Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial.
Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified. To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type. In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries. Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily. The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review. A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified. In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types. ClinicalTrials.gov Identifier: NCT03565991.


Comparison of cowpox-like viruses isolated from European zoos. Brief report.
Poxviruses isolated from captive carnivores in Russia (Moscow virus) and elephants in Germany (elephant virus) were very closely-related to cowpox virus. Immunological analysis with absorbed sera separated elephant virus but not cowpox and Moscow virus, whereas polypeptide analysis separated cowpox but not elephant and Moscow virus. A combination of biological tests separated all three. The epidemiological implications are briefly reviewed.


Toxicological studies on the organophosphorous insecticide methyl-ISP.
Methyl-ISP, a newly developed organophosphorous insecticide, is used in China to treat and protect plants from pest infestation. Our studies demonstrated that methyl-ISP is metabolized rapidly in rat and mouse. Its toxicity was low, no obvious accumulative toxicity, chronic toxicity, teratogenicity, mutagenicity, reproductive toxicity or delayed neurotoxicity could be observed. It is therefore concluded that methyl-ISP is relatively safe to animals and human subjects. methyl-ISP is now employed to replace the other commonly used insecticide hexachlorobenzene (666) in agriculture. A preliminary study was performed to elucidate the mechanism of intoxication at subcellular levels.


[Effect of long-term moderately hard and hard physical work on the psychomotor efficiency and mental work capacity (II.)].
23 women, aged 19--24, of average physical efficiency, were examined. The following aspects were taken into account: an influence of long-lasting cyclic physical work on bicycle ergometer on the results obtained during the visual and auditory reaction time, the task performed with different speed using the test of visual and motorial coordination and Piórkowski's Test, as well as work efficiency in Pauli's test and learning and reproduction of nonsensical syllables. Long-lasting physical work resulted in a significant prolongation of the visual reaction time and increased number of mistakes in case of a task performed with maximum speed using the test of visual and motorial coordination. Negative but weak effects of physical effort were observed in the results of auditory reaction time and tasks checking the mental work efficiency. In the initial stage of the experiment (the early part) in some tasks a positive effect of physical effort was observed.


Indolent zygomycosis associated with deferoxamine chelation therapy.
This paper describes a 71-year-old man with myelodysplasia who required multiple transfusions and subsequent deferoxamine chelation therapy and who then developed indolent cutaneous and probable pulmonary infection with Rhizopus species. The patient did not have rapidly progressive infection as has been described in almost all previously reported deferoxamine-treated patients with zygomycosis. Amphotericin B therapy was successful in curing the infection.


Crash characteristics of older pedestrian fatalities: dementia pathology may be related to 'at risk' traffic situations.
Older people are over represented among pedestrian casualties, and cognitive decline is an often cited possible contributory factor. Cognitive decline and dementia are intimately associated, however the role dementia might play in older pedestrian crashes has received little attention. This study describes crash characteristics for 52 fatally injured older pedestrians in the Sydney metropolitan area. It investigates the relationship between the extent of neurofibrillary tangles (NFT), a hallmark of Alzheimer's disease in the brain, and particular crash situations. The results demonstrate crash characteristics that are similar to that reported in other studies of older pedestrians. Furthermore, the results suggest that cognitive decline associated with dementia related neuropathology may be associated with specific crash situations. Compared to older pedestrians with no, or low NFT, those with moderate to high NFT were more likely to be: at least partially responsible for the incident; injured while in low complexity situations; involved in impacts with reversing vehicles; impacted in near lanes of traffic; and struck by a vehicle off road. While described as trends only (p<0.2), these findings highlight areas of concern for older pedestrians and suggest potential targets for engineering and behaviour-based countermeasures aimed at reducing casualty numbers among older pedestrians.


Colour stability and antioxidant activity of C-phycocyanin-added ice creams after in vitro digestion.
C-phycocyanin (C-PC) is a protein with bioactive properties, which is found mainly in cyanobacteria and that is used as a natural food dye. Even though it is extensively studied, few authors have reported C-PC's colour stability and antioxidant activity when applied to food matrices. Therefore, the aim of this research was to evaluate the colour stability over time and the antioxidant capacity of a food grade C-PC extract applied to milk-based ice creams. The C-PC-added ice creams showed insignificant colour loss during 182 d. Regarding antioxidant activity, the C-PC-added ice creams presented low ABTS●+ and peroxyl radicals scavenging capacities before in vitro simulated digestion. However, after in vitro digestion, the ice creams with C-PC extract addition showed antioxidant capacities of 134.63 ± 15.68 and 1425.19 ± 54.93 μmolTE.g-1 by the ORAC and ABTS methods, values 2- and 13-fold higher than the achieved by the controls, respectively. Thus, the results demonstrate that C-PC extract can be applied as a stable blue dye in ice creams and highlight the increased antioxidant activity of the C-PC-added products after in vitro simulated digestion, which can encourage the formulation of food products that attract consumers' attention for both their colour and biological activities.


Decrease in acute coronary syndrome presentations during the COVID-19 pandemic in upstate New York.
The COVID-19 virus is a devastating pandemic that has impacted the US healthcare system significantly. More than one study reported a significant decrease in acute coronary syndrome admissions during that pandemic which is still due to unknown reasons. This is a retrospective non-controlled multi-centered study of 180 patients (117 males and 63 females) with acute coronary syndrome (STEMI and NSTEMI) admitted during March/April of 2019 and March/April 2020 in Upstate New York. A total of 113 patients (61.9% males, 38.1% females) with a mean age of 72.3 ± 14.2 presented during March/April 2019 with ACS (STEMI + NSTEMI) while only 67 (70.1% males, 29.9% females) COVID-19 negative patients with a mean age of 65.1 ± 14.5 presented during the same period (March/April) in 2020. This is a drop by 40.7% (P < .05) of total ACS cases during the COVID-19 pandemic. In NSTEMI patients, 36.4% presented late (>24 hours of symptoms) during the COVID-19 pandemic in comparison with 2019 (27.1%, P = .033). The COVID-19 pandemic led to a substantial drop by 40.7% (P < .05) of total ACS admissions in our area. This decrease in hospital admissions and late presentations can be a worrisome sign for an increase in future complications of myocardial infarctions.


Delayed initial recovery and long lie after a fall among middle-aged and older people with multiple sclerosis.
To determine (1) the prevalence of lying on the floor or ground for ≥10 minutes (delayed initial recovery [IR]) and for >1 hour (long lie) after a fall; and (2) the factors associated with delayed IR among people with multiple sclerosis (PwMS). A secondary analysis of data available from a national, cross-sectional descriptive study of PwMS. Information regarding postfall experiences was extracted from open-ended questions about participants' most recent fall. Community. PwMS (N=700) aged ≥55 years were recruited from the North America Committee on Multiple Sclerosis Registry; 354 of them completed the interview, and 322 provided a fall story that included information regarding postfall experiences. Not applicable. Participants' self-reports regarding time lying on the floor or ground after their most recent fall were used to determine delayed IR and long lie. A total of 89 (27.6%) of 322 fallers reported delayed IR; 15 (4.7%) of them reported a long lie. Logistic regression analysis revealed 5 factors associated with delayed IR: longer disease duration (odds ratio [OR]=1.03; 95% confidence interval [CI], 1.00-1.05), fall leading to a fracture (OR=2.73; 95% CI, 1.11-6.72), received help to get up (OR=3.94; 95% CI, 2.07-7.50), depression (OR=1.96; 95% CI, 1.10-3.49), and leg weakness (OR=2.14; 95% CI, 1.13-4.03). No significant differences were found between fallers who reported a long lie and those who reported a delayed IR. The findings suggest that while delayed IR is common, long lies are not prevalent among PwMS. The high prevalence of delayed IR highlights the importance of including fall management strategies in fall prevention programs for PwMS.


Recombinant bacterial RNA polymerase: preparation and applications.
Availability of DNA-dependent RNA polymerase from various bacteria is a key for setting up specific in vitro transcription systems necessary for understanding species-specific transcription regulation. We describe here two main strategies for recombinant RNA polymerase preparation-through in vitro reconstitution and heterologous co-overproduction in Escherichia coli. Both strategies can be used for preparation of large amounts of RNA polymerases from any bacteria for which sequences of rpo (RNA polymerase) genes are known.


Primary salivary gland malignancies: a review of clinicopathological evolution, molecular mechanisms and management.
Salivary gland cancers are a complex group of tumours with variations in location, type and grade, all of which influence their biological behaviour. The understanding of salivary gland pathology has evolved at the molecular level in the last decade leading to identification of distinct entities, development of improved methods of diagnosis as well as identifying therapeutic targets for selected high-grade tumours. This article focuses on these advances and their impact on the management of primary salivary gland cancers.


