnesylation of the C220 site may be required for the protective effects of UCHL1.


HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1.
Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development.


Physico-chemical analysis of a Herbo-mineral compound Mehamudgara vati - A pilot study.
Efforts have been made to lay down analytical standards for Mehamudgara vati (MMV), which were not found reported till date. Weight variation showed that 90% tablets of MV manufactured in the Gujarat Ayurved University Pharmacy were within acceptable range (323 mg ± 10%), pH 4.58, and disintegration time 17 min, whereas hardness was 1.25 kg/cm(2). Loss on drying was found to be 9.3% w/w, acid insoluble ash was 0.9 %w/w, water soluble extract was 24.06% w/w and methanol soluble extract 14.1% w/w. Determination of iron as Fe(2)O(3) was done as Lauha bhasma being the major ingredient of MMV. The result showed that iron content was reduced in the formulation (28.67%) as compared to that in Lauha bhasma (61.19%). In TLC, 5 spots each at 254 nm and 366 nm were found.


Stable RNA/DNA hybrids in the mammalian genome: inducible intermediates in immunoglobulin class switch recombination.
Although it is well established that mammalian class switch recombination is responsible for altering the class of immunoglobulins, the mechanistic details of the process have remained unclear. Here, we show that stable RNA/DNA hybrids form at class switch sequences in the mouse genome upon cytokine-specific stimulation of class switch in primary splenic B cells. The RNA hybridized to the switch DNA is transcribed in the physiological orientation. Mice that constitutively express an Escherichia coli ribonuclease H transgene show a marked reduction in RNA/DNA hybrid formation, an impaired ability to generate serum immunoglobulin G antibodies, and significant inhibition of class switch recombination in their splenic B cells. These data provide evidence that stable RNA/DNA hybrids exist in the mammalian nuclear genome, can serve as intermediates for physiologic processes, and are mechanistically important for efficient class switching in vivo.


Systems view on spatial planning and perception based on invariants in agent-environment dynamics.
Modeling agile and versatile spatial behavior remains a challenging task, due to the intricate coupling of planning, control, and perceptual processes. Previous results have shown that humans plan and organize their guidance behavior by exploiting patterns in the interactions between agent or organism and the environment. These patterns, described under the concept of Interaction Patterns (IPs), capture invariants arising from equivalences and symmetries in the interaction with the environment, as well as effects arising from intrinsic properties of human control and guidance processes, such as perceptual guidance mechanisms. The paper takes a systems' perspective, considering the IP as a unit of organization, and builds on its properties to present a hierarchical model that delineates the planning, control, and perceptual processes and their integration. The model's planning process is further elaborated by showing that the IP can be abstracted, using spatial time-to-go functions. The perceptual processes are elaborated from the hierarchical model. The paper provides experimental support for the model's ability to predict the spatial organization of behavior and the perceptual processes.


Detection of bovine milk proteins in soymilk by Western blotting.
A Western blotting method for the detection of whey milk proteins in commercial soymilks was applied to assess the food safety. Soy proteins and milk proteins were separated by SDS-PAGE in PhastSystem equipment. After the electrophoretic separation, immunodetection with anti-bovine alpha-lactalbumin and anti-bovine beta-lactoglobulin antisera was performed. Adulteration with bovine protein in percentages of 0.1% in soy protein can be detected. Western blotting of bovine alpha-lactalbumin and bovine beta-lactoglobulin was applied to detect adulteration by bovine milk proteins in different soymilks: powdered soymilk and soy infant formulas.