Drug Safety Monitoring in Children: Performance of Signal Detection Algorithms and Impact of Age Stratification.
Spontaneous reports of suspected adverse drug reactions (ADRs) can be analyzed to yield additional drug safety evidence for the pediatric population. Signal detection algorithms (SDAs) are required for these analyses; however, the performance of SDAs in the pediatric population specifically is unknown. We tested the performance of two SDAs on pediatric data from the US FDA Adverse Event Reporting System (FAERS) and investigated the impact of age stratification and age adjustment on the performance of SDAs. We tested the performance of two established SDAs: the proportional reporting ratio (PRR) and the empirical Bayes geometric mean (EBGM) on a pediatric dataset from FAERS (2004-2012). We compared the performance of the SDAs with a published pediatric-specific reference set by calculating diagnostic test-related statistics, including the area under the curve (AUC) of receiver operating characteristics. Impact of age stratification and age-adjustment on the performance of the SDAs was assessed. Age adjustment was performed by pooling (Mantel-Hanszel) stratum-specific estimates. A total of 115,674 pediatric reports (patients aged 0-18 years) comprising 893,587 drug-event combinations (DECs) were analysed. Crude values of the AUC were similar for both SDAs: 0.731 (PRR) and 0.745 (EBGM). Stratification unmasked four DECs, e.g., 'ibuprofen and thrombocytopenia'. Age adjustment did not improve performance. The performance of the two tested SDAs was similar in the pediatric population. Age adjustment does not improve performance and is therefore not recommended to be performed routinely. Stratification can reveal new associations, and therefore is recommended when either drug use is age-specific or when an age-specific risk is suspected.


Tall stature: a difficult diagnosis?
Referral for an assessment of tall stature is less common than for short stature. Tall stature is defined as a height more than two standard deviations above the mean for age. The majority of subjects with tall stature show a familial tall stature or a constitutional advance of growth (CAG), which is a diagnosis of exclusion. After a careful physical evaluation, tall subjects may be divided into two groups: tall subjects with normal appearance and tall subjects with abnormal appearance. In the case of normal appearance, the paediatric endocrinologist will have to evaluate the growth rate. If it is normal for age and sex, the subject may be classified as having familial tall stature, CAG or obese subject, while if the growth rate is increased it is essential to evaluate pubertal status and thyroid status. Tall subjects with abnormal appearance and dysmorphisms can be classified into those with proportionate and disproportionate syndromes.A careful physical examination and an evaluation of growth pattern are required before starting further investigations. Physicians should always search for a pathological cause of tall stature, although the majority of children are healthy and they generally do not need treatment to cease growth progression.The most accepted and effective treatment for an excessive height prediction is inducing puberty early and leading to a complete fusion of the epiphyses and achievement of final height, using testosterone in males and oestrogens in females. Alternatively, the most common surgical procedure for reducing growth is bilateral percutaneous epiphysiodesis of the distal femur and proximal tibia and fibula.This review aims to provide up-to-date information and suggestions about the diagnosis and management of children with tall stature.


A fast and label-free detection of hydroxymethylated DNA using a nozzle-jet printed AuNPs@Ti3C2 MXene-based electrochemical sensor.
5-hydroxymethylcytosine (5hmC) is a key epigenetic mark in the mammalian genome that has been proposed as a promising cancer biomarker with diagnostic and prognostic potentials. A new type of two-dimensional (2D) material called MXene includes transition metal carbides and nitrides and possesses unique physico-chemical properties suitable for diverse applications, including electrochemical sensors. Here, we report a new nozzle-jet printed electrochemical sensor using gold nanoparticles (AuNPs)@Ti3C2 MXene nanocomposite for the real-time and label-free detection of 5hmC in the genome. We utilized Ti3C2 MXene as a platform to immobilize AuNPs, which have been shown to exhibit different affinity interactions toward 5-methylcytosine (5 mC) and 5hmC, and thus produce distinct electrochemical responses. To fabricate the electrode, a highly conductive and adhesive silver ink was prepared to generate a silver line onto polyethylene terephthalate (PET) substrate using nozzle-jet printing, followed by deposition of AuNPs@Ti3C2 MXene ink at one end via dropcasting. Analyses of morphology and chemical composition showed that all steps of the sensor fabrication were successful. The fabricated sensor coupled with cyclic voltammetry showed excellent performance in distinguishing 5 mC- or 5hmC-enriched cellular genomic DNAs. As a proof-of-concept investigation, we confirmed that our sensor readily and consistently detected 5hmC diminution in multiple tumors, compared to the paired normal tissues. Thus, our simple and cost-effective sensing strategy using printable AuNPs@Ti3C2 MXene ink holds promise for a wide range of practical applications in epigenetic studies as well as clinical settings.


Expression of the human TRIM14 and its mutant form (P207L) promotes apoptosis in transgenic loaches.
The tripartite-motif (TRIM)14 protein, one of the TRIM family members, was shown to participate in the antiviral and antibacterial defence. Besides, it appears to play an essential role in the processes of oncogenesis. In some types of human tumour cells, TRIM14 has been shown to inhibit apoptosis, while in others-the overexpression of TRIM14 promotes apoptosis. However, whether TRIM14 mediates apoptosis in the normal cells remains unknown. In the present study, we investigated the possible participation of the human TRIM14 gene and its mutant form (620C > T) in the induction of apoptosis in the transgenic larvae loach Misgurnus fossilis L. We observed that the expression of both forms of TRIM14 gene was accompanied by the increase of the frequency of pyknotic nuclei in fish embryos compared to control groups. Accordingly, using the TUNEL assay, the enhanced apoptosis was revealed upon expression of both forms of TRIM14 gene. The transcription of proapoptotic genes (bax, tp53, and casp9) was significantly increased in transgenic loaches expressing human wild-type TRIM14, but remained unchanged upon expression of its mutant form. In addition, the transcription of c-myc was upregulated in transgenic loaches expressing both forms. Thus, it can be assumed that during embryonic development TRIM14 has a proapoptotic effect on the cells via the activation of c-myc, tp53, and bax genes. Apparently, the mutant TRIM14 directs apoptosis via c-myc by p53-independent mechanism.


Lunate osteochondroma: a case report.
We report a case of osteochondroma of the lunate. A 16-year-old boy had a 6-year history of irritable snapping of the right wrist associated with numbness of the ipsilateral middle finger. At surgery we found that the median nerve became caught on the lunate osteochondroma while the wrist was extended and slipped over it when the wrist was flexed rapidly, thereby causing a snapping phenomenon. The symptoms disappeared completely after the protruding lesion was excised. Several cases of solitary carpal osteochondroma have been reported previously.


Challenges for cocaine detection in smuggling samples.
Screening of seized cocaine powders is routinely performed by means of colour tests. An alternative fast screening technique is Mid-InfraRed (MIR) spectroscopy. In the context of smuggling cases, however, drugs are often processed to circumvent detection. In this study, the current screening techniques (cocaine colour test and MIR spectroscopy using libraries and chemometrics) were applied to five smuggling cases. For each case, all samples were first screened with a cocaine colour test and MIR analysis, followed by confirmation analyses with GC-MS and GC-FID to identify and quantify cocaine and cutting agents. Finally, Scanning Electron Microscopy-Energy Dispersive X-ray spectroscopy (SEM-EDX) analyses were performed for additional characterization. All smuggling samples tested negative, both on-site as in the laboratory, for cocaine with the cocaine colour test. Four smuggling cases consisted of coloured samples. Consequently the colour test result was influenced because discolouration of the test showed almost the same colour as the colour of the powders (brown, green, red or black). In contrast, the (coloured) powders could be measured with MIR, but the MIR spectra showed no hit for cocaine using a reference library search. Moreover, cocaine was not detected in four out of the five cases after application of a chemometric classification model. GC-MS analysis, the golden standard for identification, resulted in a positive identification of cocaine in all cases. These samples contained cocaine ranging between 0.8w% and 35w%. Taking into account the results of the screening, the chromatographic and the SEM-EDX analyses, it could be presumed that cocaine was masked. False negative screening results were caused by chemically modified cocaine and/or cocaine mixed with coloured powders. In additional experiments, a sample extraction step prior to the screening techniques was performed. Two sample preparation methods (acetone and ethyl acetate) were tested and resulted in a positive screening of cocaine with the colour test and/or MIR spectroscopy. It can be concluded that the outcome of screening techniques such as colour tests and MIR spectroscopy is only presumptive and should always be confirmed.


Effect of cholesterol on the valinomycin-mediated uptake of rubidium into erythrocytes and phospholipid vesicles.
Human erythrocytes have been treated with lipid vesicles in order to alter the cholesterol content of the cell membrane. Erythrocytes have been produced with cholesterol concentrations between 33 and 66 mol% of total lipid. The rate of valinomycin-mediated uptake of rubidium into the red cells at 37 degrees C was lowered by increasing the cholesterol concentration of the cell membrane. Cholesterol increased the permeability to valinomycin at 20 degrees C of small (less than 50 nm), unilamellar egg phosphatidylcholine vesicles formed by sonication. Cholesterol decreased the permeability to valinomycin at 20 degrees C of large (up to 200 nm) unilamellar egg phosphatidylcholine vesicles formed by freeze-thaw plus brief sonication. It is concluded that cholesterol increases the permeability of small membrane vesicles to hydrophobic penetrating substances while above the transition temperature but has the opposite effect on large membrane vesicles and on the membranes of even larger cells.


Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study.
To determine the effectiveness and safety outcomes of cenobamate in a cohort of patients with highly refractory focal epilepsy in routine clinical practice. Observational, retrospective, phase 4 study on subjects receiving cenobamate in three Spanish centers. The primary endpoint was the retention rate at the last follow-up. The main secondary endpoints were the 50%-responder and seizure-free rates at three months and the last follow-up. Other secondary endpoints were Global Clinical Impressions-Improvement (CGI-I) scores and treatment-emergent adverse events (TEAEs). Fifty-one patients with highly refractory focal epilepsy with 24.7 years of disease evolution, ten previously tried ASM, and a 23.5% of previous epilepsy surgery were included. The retention rate at the last follow-up was 80.4%. The 50% responder rate in focal seizures at three months was 56.5% (median reduction per month 51%, 0-74.6; p < 0.0001) and in focal to bilateral tonic-clonic seizures was 63.6% (median reduction per month 89%, 0-100; p = 0.022). A total of 54.3% of subjects reported a reduction in the intensity of focal seizures, and 66% manifested clinically significant satisfaction. Cenobamate allowed a significant decrease in concomitant ASM, especially sodium channel blockers. TEAEs were reported in 43.1% of individuals, 85% of whom resolved or improved, with no new safety findings. In this analysis of patients with highly refractory focal epilepsy treated with cenobamate according to standard clinical practice, there was evidence of a high reduction in both seizure frequency and intensity, with a manageable safety profile.


Utilization and outcomes of transcatheter aortic valve replacement in the United States shortly after device approval.
The objective of this study was to assess the national uptake of TAVR, associated in-hospital outcomes, and the effect of procedural experience on outcomes in the first two years following device approval. Transcatheter aortic valve replacement (TAVR) is a newly established therapy for high-risk patients with severe aortic stenosis. Evaluating the manner in which TAVR has disseminated into real-world practice is essential for understanding its impact on population health. We identified patients undergoing TAVR from the National Inpatient Sample from January 2012 through December 2013. During this period, an estimated 21,185 cases were performed in the United States. Mean age was 81.1 years, 50.8% were male, 86.5% were Caucasian, and 89.6% were Medicare patients. The number of TAVRs performed and of hospitals performing the procedure nationally grew linearly throughout the study period. The most frequent complications included bleeding (26.9%), respiratory failure (19.3%), and renal/metabolic issues (17.2%). Median hospital length of stay was 6 days (IQR 4-10). In-hospital mortality was estimated to be 4.9%. A majority of cases were performed in large (80.8%) and in urban teaching (87%) hospitals. In the first year post-market approval, prior institutional experience with TAVR was associated with significantly reduced risk-adjusted, in-hospital mortality (OR 0.82 per 25 additional TAVRs performed, CI 0.70-0.951, P = 0.009). Following device approval, the number of TAVRs and hospitals performing TAVR grew dramatically. Procedural complications were frequent and in-hospital mortality was approximately 4.9%. Finally, increased procedural experience was strongly associated with a reduction in inpatient mortality. © 2017 Wiley Periodicals, Inc.


Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer.
Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. Here we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy. We demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs. While SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs.


Adoption of Expansion Margins to Reduce the Dose Received by the Coronary Arteries and the Risk of Cardiovascular Events in Lymphoma Patients.
Mediastinal radiation therapy (RT) in patients with lymphoma implies involuntary coronary artery (CA) exposure, resulting in an increased risk of coronary artery disease (CAD). Accurate delineation of CAs may spare them from higher RT doses. However, heart motion affects the estimation of the dose received by CAs. An expansion margin (planning organ at risk volume [PRV]), encompassing the nearby area where CAs displace, may compensate for these uncertainties, reducing CA dose and CAD risk. Our study aimed to evaluate if a planning process optimized on CA-specific PRVs, rather than just on CAs, could provide any dosimetric or clinical benefit. Forty patients receiving RT for mediastinal lymphomas were included. We contoured left main trunk, left anterior descending, left circumflex, and right coronary arteries. An isotropic PRV was then applied to all CAs, in accordance with literature data. A comparison was then performed by optimizing treatment plans either on CAs or on PRVs, to detect any difference in CA sparing in terms of maximum (Dmax), median (Dmed), and mean (Dmean) dose. We then investigated, through risk modeling, if any dosimetric benefit obtained with the PRV-related optimization process could translate to a lower risk of ischemic complications. Plan optimization on PRVs demonstrated a significant dose reduction (range, 7%-9%) in Dmax, Dmed, and Dmean for the whole coronary tree, and even higher dose reductions when vessels were located 5- to 20-mm from PTV (range, 13%-15%), especially for left main trunk and left circumflex (range, 16%-21%). This translated to a mean risk reduction of developing CAD of 12% (P < .01), which increased to 17% when CAs were located 5- to 20-mm from PTV. Integration of CA-related PRVs in the optimization process reduces the dose received by CAs and translates to a meaningful prevention of CAD risk in patients with lymphoma treated with mediastinal RT.


In vivo early and mid-term flow-mediated endothelial function of the radial artery used as a coronary bypass graft.
We sought to evaluate the in vivo endothelial function of the radial artery (RA) used as a coronary graft. The RA is becoming a recognized alternative coronary bypass conduit. In vivo endothelial function is a possible predictor of long-term performance. Sixty consecutive patients underwent coronary artery bypass graft surgery (CABG); all received RA and left internal mammary artery (LIMA) grafts. Three weeks after CABG, 36 patients underwent angiography under basal conditions, during pacing and after intragraft injection of glyceryl trinitrate (GTN). Angiography was repeated at six months in 20 patients. The estimated mean difference of 66 segments of the radial graft on the first QCA study was 0.170 mm (95% confidence interval [CI] 0.101 to 0.258, p < 0.001) between baseline and pacing, and 0.310 mm (CI 0.225 to 0.401, p < 0.001) between baseline and GTN. At six months, the differences between baseline and pacing and baseline and GTN were 0.112 mm (CI 0.062 to 0.162, p < 0.001) and 0.274 (CI 0.192 to 0.353, p < 0.001), respectively. The difference between baseline values at three weeks and six months was 0.416 mm (CI 0.236 to 0.603, p < 0.001). In the LIMA segments, the difference between baseline and pacing and baseline and GTN were 0.206 mm (CI 0.136 to 0.278, p < 0.001) and 0.304 mm (CI 0.213 to 0.396, p < 0.001), respectively. At six months, the differences between baseline and pacing and baseline and GTN were 0.098 mm (CI 0.014 to 0.173, p < 0.001) and 0.218 mm (CI 0.130 to 0.298, p < 0.001). The difference between baseline values at three weeks and six months was 0.061 mm (CI 0.064 to 0.176, p > 0.05). In vivo flow-mediated dilation of the RA is comparable to that of pedicled LIMA. The increased dilation both at baseline and after pacing at six months represents a time-related improvement in the vasomotor function of the RA, which could have implications for its performance as a coronary conduit.


The Australian mental health system: An economic overview and some research issues.
This article is concerned with the key economic characteristics of Australia's mental health system. First, some brief conceptual and empirical descriptions are provided of Australia's mental health services, both as a total system, and of its two principal components, viz. public psychiatric institutions and private psychiatry services. Expenditures on public psychiatric hospitals clearly demonstrate the effect of deinstitutionalisation. Data from 1984 on private practice psychiatry indicate that per capita utilisation rates peaked in 1996 and have since fallen. Generally, since 1984 gross fees have not risen. However, for both utilisation and fees, there is evidence (of a statistical kind) that there are significant differences between the states of Australia, in these two variables (utilisation and fees). Emphasis is also placed on the economic incentives that arise from health insurance and the heterogeneous nature of mental illness. The effects of these incentives are regarded as by-products of the health insurance mechanism; and another effect, "unmet need" and "met non-need", is a somewhat unique problem of an informational kind. Discussion of many of these issues concludes on a somewhat negative note, e.g. that no empirical results are available to quantify the particular effect that is discussed. This is a manifestation of the lacunae of economic studies of the mental health sector.


Ultrahigh frequency voltammetry: effect of electrode material and frequency of alternating potential modulation on mass transport at hot-disk microelectrodes.
Ultrahigh frequency voltammetry involves low scan rate voltammetric measurements with microelectrodes polarized by high-frequency large-amplitude alternating potential. The method provides a simple means for studying electrothermal and dielectrophoretic effects, which are important in micro and nanofluidic systems. The method also allows for indirect measurements of electrode impedance at gigahertz frequencies. This increases the upper frequency limit in impedance measurements about 1000 times. In this work we demonstrated, for the first time, that the effect of dielectric relaxation of water can be observed in a simple voltammetric experiment. The paper focuses on the description of electrothermal convection at ac heated disk microelectrodes as a function of frequency and provides a comparison of numerical simulations with experimental results.