Coordinated response of phospholipids and acyl components of membrane lipids in Pseudomonas putida A (ATCC 12633) under stress caused by cationic surfactants.
The present study assessed the role of membrane components of Pseudomonas putida A (ATCC 12633) under chemical stress conditions originated by treatment with tetradecyltrimethylammonium bromide (TTAB), a cationic surfactant. We examined changes in fatty acid composition and in the fluidity of the membranes of cells exposed to TTAB at a specific point of growth as well as of cells growing with TTAB. The addition of 10-50 mg TTAB l(-1) promoted an increase in the saturated/unsaturated fatty acid ratio. By using fluorescence polarization techniques, we found that TTAB exerted a fluidizing effect on P. putida A (ATCC 12633) membranes. However, a complete reversal of induced membrane fluidification was detected after 15 min of incubation with TTAB. Consistently, the proportion of unsaturated fatty acids was lower in TTAB-treated cells as compared with non-treated cells. In the presence of TTAB, the content of phosphatidylglycerol increased (120 %), whilst that of cardiolipin decreased (60 %). Analysis of the fatty acid composition of P. putida A (ATCC 12633) showed that phosphatidylglycerol carried the major proportion of saturated fatty acids (89 %), whilst cardiolipin carried an elevated proportion of unsaturated fatty acids (18 %). The increase in phosphatidylglycerol and consequently in saturated fatty acids, together with a decrease in cardiolipin content, enabled greater membrane resistance, reversing the fluidizing effect of TTAB. Therefore, results obtained in the present study point to changes in the fatty acid profile as an adaptive response of P. putida A (ATCC 12633) cells to stress caused by a cationic surfactant.


Steroidogenic Factor 1 Regulates Transcription of the Inhibin B Coreceptor in Pituitary Gonadotrope Cells.
The inhibins control reproduction by suppressing follicle-stimulating hormone synthesis in pituitary gonadotrope cells. The newly discovered inhibin B coreceptor, TGFBR3L, is selectively and highly expressed in gonadotropes in both mice and humans. Here, we describe our initial characterization of mechanisms controlling cell-specific Tgfbr3l/TGFBR3L transcription. We identified two steroidogenic factor 1 (SF-1 or NR5A1) cis-elements in the proximal Tgfbr3l promoter in mice. SF-1 induction of murine Tgfbr3l promoter-reporter activity was inhibited by mutations in one or both sites in heterologous cells. In homologous cells, mutation of these cis-elements or depletion of endogenous SF-1 similarly decreased reporter activity. We observed nearly identical results when using a human TGFBR3L promoter-reporter. The Tgfbr3l gene was tightly compacted and Tgfbr3l mRNA expression was essentially absent in gonadotropes of SF-1 (Nr5a1) conditional knockout mice. During murine embryonic development, Tgfbr3l precedes Nr5a1 expression, though the two transcripts are fully colocalized by embryonic day 18.5 and thereafter. Collectively, these data indicate that SF-1 directly regulates Tgfbr3l/TGFBR3L transcription and is required for postnatal expression of the gene in gonadotropes.


A quality assurance phantom for electronic portal imaging devices.
Electronic portal imaging device (EPID) plays an important role in radiation therapy portal imaging, geometric and dosimetric verification. Consistent image quality and stable radiation response is necessary for proper utilization that requires routine quality assurance (QA). A commercial 'EPID QC' phantom weighing 3.8 kg with a dimension of 25 × 25 × 4.8 cm³ is used for EPID QA. This device has five essential tools to measure the geometric accuracy, signal-to-noise ratio (SNR), dose linearity, and the low- and the high-contrast resolutions. It is aligned with beam divergence to measure the imaging and geometric parameters in both X and Y directions, and can be used as a baseline check for routine QA. The low-contrast tool consists of a series of holes with various diameters and depths in an aluminum slab, very similar to the Las Vegas phantom. The high-resolution contrast tool provides the modulation transfer function (MTF) in both the x- and y-dimensions to measure the focal spot of linear accelerator that is important for imaging and small field dosimetry. The device is tested in different institutions with various amorphous silicon imagers including Elekta, Siemens and Varian units. Images of the QA phantom were acquired at 95.2 cm source-skin-distance (SSD) in the range 1-15MU for a 26 × 26 cm² field and phantom surface is set normal to the beam direction when gantry is at 0° and 90°. The epidSoft is a software program provided with the EPID QA phantom for analysis of the data. The preliminary results using the phantom on the tested EPID showed very good low-contrast resolution and high resolution, and an MTF (0.5) in the range of 0.3-0.4 lp/mm. All imagers also exhibit satisfactory geometric accuracy, dose linearity and SNR, and are independent of MU and spatial orientations. The epidSoft maintains an image analysis record and provides a graph of the temporal variations in imaging parameters. In conclusion, this device is simple to use and provides testing on basic and advanced imaging parameters for daily QA on any imager used in clinical practices.


Model molecules mimicking asphaltenes.
Asphalthenes are typically defined as the fraction of petroleum insoluble in n-alkanes (typically heptane, but also hexane or pentane) but soluble in toluene. This fraction causes problems of emulsion formation and deposition/precipitation during crude oil production, processing and transport. From the definition it follows that asphaltenes are not a homogeneous fraction but is composed of molecules polydisperse in molecular weight, structure and functionalities. Their complexity makes the understanding of their properties difficult. Proper model molecules with well-defined structures which can resemble the properties of real asphaltenes can help to improve this understanding. Over the last ten years different research groups have proposed different asphaltene model molecules and studied them to determine how well they can mimic the properties of asphaltenes and determine the mechanisms behind the properties of asphaltenes. This article reviews the properties of the different classes of model compounds proposed and present their properties by comparison with fractionated asphaltenes. After presenting the interest of developing model asphaltenes, the composition and properties of asphaltenes are presented, followed by the presentation of approaches and accomplishments of different schools working on asphaltene model compounds. The presentation of bulk and interfacial properties of perylene-based model asphaltene compounds developed by Sjöblom et al. is the subject of the next part. Finally the emulsion-stabilization properties of fractionated asphaltenes and model asphaltene compounds is presented and discussed.


Association of Age and Pediatric Household Transmission of SARS-CoV-2 Infection.
As a result of low numbers of pediatric cases early in the COVID-19 pandemic, pediatric household transmission of SARS-CoV-2 remains an understudied topic. To determine whether there are differences in the odds of household transmission by younger children compared with older children. This population-based cohort study took place between June 1 and December 31, 2020, in Ontario, Canada. Private households in which the index case individual of laboratory-confirmed SARS-CoV-2 infection was younger than 18 years were included. Individuals were excluded if they resided in apartments missing suite information, in households with multiple index cases, or in households where the age of the index case individual was missing. Age group of pediatric index cases categorized as 0 to 3, 4 to 8, 9 to 13, and 14 to 17 years. Household transmission, defined as households where at least 1 secondary case occurred 1 to 14 days after the pediatric index case. A total of 6280 households had pediatric index cases, and 1717 households (27.3%) experienced secondary transmission. The mean (SD) age of pediatric index case individuals was 10.7 (5.1) years and 2863 (45.6%) were female individuals. Children aged 0 to 3 years had the highest odds of transmitting SARS-CoV-2 to household contacts compared with children aged 14 to 17 years (odds ratio, 1.43; 95% CI, 1.17-1.75). This association was similarly observed in sensitivity analyses defining secondary cases as 2 to 14 days or 4 to 14 days after the index case and stratified analyses by presence of symptoms, association with a school/childcare outbreak, or school/childcare reopening. Children aged 4 to 8 years and 9 to 13 years also had increased odds of transmission (aged 4-8 years: odds ratio, 1.40; 95% CI, 1.18-1.67; aged 9-13 years: odds ratio, 1.13; 95% CI, 0.97-1.32). This study suggests that younger children may be more likely to transmit SARS-CoV-2 infection compared with older children, and the highest odds of transmission was observed for children aged 0 to 3 years. Differential infectivity of pediatric age groups has implications for infection prevention within households, as well as schools/childcare, to minimize risk of household secondary transmission. Additional population-based studies are required to establish the risk of transmission by younger pediatric index cases.