Different physiological relevance of yeast THO/TREX subunits in gene expression and genome integrity.
THO/TREX is a conserved nuclear complex that functions in mRNP biogenesis and plays a role in preventing the transcription-associated genetic instability. THO is composed of Tho2, Hpr1, Mft1 and Thp2 subunits, which associate with the Sub2-Yra1 export factors and Tex1 to form the TREX complex. To compare the functional relevance of the different THO/TREX subunits, we determined the effect of their null mutations on mRNA accumulation and recombination. Unexpectedly, we noticed that a full deletion of HPR1, hpr1DeltaK, conferred stronger hyper-recombination phenotype and gene expression defects than did hpr1DeltaH, the allele encoding a C-terminal truncated protein which was used in most previous studies. We show that tho2Delta and, to a lesser extent, hpr1DeltaK are the THO mutations with the highest impact on all phenotypes, and that sub2Delta shows a similar transcription-dependent hyper-recombination phenotype and in vivo transcription impairment as hpr1DeltaK and tho2Delta. Recombination and transcription analyses indicate that THO/TREX mutants share a moderate but significant effect on gene conversion and ectopic recombination, as well as transcription impairment of even short and low GC-content genes. Our data provide new information on the relevance of these proteins in mRNP biogenesis and in the maintenance of genomic integrity.


Centrifugation as a countermeasure during bed rest and dry immersion: What has been learned?
We review the studies that have evaluated intermittent short-radius centrifugation as a potential countermeasure for cardiovascular, musculoskeletal, and sensorimotor deconditioning in simulated weightlessness. The findings from 18 experimental protocols that have used bed rest and dry immersion for comparing the protective effects of centrifugation versus standing upright or walking, and the effects of continuous vs. periodic exposure to centrifugation are discussed. Centrifugation for as little as 30 min per day was found to be effective in mitigating orthostatic intolerance and strength in postural muscle after 5 days of bed rest, but it was not effective in mitigating plasma volume loss. To determine the optimal prescription for centrifugation as a countermeasure, we recommend further studies using (a) bed rest of longer duration, (b) individualized prescriptions of centrifugation combined with exercise, and


Employment of marine polysaccharides to manufacture functional biocomposites for aquaculture feeding applications.
In this study, polysaccharides of marine origin (agar, alginate and κ-carrageenan) were used to embed nutrients to fabricate biocomposites to be employed in animal feeding. The consistency of biocomposites in water has been evaluated up to 14 days, by several methods: swelling, nutrient release and granulometric analysis. Biocomposites were produced with varying percentages of nutrients (5%-25%) and polysaccharides (1%-2%-3%). All possible biopolymer combinations were tested in order to select those with the best network strength. The best performing biocomposites were those manufactured with agar 2% and nutrients 10%, showing the lowest percentage of water absorption and nutrient release. Biocomposites made of agar 2% and nutrients 10% were the most stable in water and were therefore used to analyze their behavior in water with respect to the release of quercetin, a phenolic compound with demonstrated high antibacterial and antioxidant activities. The leaching of such molecules in water was therefore employed as a further indicator of biocomposite water stability. Altogether, our results confirm the suitability of agar as a binder for biocomposites and provide a positive contribution to aquaculture.


The use of medicinal plants in common ophthalmic disorders: A systematic review with meta-analysis.
This study aimed to assess and compile the available research articles about medicinal plants used for ocular diseases. A total of 2949 articles were retrieved, 35 full-text articles were assessed for eligibility, and seven studies (4 observational and three experimental) with low to moderate quality were eligible and involved in the systematic review, with a total of 600 plants from 4 countries. Among the 600 plants, only 24 (4%) were used to assess the status. Both the fixed and random models of the studies showed that the included studies tended to predict the results for the observational studies (OR = 0.062, CI = 0.043-0.090 OR = 0.039, CI = 0.012-0.122) for different plants used for ocular diseases. High heterogeneity (estimated as I2 = 87.078, Tau2 = 1.161 and Q-value = 23.217 with a p-value of 0.000), while for experimental studies (I2 = 94.928, Tau2 = 23.211 and Q-value = 39.434 with a p-value of 0.000) and publication bias were reported. Few articles representing approximately 600 plants of low to moderate quality reported using medicinal plants for ocular diseases. The meta-analysis confirmed the systematic review findings regarding the plants' traditional use with high heterogeneity and publication bias. A considerable gap was proven in the use of medicinal plants in ocular diseases requiring intensive research.


Trends, Factors, and Outcomes Associated with Immediate Sequential Bilateral Cataract Surgery among Medicare Beneficiaries.
To report the incidence of immediate sequential bilateral cataract surgery (ISBCS) and delayed sequential bilateral cataract surgery (DSBCS) and to identify factors associated with undergoing ISBCS. Retrospective cohort study. Medicare beneficiaries aged ≥ 65 who underwent ISBCS and DSBCS from 2011 through 2019. Population-based analysis of the 100% Medicare fee-for-service carrier claims data. Logistic regression models were performed to evaluate factors associated with ISBCS. Incidence of ISBCS and DSBCS; demographic, ocular, and medical characteristics associated with receipt of ISBCS; and rates of endophthalmitis and cystoid macular edema (CME) after ISBCS or DSBCS. A total of 4014 (0.2%) ISBCS and 1 940 965 (99.8%) DSBCS patients were identified. Black (odds ratio [OR], 2.31; 95% confidence interval [CI], 2.06-2.59), Asian (OR, 1.82; 95% CI, 1.51-2.19), and Native American (OR, 2.42; 95% CI, 1.81-3.23) patients were more likely to receive ISBCS than White patients. Patients residing in rural areas showed a higher likelihood of ISBCS (OR, 1.26; 95% CI, 1.17-1.35) than patients in metropolitan areas. Patients undergoing surgery at a hospital, compared with an ambulatory setting (OR, 2.71; 95% CI, 2.53-2.89), were more likely to receive ISBCS. Patients with bilateral complex versus noncomplex cataract (OR, 3.23; 95% CI, 2.95-3.53) were more likely to receive ISBCS. Patients with a Charlson comorbidity index (CCI) of 1 to 2 (OR, 1.45; 95% CI, 1.29-1.62), 3 to 4 (OR, 1.70; 95% CI, 1.47-1.97), 5 to 6 (OR, 1.97; 95% CI, 1.62-2.39), and CCI ≥ 7 (OR, 1.97; 95% CI, 1.55-2.50) were more likely to receive ISBCS than those with a CCI of 0. In contrast, patients with glaucoma (OR, 0.82; 95% CI, 0.76-0.89), macular degeneration (OR, 0.75; 95% CI, 0.68-0.82), and macular hole or epiretinal membrane (OR, 0.55; 95% CI, 0.48-0.65) were less likely to undergo ISBCS than those without. Cumulatively, no significant difference was found in endophthalmitis rates within 42 days between ISBCS (1.74 per 1000 ISBCS procedures) and DSBCS (1.01 per 1000 DSBCS procedures; P = 0.15). Similarly, there was no significant cumulative difference between CME rates (P = 0.45) in ISBCS (1.79 per 100 ISBCS procedures) and DSBCS (1.96 per 100 DSBCS procedures). Overall use of ISBCS among Medicare beneficiaries remained low over the past decade, although rates of endophthalmitis and CME were comparable to DSBCS. Race, geography, and systemic and ocular comorbidities were associated with receiving ISBCS. ISBCS represents a potential opportunity to improve access to cataract surgery.


Non-invasive Estimation of Right Atrial Pressure Using Inferior Vena Cava Echography.
The pulsatility of the inferior vena cava (IVC) reflects the volume status and central venous pressure of patients. The standard clinical indicator of IVC pulsatility is the caval index (CI), measured from ultrasound recordings. However, its estimation is not standardized and is vulnerable to artifacts, mostly because of IVC movements during respiration. Thus, we used a (recently patented) semi-automated method that tracks IVC movements and averages the CI across an entire section of the vein, which provides a more stable indication of pulsatility. This algorithm was used to estimate the CI, pulsatility indicators reflecting either respiratory or cardiac stimulation and the mean diameter of the IVC. These IVC indices, together with anthropometric information, were used as potential features to build an innovative model for the estimation of the right atrial pressure (RAP) recorded from 49 catheterized patients. An exhaustive search was carried out for the best among all possible models that could be obtained by using combinations of these features. The model with minimum estimation error (tested with a leave-one-out approach) was selected. This model estimated RAP with an error of about 3.6 ± 2.6 mm Hg (mean ± standard deviation); the error when using only operator measured variables, without software, was about 4.0 ± 2.5 mm Hg. These promising results underline the need for further study of our RAP estimation method on a larger data set.


The effect of double W tension-reduced suture technique on the abdominal scars following the da Vinci robot-assisted gastrectomy for severely obese patients.
To analyze the effect of a new type of tension-reduced suture named "double W tension-reduced suture technique" on the abdominal scars following the da Vinci robot-assisted gastrectomy for severely obese patients. 40 abdominal incisions following the da Vinci robot-assisted gastrectomy on severely obese patients from September 1st, 2021 to March 1st, 2022 were comprised in the study. 20 incisions were closed by the conventional full-thickness surgical suture as the control group, and 20 incisions were sewn up by double W tension-reduced suture as the double W group. The scars were assessed at the 1-month follow-up visit using the Vancouver scar scale (VSS), ultrasound and patient satisfaction. Meanwhile, digital photographs of scars were taken as well. The VSS score was 6.80 ± 2.16 in the control group, while that of the double W group was 2.60 ± 1.89. The difference between groups was significant. Digital photographs showed that the scar color was not only light and close to the skin color, but also flat and soft in the double W group. Ultrasound showed that the fibers of subcutaneous tissue in the double W group were arranged neatly, the ultrasonic signal intensity was relatively uniform, and the tunnel was small without obvious lacunae. More patients were satisfied and very satisfied with scars in the double W group. Double W tension-reduced suture technique could significantly improve the appearance and reduce comorbidities of scars following the da Vinci robot-assisted gastrectomy for severely obese patients.