Selective functional characteristics of rate-induced fatigue in rabbit atrioventricular node.
The slowly developing rate-induced prolongation in atrioventricular nodal conduction time, termed "fatigue," was selectively studied using specifically designed stimulation protocols in isolated rabbit heart preparations. A nodal recovery curve (A2H2 versus H1A2 intervals; nodal conduction time of each premature beat plotted against corresponding recovery time) was obtained before and after a stable and nearly maximum fatigue had been reached by driving the atrium for 5 minutes at a fast rate close to the upper limit of 1:1 nodal conduction. The fatigue uniformly prolonged all A2H2 intervals (12.3 +/- 1.3 msec) and systematically increased the minimum H1A2 interval at which complete nodal block occurred (24.8 +/- 4.0 msec) (p less than 0.01, n = 6). To study the rate and time dependence of fatigue, nodal conduction times were obtained during three rapid 5-minute pacings corresponding to 50%, 75%, and 100% shortening of the pacing interval in the 1:1 nodal conduction range. The respective maximum fatigue-induced increases in conduction time were 5.4 +/- 1.8, 9.0 +/- 2.7, and 12.5 +/- 2.1 msec (p less than 0.01, n = 6). However, the pacing interval had no significant effect on the time required to reach either 50% (17.1 +/- 3.5 seconds) or 90% (92.6 +/- 15.4 seconds) of the fatigue observed after 5 minutes of fast rate. At the termination of any rapid stimulation, the fatigue effect dissipated with a time course that was inverse but symmetrical to that of its induction. These findings support the existence of an independent, slow, nodal memory process by which the conduction time changes according to past events with a long time constant.


Pupil in clinical diagnosis. Light reflex anatomy and the afferent pupil defect.
The neuroanatomy for the light reflex has been reviewed. The importance of the semidecussation of visual pathways in the afferent portion of the system has been emphasized. The anatomy of the near synkinesis and its relation to the anatomy of the light reflex have been reviewed. The various abnormalities of sensory pupil function have been outlined. Particular stress has been placed on the value of the afferent pupil defect in the diagnosis of sensory lesions affecting the eye because of retinal or optic nerve disease. In addition, the value of the consensual pupil in the diagnosis of afferent defects has received special comment.


[Cytomegalovirus nephrotic syndrome].
The case of a 5 months old infant with a nephrotic syndrome after neonatal cytomegalovirus infection is reported. Genomic amplification nested-PCR for CMV was positive in renal biopsy. Treatment with gancyclovir was effective to maintain nephrotic syndrome remission. We stresses the importance to discharge an infections cause of the nephrotic syndrome of newborns and infants due to the possibility on curative treatment.


The mutational spectrum of HRAS, KRAS, NRAS and FGFR3 genes in bladder cancer.
Bladder cancer is one of the most common cancers worldwide. A number of genetic and epigenetic alterations have been identified in bladder tumorigenesis, including activating mutations in fibroblast growth factor receptor 3 (FGFR3) and RAS family genes. In this study, we have analysed the mutational spectrum of FGFR3 and RAS genes (HRAS, NRAS and KRAS). We have also studied the relationship between mutations. A total of 234 patients with different stages and grades were included in the present study (58 superficial low-grade, 53 superficial high-grade and 123 muscle-invasive tumours). Mutations in exons 1 and 2 of HRAS, KRAS and NRAS genes were screened by PCR and direct sequencing. The hot spot mutations in exons 7, 10 and 15 of the FGFR3 oncogene were studied by multiplex PCR and the SNaP-shot protocol. Overall, 8.97% (21/234) of samples were mutant for one of the RAS genes. Among these mutations 47.61% were detected in KRAS, 33.33% in HRAS and only 19.04% most frequent RAS mutations were KRAS p.G12C and p.G12D. The correlation between RAS mutations and tumour subgroups does not report a statistical significant association (p=0.876). The FGFR3 mutations were detected in 31.19% (73/234) of bladder tumours and were associated with low stages and grades. The study of relationship between RAS and FGFR3 genes revealed that FGFR3 mutations were mutually exclusive with RAS ones (p=10(-4)). In conclusion we retain that activated RAS and FGFR3 do not appear to be drivers in bladder cancer but the mutually exclusive relationship between RAS and FGFR3 mutations indicates a possible clonal advantage of modified signaling via a common pathway.


The comparison of clinicopathological characteristics in primary malignant mixed műllerian tumour with epithelial endometrial carcinoma.
We performed an age-matched case-control study to compare the clinical and pathology outcomes between histologically diagnosed primary malignant mixed műllerian tumour (MMMT) of the uterus and endometrial carcinoma. Thirty-two women were treated for primary MMMT at seven tertiary medical centres in Korea from 2000 to 2006. For each woman with MMMT, four women with endometrioid and two with non-endometrioid endometrial carcinoma were selected as age-matched controls for analysis. Medical records were retrospectively reviewed to obtain outcome data. The incidence of MMMT was 2.57% (32/1244). In comparison with women with endometrioid endometrial cancer, those with MMMT were characterised by large tumour size, higher incidence of adnexal involvement and lymph node metastases, leading to advanced disease stage. Despite the frequent use of adjuvant treatment, the 5-year survival rate of women with MMMT was significantly poorer than those with endometrioid endometrial cancer. However, women with MMMT were not significantly different from those with non-endometrioid endometrial cancer in terms of important pathologic variables, apart from larger tumour size. In addition, the 5-year survival rate of women MMMT was poorer than that those with non-endometrioid endometrial cancer, but the difference was not statistically significant. Malignant mixed műllerian tumour is characterised by a high incidence of lymph node metastases and advanced stage at diagnosis, leading to poorer overall survival than other subtypes of endometrial carcinoma. Clinical trials for MMMT are critical for improving treatment strategies.


HIV-status disclosure and depression in the context of unintended pregnancy among South African women.
Depressive symptoms are common among pregnant women living with HIV, and an unintended pregnancy may heighten vulnerability. HIV-status disclosure is thought to improve psychological well-being, but few quantitative studies have explored the relationships among disclosure, pregnancy intention and depression. Using multivariable linear regression models, we examined the impact of disclosure on depressive symptoms (Edinburgh Postnatal Depression Scale; EPDS) during pregnancy and postpartum among women who tested HIV-positive during the pregnancy in South Africa; and explored the role of pregnancy intention in this relationship. Among 350 women (median age: 27 years; 70% reporting that their current pregnancy was unintended), neither disclosure to a male partner nor disclosure to ≥1 family/community member had a consistent effect on depressive symptoms. However, pregnancy intention modified the association between disclosure to a male partner and depression during pregnancy: disclosure was associated with higher depression scores among women who reported that their current pregnancy was unintended but was associated with lower depression scores among women who reported that their pregnancy was intended. During the early postpartum period, disclosure to ≥1 family/community member was associated with higher depression scores. Counselling around disclosure in pregnancy should consider the heightened vulnerability that women face when experiencing an unintended pregnancy.


Cangrelor for treatment during percutaneous coronary intervention.
Dual antiplatelet therapy consisting of aspirin and a P2Y12-receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention (PCI). The current P2Y12-receptor antagonists are only available for oral administration and exhibit a delayed onset of action. Furthermore, several days are required for platelet function to return to normal following cessation of therapy. Cangrelor is an intravenous ATP analog that directly, selectively and reversibly inhibits P2Y12 receptors on platelets. A 30-μg/kg bolus dose followed by a 4-μg/kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration. Cangrelor also demonstrates a fast offset as normal platelet function is restored 1-2 h after cessation of the infusion. Three large, double-blind, randomized trials - CHAMPION PLATFORM, CHAMPION PCI and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel (during or immediately after PCI) or placebo in the setting of PCI. In the most recent CHAMPION PHOENIX trial, cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding. Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset, cangrelor may provide benefit in certain patients undergoing PCI.