Microwave-accelerated methylation of starch.
A novel microwave-accelerated method for methylating soluble starch is described. Soluble starch could be fully methylated in 72% yield within 4.66 min using iodomethane and 30% potassium hydroxide under microwave irradiation. The completely methylated starch thus obtained was hydrolyzed with 60% HCO(2)H for 1.5 min under 80% MW power, followed by 0.05 M H(2)SO(4) for 2.0 min under 100% MW power. The partially methylated monosaccharides were separated by preparative paper chromatography and identified by their melting points and optical rotations.


Metal ion effects on different types of cell line, metal ion incorporation into L929 and MC3T3-E1 cells, and activation of macrophage-like J774.1 cells.
V ions showed high cytotoxicity for mouse fibroblast L929, osteoblastic MC3T3-E1, and macrophage-like J774.1 cells compared with Pb, Cu, Ni, Co, Zn, and Mo ions. The quantities of metal ions incorporated into the L929 and MC3T3-E1 cells increased with increasing metal concentration in the medium, depending on the metal ion type. In particular, the quantities of V incorporated into the cells were markedly higher than those of other metals. It was suggested that the cytotoxicity of a metal ion changes with the quantity of the metal ion incorporated into cells. It was also considered that V ions are incorporated into cells through xanthine derived from fetal bovine serum by high-performance liquid chromatography (HPLC). The strong interaction of Co, Ni and Mo with amino acids was analyzed by HPLC. The rate of increase of nitric oxide (NO) concentration released with the activation of the mouse macrophage-like J774.1 cells increased at a concentration of V ions ten times lower than that of Ni ions. The release of the cytokine tumor necrosis factor-α (TNF-α) from the J774.1 cells started at approximately 0.5 ppm V; interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) showed a marked increase in the rate of increase at more than 1 ppm V. No increase in the concentration of IL-1α, IL-8, IL-15 or granulocyte macrophage-colony stimulating factor (GM-CSF) was observed for V and Ni ions.


The John Insall Award: A minimum 10-year outcome study of autologous chondrocyte implantation.
Autologous chondrocyte implantation (ACI) has demonstrated good and excellent results in over 75% of patients up to 10 years after surgery. Reports of longer-term outcomes, however, remain limited. The purposes of this study were to describe the (1) survivorship of ACI grafts; (2) the long-term functional outcomes using validated scoring tools after ACI; and (3) to provide an analysis of potential predictors for failure. Two hundred ten patients treated with ACI were followed for more than 10 years. Indications for the procedure included symptomatic cartilage defects in all compartments of the knee unresponsive to nonoperative measures. Mean age at surgery was 36 ± 9 years; mean defect size measured 8.4 ± 5.5 cm(2). Outcome scores were prospectively collected pre- and postoperatively at the last followup. At a mean of 12 ± 2 years followup, 53 of 210 patients (25%) had at least one failed ACI graft. Nineteen of these patients went on to arthroplasty, 27 patients were salvaged with revision cartilage repair, and seven patients declined further treatment; three patients were lost to followup. The modified Cincinnati increased from 3.9 ± 1.5 to 6.4 ± 1.5, WOMAC improved from 39 ± 21 to 23 ± 16, Knee Society Score (KSS) knee score rose from 54 ± 18 to 79 ± 19, and KSS function from 65 ± 23 to 78 ± 17 (all p < 0.0001). The Physical Component of the SF-36 score increased from 33 ± 14 to 49 ± 18, whereas the Mental Component improved from 46 ± 14 to 52 ± 15 (both p < 0.001). Survivorship was higher in patients with complex versus salvage-type lesions (p = 0.03) with primary ACI versus ACI after prior marrow stimulation (p = 0.004) and with concomitant high tibial osteotomy (HTO) versus no HTO (p = 0.01). ACI provided durable outcomes with a survivorship of 71% at 10 years and improved function in 75% of patients with symptomatic cartilage defects of the knee at a minimum of 10 years after surgery. A history of prior marrow stimulation as well as the treatment of very large defects was associated with an increased risk of failure.


FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells.
Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.


Uterine lesions with sex cord-like architectures: a systematic review.
Sex cord-like elements are rarely observed in uterine lesions, but these morphological patterns could appear in a variety of uterine tumors and non-tumorous lesions. In this review, we collected the literatures regarding the uterine tumorous and non-tumorous lesions containing sex cord-like elements and summarized these lesions in terms of clinicopathological, immunohistochemical, and molecular features in order to further understand these lesions and provide some new ideas for differential diagnosis. This section provides a comprehensive overview of the clinicopathological, immunohistochemical, and molecular features of uterine lesions with sex cord-like architectures including uterine tumors resembling ovarian sex cord tumors, endometrial stromal tumors, adenomyosis, endometrial polyps, leiomyoma, epithelioid leiomyosarcoma, adenosarcoma, sertoliform endometrioid carcinoma, corded and hyalinized endometrioid carcinoma, mesonephric adenocarcinoma, and mesonephric-like adenocarcinoma. The differential diagnosis based on morphology, immunohistochemistry, and molecular alterations has also been discussed. The sex cord-like areas in these lesions show heterogeneous but similar morphological features. Additionally, immunohistochemical staining plays a limited role in differential diagnosis. Furthermore, it is of significance for pathologists to better understand these lesions in order to avoid confusion and mistakes during pathological diagnosis, especially in a biopsy/curettage specimen.


The measurement of radiation doses from P32 chromic phosphate therapy of the peritoneum using SPECT.
Single photon emission computed tomography (SPECT) has been shown to be of value in estimating the radiation dose to the peritoneum from 32P therapy. Simple dosimetry calculations, assuming uniform irradiation of tissue, indicate that radiation doses of approximately 40 Gy to the peritoneal surface are achieved. However, the images show that the radionuclide distribution is non-uniform, giving rise to radiation dose variations of at least a factor of 10.


Inside-outside Ag nanoparticles-loaded polylactic acid electrospun fiber for long-term antibacterial and bone regeneration.
Bone infections caused by bacteria during bone graft implantations can impair the ability of bone tissue repair, which is currently a clinical problem. In this study, the electrospinning technique was used to prepare a polylactic acid (PLLA)/silver (Ag) composite fiber, in which the silver nanoparticles (Ag-NPs) were uniformly distributed on the inner surface of PLLA fibers; dopamine (DA) was self-polymerized on the composite fiber surface to construct the adhesive polydopamine (PDA) film and chitosan (CS) was used to regulate Ag+ in situ through pulse electrochemical deposition for the construction of a stable Ag-NPs coating (CS/Ag), achieving the steady and slow release of Ag-NPs, therefore accomplishing the construction of a "inside-outside" Ag-NPs-loaded PLLA/Ag@PDA@CS/Ag composite fiber with dual functions of long-lasting antibacterial effect as well as bone regeneration promotion ability. The study results showed that the composite fiber has an excellent antibacterial effect against E. coli and S. aureus, and good osteoinductive and angiogenic properties. In summary, under the dual regulations of the strong adhesion of PDA and CS chelation, the "inside-outside" Ag-NPs-loaded composite fiber was endowed with good physiological stability, long-term antibacterial effect and bone infection inhibition ability, making it a promising bone implant material.


Urban nature at the fingertips: Investigating wild food foraging to enable nature interactions of urban dwellers.
Meaningful human-nature interactions can counteract the extinction of experience and positively influence people's nature relatedness, health and wellbeing. In this study, we explored urban wild food foraging to understand how best to enable human-nature interactions in cities by means of foraging. Using a structured questionnaire, a total of 458 residents of Vienna, Austria were surveyed. Sixty-four percent of visitors of public urban green spaces previously foraged for wild food species, whereas foraging frequencies were related to the targeted plant species and their life forms. People who foraged more frequently had greater nature relatedness, more childhood foraging experiences and lived on the outskirts of the city, but their socio-demographic backgrounds were heterogeneous. Social acceptance and lack of access to wild foods were perceived to be barriers. To promote nature relatedness through urban foraging, the legal framework, access to low-contamination foraging areas, availability of wild foods and social acceptance need to be improved.


[Modern methods for surveillance of communicable disease: general introduction (author's transl)].
Epidemiological surveillance has now become a fully developed discipline, to which several technical specialties contribute. All kinds of new problems resulting from present conditions of life have enlarged the field of surveillance beyond the old concept of morbidity-mortality. This has necessitated the application of new methodology--a stimulating challenge for those who are engaged in epidemiological surveillance.


Synthesis of a photocaged tamoxifen for light-dependent activation of Cre-ER recombinase-driven gene modification.
We report the design of a water-soluble, quaternized tamoxifen photoprobe and demonstrate its application in light-controlled induction of green fluorescent protein expression via a Cre-ER recombinase system.