Early postoperative pain following Epi-LASIK and photorefractive keratectomy: a prospective, comparative, bilateral study.
To compare postoperative pain associated with epi-LASIK versus photorefractive keratectomy (PRK). This prospective observer-masked randomized study included 40 eyes of 20 patients with myopia and astigmatism who received epi-LASIK (Moria Epi-K) in one eye and PRK in the contralateral eye. Corneal ablation was done using the NIDEK EC-5000 excimer laser. Patients were seen at days 1, 3, and 6 to rate their pain via three measuring tools: 1) a global subjective rating, 2) a 10-cm visual analog scale, and 3) an 11-point numeric scale of pain. On postoperative day 1, 19 of 20 patients reported pain in both eyes. Using the global subjective rating scale, patients reported more pain for those eyes treated by PRK. Although clinically relevant, this difference was not statistically significant (P = .56). Based on the 11-point numeric scale of pain and visual analog scale, mean pain scores were similar for both groups. On day 3, using the global subjective rating scale, 11 of 12 patients who had pain reported more in the epi-LASIK treated eye (P = .0005). In addition, epi-LASIK eyes demonstrated higher mean pain scores based on the other two scales (visual analog scale, P = .045 and 11-point numeric scale of pain, P = .023). Only 6 patients reported minimal pain on day 6. It was more frequently reported and slightly more marked in epi-LASIK eyes, but did not reach statistical significance. Epi-LASIK and PRK have similar pain on postoperative day 1, but epi-LASIK demonstrated statistically more pain than PRK on days 3 and 6.


Project Wings, a coping intervention for Latina adolescents: a pilot study.
The authors examined the feasibility and preliminary outcomes of Project Wings Girls' Groups, a school-based mental health promotion program designed to improve well-being in Latina adolescents, as observed in outcomes, including perceived stress, depressive symptoms, coping, and connectedness. This pilot randomized controlled trial compared outcomes over 9 months postintervention for 42 9th and 10th grade adolescents attending two urban high schools. Girls were randomized to Project Wings Girls' Groups, a 16-session facilitated curriculum, including sharing circles, mind-body exercises, and coping skills building or the attention control (i.e., similar format but focused on general health topics). Feasibility of retention and long-term follow-up data collection was demonstrated, with lessons learned for future study. Although not statistically powered, this trial demonstrated findings in the expected direction, including reduced perceived stress and depression and increased connectedness. A trial with sufficient power is warranted to examine Project Wings' effects on mental health problems among Latina adolescents.


Infrared light scattering from surfaces covered with multiple dielectric overlayers.
Formulas are derived, using first-order perturbation theory, which predict light scattering from substrates coated with multiple dielectric overlayers. The scattering is assumed to result from surface irregularity. Numerical analysis is given for three types of dielectric stack configurations designed to typify experimental situations. The three configurations are substrate profile replicated at each dielectric interface, profile present at outermost dielectric layer only, and random roughness present at each interface. The formulas and configurations are used to model low efficiency rectangular groove gratings as beam sampling optical components and multilayer-overcoated metallic mirror substrates. Consideration is given to thermal expansion and fabrication error of thicknesses of the dielectric layers.


Elements of olfactory reception in adult Drosophila melanogaster.
The olfactory system of Drosophila has become an attractive and simple model to investigate olfaction because it follows the same organizational principles of vertebrates, and the results can be directly applied to other insects with economic and sanitary relevance. Here, we review the structural elements of the Drosophila olfactory reception organs at the level of the cells and molecules involved. This article is intended to reflect the structural basis underlying the functional variability of the detection of an olfactory universe composed of thousands of odors. At the genetic level, we further detail the genes and transcription factors (TF) that determine the structural variability. The fly's olfactory receptor organs are the third antennal segments and the maxillary palps, which are covered with sensory hairs called sensilla. These sensilla house the odorant receptor neurons (ORNs) that express one or few odorant receptors in a stereotyped pattern regulated by combinations of TF. Also, perireceptor events, such as odor molecules transport to their receptors, are carried out by odorant binding proteins. In addition, the rapid odorant inactivation to preclude saturation of the system occurs by biotransformation and detoxification enzymes. These additional events take place in the lymph that surrounds the ORNs. We include some data on ionotropic and metabotropic olfactory transduction, although this issue is still under debate in Drosophila.


[Current State of Corneal Pathology in Germany: Results of a Survey Conducted Among Members of the Cornea Section of the German Ophthalmological Society (DOG)].
The current situation of corneal pathology is widely unknown. Especially, there are no data available how corneal tissue is processed after penetrating keratoplasty. In November 2002 a questionnaire with 15 questions was sent to all registered members of the cornea section of the German Ophthalmological Society (DOG) ( www.sektionkornea.org ) via email. Only one answer per eye clinic was allowed. Answers were obtained from 40 eye hospitals in which 3070 penetrating keratoplasties had been performed in 2001. 90 % of the surgeons believe that ophthalmopathological investigations of excised corneal specimens are always or at least in some cases important, and 80 % examine 75 to 100 % of all corneal buttons. However, the corneoscleral rim is investigated only exceptionally. 45 % of all corneal buttons are examined by a pathologist within the hospital while 33 % of the corneal specimens are investigated by an ophthalmopathologist in an ophthalmopathological laboratory. In most cases the hospital itself has to bear the cost. Clinics with a high number of corneal transplantations do not differ from the average regarding the fate of corneal buttons. Morphological investigations and publications concerning the cornea are more frequent when an ophthalmopathological laboratory is available in the hospital. For most eye hospitals performing keratoplasties, the histopathological examination of excised corneal buttons is very important. It is carried out to a large extent by pathologists, but specialised ophthalmopathological laboratories are consulted when a profound expertise is needed. Thus, this survey is an argument for the preservation of these laboratories too. Based on the obtained data and on several comments by the section members initiatives to intensify histopathological investigations of excised corneal specimens should be undertaken.


[A case of solitary fibrous tumor from the greater omentum resected via laparoscopic surgery].
Solitary fibrous tumor (SFT) are relatively rare neoplasms that usually arise in the thoracic cavity in adults. Although many cases of extrathoracic SFT have been recently reported, SFT from the omentum is rare. A 32-year-old woman consulted a gynecologist complaining of irregular vaginal bleeding. Magnetic resonance imaging (MRI) revealed a tumor in the omentum, and the patient was admitted to our department. The patient underwent laparoscopic tumorectomy. The tumor size was 48 × 35 × 30 mm, and grayish-white nodules were observed. Histological examination showed hyperplastic spindle-shaped tumor cells with a pattern-less arrangement. Immunohistochemical staining showed the tumor was positive for CD34 and bcl-2, slightly positive for alpha smooth muscle actin(a-SMA), and negative for S-100 and c-kit. Accordingly, a diagnosis of SFT was made. The patient has not shown any recurrence 12 months after surgery. Most SFTs are benign, although there are some reports of recurring tumors. There are no clear guidelines for the treatment of SFT because of its rarity. Therefore, close long-term follow-up should be performed.


Cytochrome P450-derived renal HETEs: storage and release.
We have established an assay based on gas chromatography-mass spectrometry to profile and quantitate endogenous cytochrome P450 monooxygenase (P450)-hydroxyeicosatetraenoic acids (HETEs) exiting the isolated perfused rabbit kidney in response to hormonal stimulation. In response to angiotensin II (Ang II) P450-derived HETEs (16-, 17-, 18-, 19- and 20-) are released from the isolated Kreb's perfused rabbit kidney. Ang II produced a several-fold increase in the levels of P450-HETEs above basal levels in both urinary (such as for 20-HETE from 0.93 +/- 0.7 to 2.31 +/- 0.9 ng/min) and venous (from 0.1 +/- 0.05 to 0.3 +/- 0.05 ng/min) effluents. However, inhibition of P450, which reduced basal release, did not prevent Ang II-induced release of P450-AA products from the rabbit kidney; for example, urinary 20-HETE in the presence of 17-ODYA (1 microM) was undetectable and increased to 0.93 +/- 0.4 ng/min with Ang II and venous 20-HETE increased from 0.06 +/- 0.03 to 0.24 +/- 0.07 ng/min. Similar results were obtained with clotrimazole (1 microM). As 16-, 18-, 19- and 20-HETEs are vasodilators in the rabbit kidney and 16- and 17-HETEs inhibit proximal tubular ATPase activity, we investigated their possible sites of esterification. Cortical and medullary lipids were extracted, separated by HPLC and P450-HETEs quantitated following alkaline hydrolysis. The P450-HETEs were incorporated into both neutral lipids (NL) and phospholipids [phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS) and phosphatidylcholine (PC)]. However, the assignment of a HETE to a specific phospholipid pool must be regarded as tentative as the appropriate standards containing P450-HETEs in the Sn-2 position (such as 20-HETE-PF., 20-HETE-PC, etc.) were not available. Esterified HETEs were found in larger quantities in the cortex as compared to the medulla (34.40 +/- 1.12 versus 22.76 +/- 0.53 ng/g). The PI fraction in the cortex yielded the largest quantity of HETEs and the PC fraction the lowest. In the medulla, the largest quantities of esterified HETEs were found in neutral lipids and only slightly lesser amounts in PE and PI. Esterified 18-HETE was localized only to the NI fraction. This fraction also contained the other HETEs, 19- and 20-HETE being the most abundant. Notably only 16- and 17-HETE were present in PF, whereas, 19- and 20-HETE were also present in PI, PS and PC. Thus, P450-HETEs, like EETs are stored in the kidney and are, presumably, subject to release by peptide activation of acylhydrolases.