Tank treading of optically trapped red blood cells in shear flow.
Tank-treading (TT) motion is established in optically trapped, live red blood cells (RBCs) held in shear flow and is systematically investigated under varying shear rates, temperature (affecting membrane viscosity), osmolarity (resulting in changes in RBC shape and cytoplasmic viscosity), and viscosity of the suspending medium. TT frequency is measured as a function of membrane and cytoplasmic viscosity, the former being four times more effective in altering TT frequency. TT frequency increases as membrane viscosity decreases, by as much as 10% over temperature changes of only 4°C at a shear rate of ∼43 s(-1). A threshold shear rate (1.5 ± 0.3 s(-1)) is observed below which the TT frequency drops to zero. TT motion is also observed in shape-engineered (spherical) RBCs and those with cholesterol-depleted membranes. The TT threshold is less evident in both cases but the TT frequency increases in the latter cells. Our findings indicate that TT motion is pervasive even in folded and deformed erythrocytes, conditions that occur when such erythrocytes flow through narrow capillaries.


Evaluation of copper slag to catalyze advanced oxidation processes for the removal of phenol in water.
The aim of this work was to evaluate the use of copper slag to catalyze phenol degradation in water by advanced oxidation processes (AOPs). Copper slag was tested in combination with H(2)O(2) (slag/H(2)O(2)) and H(2)O(2)/UV (slag/H(2)O(2)/UV). The studied methods promoted the complete photocatalytic degradation of phenol. Besides, they were able to reduce about 50% the TOC content in the samples. Slag/H(2)O(2)/UV and slag/H(2)O(2) treatments have favored biodegradability increment along the reaction time. Nevertheless, the irradiated method achieved higher values of the biodegradability indicator (BOD(5)/TOC). The toxicity assessment indicated the formation of more toxic compounds in both treatments. However, the control of the reaction time would minimize the environmental impact of the effluents.


Effects of a stand-alone web-based electronic screening and brief intervention targeting alcohol use in university students of legal drinking age: A randomized controlled trial.
Many intervention efforts targeting student drinking were developed to address US college students, which usually involves underage drinking. It remains unclear, if research evidence from these interventions is generalizable to university and college students of legal drinking age, e.g., in Europe. To evaluate the effectiveness of a translated and adapted version of the eCHECKUP TO GO, applied as stand-alone web-based electronic screening and brief intervention (e-SBI), in German university students at risk for hazardous drinking. A fully automated web-based two-arm parallel-group randomized controlled trial was conducted. Participants were randomized to an e-SBI or assessment-only (AO) condition. The current paper analyzed students with baseline AUDIT-C scores ≥3 for women and ≥4 for men (sample at baseline: e-SBI [n=514], AO [n=467]; 3-month follow-up: e-SBI [n=194], AO [n=231]; 6-month follow-up: e-SBI [n=146], AO [n=200]). The primary outcome was prior four weeks' alcohol consumption. Secondary outcomes were frequency of heavy drinking occasions, peak blood alcohol concentration, and number of alcohol-related problems. Mixed linear model analyses revealed significant interaction effects between groups and time points on the primary outcome after 3 and 6months. Compared to students in the AO condition, students in the e-SBI condition reported consuming 4.11 fewer standard drinks during the previous four weeks after 3months, and 4.78 fewer standard drinks after 6months. Mixed results were found on secondary outcomes. The results indicate that evidence on and knowledge of web-based e-SBIs based on US college student samples is transferable to German university students of legal drinking age. However, knowledge of what motivates students to complete programs under voluntary conditions, although rare, is needed.


Ultra-trace determination of methylmercuy in seafood by atomic fluorescence spectrometry coupled with electrochemical cold vapor generation.
A homemade electrochemical flow cell was adopted for the determination of methylmercury. The cold vapor of mercury atoms was generated from the surface of glassycarbon cathode through the method of electrolytic reduction and detected by atomic fluorescence spectroscopy subsequently. The operating conditions were optimized with 2 ng mL(-1) methylmercury standard solution. The caliberation curve was favorably linear when the concentrations of standard HgCH3(+) solutions were in the range of 0.2-5 ng mL(-1)(as Hg). Under the optimized conditions, the limit of detection (LOD) for methylmercury was 1.88×10(-3)ng mL(-1) and the precision evaluated by relative standard deviation was 2.0% for six times 2 ng mL(-1) standard solution replicates. The terminal analytical results of seafood samples, available from local market, showed that the methylmercury content ranged within 3.7-45.8 ng g(-1). The recoveries for methylmercury spiked samples were found to be in the range of 87.6-103.6% and the relative standard deviations below 5% (n=6) were acquired, which showed this method was feasible for real sample analysis.


Nicotine Induces Cardiomyocyte Hypertrophy Through TRPC3-Mediated Ca2+/NFAT Signalling Pathway.
Nicotine is thought to be an important risk factor for the development of cardiovascular diseases. However, the effects of nicotine on cardiomyocyte hypertrophy are poorly understood. The present study was designed to explore the role of nicotine in cardiomyocyte hypertrophy and its underlying mechanism. We used primary cardiomyocytes isolated from Wistar rats to examine the effects of nicotine on intracellular Ca2+ mobilization and hypertrophy determined by immunofluorescence, quantitative polymerase chain reaction, and western blot analysis. A luciferase reporter assay was used to examine the activity of NFAT signalling. We found that nicotine caused cardiomyocyte hypertrophy, which was accompanied by increased intracellular Ca2+. Nicotine-enhanced intracellular Ca2+ concentration ([Ca2+]i) was significantly abolished by store-operated Ca2+ entry (SOCE) and TRPC inhibitors. Knockdown of TRPC3 significantly decreased nicotine-induced SOCE and hypertrophy. Moreover, calcineurin-nuclear factor of activated T cells (NFAT) is involved in TRPC3-mediated Ca2+ signalling and cardiomyocyte hypertrophy. Notably, upregulation of TRPC3 by nicotine requires TRPC3-mediated Ca2+ influx and calcineurin-NFAT signalling activation. Our findings demonstrate that the prohypertrophic effect of nicotine on cardiomyocytes is dependent on enhanced TRPC3 expression through a calcium-dependent regulatory loop, which could become a potential target for prevention and treatment of cardiac hypertrophy.


A case of cutaneous myiasis due to Dermatobia hominis in Japan.
We report the 34th imported case of cutaneous myiasis caused by Dermatobia hominis in Japan, which is not a habitat of the fly. A 41-year-old Japanese man noticed an insect-sting-like papule on his left upper back during his stay in Ecuador in March 2004. After his return home, the lesion gradually increased to become a red subcutaneous nodule with a central pore from which serosanguineous fluid drained. Because antimicrobial treatment under a diagnosis of inflammatory atheroma was ineffective, the lesion was incised and a 3rd instar larva of D. hominis was then found and removed. We checked the literature on D. hominis myiasis reported from Japan, and noted the fact, which nobody had previously pointed out, that in Japan only one case of D. hominis myiasis had been diagnosed correctly before a larva was found, and most of the cases were misdiagnosed and inappropriately treated, including 11 cases given unnecessary resection of the nodules. Doctors in Japan should be aware of myiasis so that patients are neither anxious about the disease nor suffer pain, and doctors avoid performing unnecessary resections of the lesions.


The Effect of Road Traffic Noise on Reaction Time.
Traffic noise is one of the main important sources in urban noise pollution, which causes various physiological and psychological effects that can cause disturbs in performance, sleep disturbances, hearing loss and impact on job performance. This study was conducted to verify the impact of road traffic noise on reaction time in terms of extraversion and sex. Traffic noise was measured and recorded in 10 arterial streets in Tehran, and then the recorded noise was emitted towards participants in an acoustic room. The participants were 80 (40 cases and 40 controls) students. Personality type was determined by Eysenck Personality Inventory (EPI) questioner. Reaction time before and after exposure to traffic noise was measured. Reaction time before exposure to traffic noise did not differ (P=0.437) significantly between introverts and extraverts. However, it was increased significantly in both groups after exposure to traffic noise (P<0.01). Introvert's reaction time was more increased than that of extraverts. Traffic noise augmented reaction time of both males and females. This study also revealed that exposure to traffic noise leads to increase in reaction time.


The pigmentary system of planaria. I. Morphology.
The pigmentary system of the planaria, Dugesia gonocephala s.l. (Platyhelminthes, Turbellaria, Tricladida), has been studied by light and electron microscopy. The system consists of granules contained in chromatophore-like cells embedded in the parenchyma. The cell processes penetrate between the muscle layers and extend to the sub-epidermal basal lamina. The nature of the pigment and the comparative anatomical significance of the chromatophore structure is discussed.