Roles of hypoxia-inducible factor-1α and its target genes in neonatal hypoxic pulmonary hypertension.
To investigate the role of hypoxia-inducible factor-1α and its target genes in hypoxic pulmonary hypertension in neonates. A total of 117 newborns were selected and divided into two groups for clinical experiments: 85 cases in the hypoxic pulmonary hypertension (HPH) group, including mild, moderate and severe subgroups, and 32 cases in the case-control group. ELISA was used to detect the serum HIF-1α, endothelin-1 (ET-1) and adrenomedullin (ADM) levels, and echocardiography was used to detect the dynamic changes in pulmonary artery systolic pressure (PASP), right ventricular ejection fraction (RVEF), tricuspid E peak and A peak ratio (E/A) and right ventricular Tei index. The average PASP level of the HPH group was significantly higher than that of the control group at 1 d and 3 d after birth (p < 0.05). The average PASP level was still higher in the severe HPH group than that in the control group at 7 d after birth, while the average levels in the mild and moderate HPH groups recovered to the normal. Compared with those in control group, RVEF and E/A of the tricuspid valve were decreased significantly in severe HPH patients (p < 0.05). The Tei indexes of the right ventricle were significantly higher in the mild, moderate and severe HPH groups than those in control group and the right ventricular Tei index was positively correlated with PASP. The levels of serum ADM, HHH-1α and ET-1 in all the three HPH subgroups were significantly higher than those in the control group at 1 d after birth and showed positive correlations with PASP (p < 0.05), except that serum ADM in mild HPH showed no obvious difference from the control group. The levels of serum HIF-1α and ADM in the severe HPH group and the ET-1 levels in the moderate and severe groups were increased significantly at 3 d after birth (p < 0.05). The PASP level in neonates with HPH is related to the serum HIF-1α, ET-1 and ADM levels, indicating that hypoxia can increase the level of HIF-1α, which in turn will enhance the expression of downstream target genes ET-1 and ADM, further leading to pulmonary hypertension. The right ventricular Tei index can be used to sensitively detect right ventricular dysfunction of mild, moderate and severe HPH groups.


A radiologist's guide to median sternotomy.
Median sternotomy is widely recognised as the primary incision technique in cardiac surgery. This surgical procedure involves dividing the sternum to gain access to the heart and lungs, making it invaluable in correcting congenital heart defects. Furthermore, it is frequently employed in adult patients, particularly during coronary artery bypass graft (CABG) procedures. In this imaging review, we present a comprehensive overview of the pre-procedural assessment and various post-sternotomy complications encountered within our clinical experience at a tertiary cardiothoracic centre. The focus of this review is to outline the imaging features associated with mediastinal adhesions and establish the minimal safe distance between the sternum and common mediastinal structures when considering re-sternotomy. By providing visual examples, we aim to facilitate a better understanding of these key concepts. Moreover, we delve into a detailed discussion of a spectrum of postoperative complications that may arise following median sternotomy including those related to metalwork (sternal wire fracture), bone (sternal dehiscence, non-union and osteomyelitis), and soft tissue (abscess, haematoma).