Gliosarcomas: analysis of 11 cases do two subtypes exist?
There are conflicting reports regarding gliosarcomas. The goal of this study is to examine clinical, radiological, surgical and therapeutic aspects of 11 patients with gliosarcoma. Between 1993 and 2001, 11 patients with cerebral gliosarcoma were treated at our Institute. Ten patients underwent surgery and one patient had stereotactic biopsy. Four patients received whole brain radiotherapy with (60)Co, five underwent radiotherapy with LINAC extended 2 cm beyond the edema margins. One patient refused any additional treatment after surgery and one patient was not treated postoperatively for poor clinical conditions (KPS 40). Chemotherapy (temozolomide) was administered to four patients. Four patients had a prevalence of sarcomatous component that corresponded to surgical and radiological aspects similar to meningioma while six patients showed a prevalence of gliomatous component and radiological and surgical aspects similar to those of glioblastomas. Surgical resection was total in six and subtotal in four patients. Patients with prevalent sarcomatous component showed median survival time more prolonged than patients with prevalent gliomatous component (71 +/- 6 weeks vs. 63 +/- 6; P=0.0417). Moreover, the survival rate differed in relation to the therapy: patients treated with multimodality therapy (surgery, radiotherapy and chemotherapy) had a longer survival time than patients treated in single or bimodality. Despite prognosis of gliosarcomas remains poor, a multidisciplinary approach (surgery, radiotherapy and chemotherapy) seems to be associated with slight more prolonged survival times.


Effect of muscle fatigue on the cortical-muscle network: A combined electroencephalogram and electromyogram study.
Electroencephalogram (EEG) and electromyogram (EMG) signals during motion control reflect the interaction between the cortex and muscle. Therefore, dynamic information regarding the cortical-muscle system is of significance for the evaluation of muscle fatigue. We treated the cortex and muscle as a whole system and then applied graph theory and symbolic transfer entropy to establish an effective cortical-muscle network in the beta band (12-30 Hz) and the gamma band (30-45 Hz). Ten healthy volunteers were recruited to participate in the isometric contraction at the level of 30% maximal voluntary contraction. Pre- and post-fatigue EEG and EMG data were recorded. According to the Borg scale, only data with an index greater than 14<19 were selected as fatigue data. The results show that after muscle fatigue: (1) the decrease in the force-generating capacity leads to an increase in STE of the cortical-muscle system; (2) increases of dynamic forces in fatigue leads to a shift from the beta band to gamma band in the activity of the cortical-muscle network; (3) the areas of the frontal and parietal lobes involved in muscle activation within the ipsilateral hemibrain have a compensatory role. Classification based on support vector machine algorithm showed that the accuracy is improved compared to the brain network. These results illustrate the regulation mechanism of the cortical-muscle system during the development of muscle fatigue, and reveal the great potential of the cortical-muscle network in analyzing motor tasks.


Hyperthermia response and thermotolerance capacity of an experimental rat tumour with occluded blood flow.
Thermotolerance in vivo was investigated using the rat fibrosarcoma SSBla. Hyperthermia was administered using water-bath heating, with the tumour blood supply occluded by clamping during the heating procedure. Single-dose heat treatments (10-60 min at 43.5 degrees C) yielded linear dose-response curves, with response evaluated as tumour re-growth delay. In thermotolerance studies split-dose treatments were given in which a single 'priming' treatment of 30 min at 43.5 degrees C was followed 24 or 48 hr later by a variable treatment (10-90 min), again at 43.5 degrees C. Split-dose responses produced generally less uniform results, though the dose-response curves were still approximately linear. Comparison of the slopes of the dose-response curves for single-dose and split-dose treatments gave a 'thermotolerance ratio' (TTR) of 4.09 and 3.45 at 24 and 48-hr intervals respectively. Data analysis using Monte Carlo simulation techniques also suggests that the distribution of tumour sensitivities to a second heat treatment may be considerably broader than the distribution of sensitivities to a first treatment. Uniformity of tumour response to a single heat treatment may therefore conceal a spectrum of capacities for development of thermotolerance amongst individual tumours.


Synthesis and preliminary biological investigations of O-sulphated dermorphin.
Synthesis by a classical solution method of a sulphated analogue of dermorphin is reported. The product has proved to be devoid of any peripheral and central opiate- or CCK-like activity in the tests assayed.


History of successful ballot initiatives--Massachusetts.
In this report, the author traces the Massachusetts campaign for the 1992 referendum Question 1, which raised the cigarette excise tax by 25 cents. Dr. Cady highlights the major features of the 2-year campaign with special emphasis on the need for committed leadership, coalition-building, and expert political guidance.


Naltrexone-buprenorphine interactions: effects on cocaine self-administration.
An opioid mixed agonist-antagonist analgesic, buprenorphine, significantly reduces cocaine self-administration by rhesus monkeys, but the relative contribution of buprenorphine's agonist and antagonist properties to this effect is unclear. This study examined the effects of concurrent treatment with naltrexone, a long-acting mu opioid antagonist, on buprenorphine's effects on cocaine and food self-administration by five rhesus monkeys. Cocaine (0.5 mg/kg per injection) and food self-administration (1 gm banana pellet) were maintained on a second order fixed ratio 4 (FR4) variable ratio (VR) 16:S schedule of reinforcement. Buprenorphine treatment alone (0.40 mg/kg/day) and in combination with ascending doses of naltrexone (0.05, 0.10, 0.20, and 0.40 mg/kg/day) was compared with naltrexone alone (0.40 mg/kg/day) and saline control treatment. Naltrexone was administered simultaneously or 20 minutes before buprenorphine administration. Each treatment condition was in effect for 10 days. Buprenorphine alone significantly reduced cocaine self-administration by an average of 53% in comparison to the saline treatment baseline (p < .01). When saline was substituted for buprenorphine, each monkey rapidly returned to its prebuprenorphine level of cocaine self-administration. Food self-administration in all conditions was equivalent to or significantly higher (p < .05) than food-maintained responding during the saline baseline. When buprenorphine and naltrexone were administered simultaneously, naltrexone significantly attenuated buprenorphine's suppressive effects on cocaine self-administration (p < .05 to .01). When naltrexone was administered 20 minutes before buprenorphine, there was a significant naltrexone dose-dependent (p < .01) decrease in buprenorphine's reduction of cocaine self-administration in comparison to the initial saline baseline. These data suggest that naltrexone antagonizes the partial mu agonist component of buprenorphine, which may be important for buprenorphine's effects on cocaine self-administration. Moreover, the addition of an opioid antagonist to reduce illicit diversion of buprenorphine might also compromise its effectiveness for treatment of dual dependence on cocaine and opiates.


Minimally invasive resection of synchronous thoracic esophageal and gastric carcinomas followed by reconstruction: a case report.
We report on a case of synchronous carcinomas of the esophagus and stomach. A 68-year-old man was referred to our hospital for an abnormality found during his medical examination. Further evaluation revealed squamous cell carcinoma in the thoracic lower esophagus and gastric adenocarcinoma located in the middle third of the stomach. Thoracoscopic esophagectomy in the prone position (TSEP), laparoscopic total gastrectomy (LTG) with three-field lymph node dissection, and laparoscopically assisted colon reconstruction (LACR) were performed. The patient did not have any major postoperative complications. His pathological examination revealed no metastases in 56 harvested lymph nodes and no residual tumor. He was followed up for 30 months without recurrence. To our knowledge, this is the first report of esophageal and gastric synchronous carcinomas that were successfully treated with a combination of TSEP, LTG, and LACR. These operations may be a feasible and appropriate treatment for this disease.


Psychological consequences associated with positive and negative responses to disclosure of sexual assault among college women: a prospective study.
A prospective design was utilized to explore the impact of social reactions to sexual assault disclosure among college women who experienced sexual victimization over a 4-month academic quarter. Women completed baseline, 4- and 7-month assessments of symptomatology, beliefs about why sexual assault occurs, victimization, and social reactions to sexual assault disclosure. Accounting for symptomatology or beliefs reported prior to the assault, positive social reactions were not associated with victims' subsequent symptomatology or beliefs. However, accounting for symptomatology or beliefs reported prior to the assault, higher negative social reactions were associated with victims' post-assault reports of hostility, fear, and beliefs about why sexual assault occurs.


Differential effects of domoic acid and E. coli lipopolysaccharide on tumor necrosis factor-alpha, transforming growth factor-beta1 and matrix metalloproteinase-9 release by rat neonatal microglia: evaluation of the direct activation hypothesis.
The excitatory amino acid domoic acid is the causative agent of amnesic shellfish poisoning in humans. The in vitro effects of domoic acid on rat neonatal brain microglia were compared with E. coli lipopolysaccharide (LPS), a known activator of microglia mediator release over a 4 to 24 hour observation period. LPS [3 ng/mL] but not domoic acid [1 mM] stimulated a statistically significant increase in TNF-alpha mRNA and protein generation. Furthermore, both LPS and domoic acid did not significantly affect TGF-beta1 gene expression and protein release. Finally, an in vitro exposure of microglia to LPS resulted in statistically significant MMP-9 expression and release, thus extending and confirming our previous observations. However, in contrast, no statistically significant increase in MMP-9 expression and release was observed after domoic acid treatment. Taken together our observations do not support the hypothesis that a short term (4 to 24 hours) in vitro exposure to domoic acid, at a concentration toxic to neuronal cells, activates rat neonatal microglia and the concomitant release of the pro-inflammatory mediators tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinases-9 (MMP-9), as well as the anti-inflammatory cytokine transforming growth factor beta1 (TGF-beta1).


Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis.
Necrotizing enterocolitis (NEC), a gastrointestinal inflammatory disease of unknown etiology that may also affect the liver, causes a great deal of morbidity and mortality in premature infants. We tested the hypothesis that signaling molecules, which are endogenous to the bowel, regulate the severity of intestinal and hepatic damage in an established murine NEC model. Specifically, we postulated that mucosal serotonin (5-HT), which is proinflammatory, would exacerbate experimental NEC and that oxytocin (OT), which is present in enteric neurons and is anti-inflammatory, would oppose it. Genetic deletion of the 5-HT transporter (SERT), which increases and prolongs effects of 5-HT, was found to increase the severity of systemic manifestations, intestinal inflammation, and associated hepatotoxicity of experimental NEC. In contrast, genetic deletion of tryptophan hydroxylase 1 (TPH1), which is responsible for 5-HT biosynthesis in enterochromaffin (EC) cells of the intestinal mucosa, and TPH inhibition with LP-920540 both decrease the severity of experimental NEC in the small intestine and liver. These observations suggest that 5-HT from EC cells helps to drive the inflammatory damage to the gut and liver that occurs in the murine NEC model. Administration of OT decreased, while the OT receptor antagonist atosiban exacerbated, the intestinal inflammation of experimental NEC. Data from the current investigation are consistent with the tested hypotheses-that the enteric signaling molecules, 5-HT (positively) and OT (negatively) regulate severity of inflammation in a mouse model of NEC. Moreover, we suggest that mucosally restricted inhibition of 5-HT biosynthesis and/or administration of OT may be useful in the treatment of NEC.NEW & NOTEWORTHY Serotonin (5-HT) and oxytocin reciprocally regulate the severity of intestinal inflammation and hepatotoxicity in a murine model of necrotizing enterocolitis (NEC). Selective depletion of mucosal 5-HT through genetic deletion or inhibition of tryptophan hydroxylase-1 ameliorates, while deletion of the 5-HT uptake transporter, which increases 5-HT availability, exacerbates the severity of NEC. In contrast, oxytocin reduces, while the oxytocin receptor antagonist atosiban enhances, NEC severity. Peripheral tryptophan hydroxylase inhibition may be useful in treatment of NEC.


Infantile convulsion suspected of pyridoxine responsive seizures.
A 6-month-old boy, having suffered repeated convulsive siezures since birth, died of severe epilepsy, the disease remaining unknown. However, when a brother, born after the death of the present case, displayed the same clinical symptoms and was diagnosed clinically as having pyridoxine dependent convulsion, the deceased became suspected of having been a case of familial pyridoxine dependency. Pathologically, bilateral cerebellar hemorrhages were found accompanied by subdural and subarachnoidal hemorrhages. Histologically, neuronal loss and diffuse astrocyte hyperplasia were found in the brain: Beside marginal gliosis, proliferations of astroglia and glial fibers were found, especially in the pons, medulla oblongata, and cervical cord, although the fibrillary gliosis may be representative for a physiological intermediate state. Foamy cells were found in the lymph nodes, but not in the brain. Observed in the kidneys were substances deposited in the glomeruli and Bowman's capsules and materials in the tubular lumen.


PPARgamma: observations in the hematopoietic system.
Human Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) was originally cloned from a human bone marrow library. What role does this ligand activated transcription factor play in hematopoiesis and the immune system? We note that: a) PPARgamma has potential to interact/interfere or synergize with retinoid biology, b) fatty acids and a prostaglandin have been identified as ligands, and c) lymphocytes, monocytes and neutrophils use fatty acids as a major source of energy production, d) PPARgamma has been shown to oppose TNFalpha and down regulate cytokine production in monocytes. Therefore, we undertook a review of the literature and an expression survey of PPARgamma in a number of major organs and cells involved in the hematopoietic system, for the purpose of building a database towards understanding the role and function of PPARgamma gene regulation in the developing blood and immune systems. PPARgamma is expressed before mesodermal induction in tissue in and around Speymann's organizer in the xenopus blastocyst, in erythroid precursors of blood islands and in the circulation of the day 10.0 murine embryo, in human 19 week fetal liver, in some but not all murine and human bone marrow erythroid, myeloid, and monocytoid progenitors, bone marrow stromal cells and adipocytes, osteoblasts, endothelial cells, some T, and B lymphocytes, monocytes, macrophages, and other monocytic derivatives. It can be found in the cells of Peyer's patches, lymphoid follicles, spleen, and thymus. It is not clear if it is ever or transiently expressed in megakaryocytes, mast cells, or neutrophils. Based on the above data and a review of the literature, PPARgamma seems to play a role during the elicitation of immune responses. We propose PPARgamma may be involved in changes in energy states required during activation and development of many cell types involved, and has additional immunologically relevant effects in erythroid, myeloid, monocytic, T and B lymphocytic, stromal, and endothelial cell function.


MicroRNA-451a acts as tumor suppressor in cutaneous basal cell carcinoma.
Basal cell carcinoma (BCC) is the most common type of skin cancer. The underlying mechanism leading to BCC formation is not fully uncovered. The aim of this study was to characterize miRNA-451a as a novel tumor suppressor in cutaneous BCC. We first evaluated miRNA-451a level in human BCC clinical tissues and inducible BCC mouse model. Then we studied the impact of overexpressing or inhibiting miR-451a in cell proliferation, colony formation potential, and cell cycle pattern. Next, we employed luciferase reporter assay and western blotting to evaluate TBX1 as a downstream target of miRNA-451a. Lastly, we confirmed TBX1 expressional change in BCC tissues by qPCR. miRNA-451a was significantly reduced in human BCC tissues. The downregulation of miRNA-451a was also confirmed in BCC mouse model. Overexpressing miRNA-451a in tumor cells markedly suppressed cell growth through G1 cell cycle arrest. However, inhibiting miRNA-451a in primary cells promoted cell growth and colony formation capacity. TBX1 (602054) was predicted as a downstream target of miRNA-451a and this was confirmed by luciferase assay and protein expression. Finally, TBX1 level was shown upregulated in BCC tissues as inversely to miR451a. Our studies revealed that miRNA-451a/TBX1 axis played a pivotal role in BCC tumorigenesis.


Progress in targeting HIV-1 entry.
Current HIV entry inhibitors target the binding of the viral envelope glycoprotein gp120 to cellular CD4 and co-receptors, or block a late stage of the fusogenic activation of adjacent gp41. New targets are suggested by the role of cell surface protein disulfide isomerase (PDI), which attaches to the primary receptor CD4 close to the gp120-binding site. This could enable PDI to reduce gp120 disulfide bonds, which triggers the major conformational changes in gp120 and gp41 required for virus entry. Inhibiting cell surface PDI prevents HIV-1 entry. The new potential targets outlined are PDI activity as well as the sites of PDI-CD4 and PDI-gp120 interaction.


Analysis of neuroreceptor PET-data based on cytoarchitectonic maximum probability maps: a feasibility study.
Three-dimensional maximum probability maps (MPMs) of cytoarchitectonically defined cortical regions based on postmortem histological studies have recently been made available in the stereotaxic reference space of the Montreal Neurological Institute (MNI) single subject template. This permits the use of cytoarchitectonic maps for the analysis of functional in vivo datasets, including neuroreceptor positron emission tomography (PET) studies. In this feasibility study, we used 5-hydroxytryptamine 2A (5-HT2A) receptor PET to test the applicability of maximum cytoarchitectonic probability maps for quantitative analysis. As the outcome parameter, we extracted local distribution volume ratios (DVRs) from 19 cytoarchitectonically defined volumes of interest (VOIs) per hemisphere from five healthy subjects. The experimental design included a forward ('PET to atlas' normalization) and a backward ('atlas to PET' normalization) procedure to double-check the stability of transformation and overlay. Resulting DVRs were compared with receptor densities (RDs) obtained from postmortem [3H]ketanserin autoradiography of multiple areas. Correlations between the bi-directional normalization procedures (r = 0.89; 38 VOIs) as well as between in vivo and vitro data (nine VOIs; r = 0.64 and r = 0.47 for forward and backward procedure, respectively) suggest that the implementation of cytoarchitectonic maximum probability maps is a promising method for an accurate and observer-independent analysis of neuroreceptor PET data.


Bioinorganic supramolecular coordination complexes and their biomedical applications.
The field of Bioinorganic Supramolecular Chemistry is an emerging research area including metal-based supramolecules resulting from coordination-driven self-assembly (CDSA), whereby metal ions and organic ligands can be easily linked by metal-ligand bonds via Lewis' acid/base interactions. The focus of this 'In a Nutshell' review will be on the family of supramolecular coordination complexes, discrete entities formed by CDSA, which have recently captured widespread attention as a new class of versatile multifunctional materials with broad biological applications including molecular recognition, biosensing, therapy, imaging and drug delivery. Herein, we provide a summary of the state-of-the-art use of these systems in biomedicine, with some selected representative examples, as well as our visions of the challenges and possible directions in the field.


Measurement of human cervical compliance.
A critical evaluation of the various methods for the measurement of the compliance of the human cervix uteri was made. The resistance of this tissue to a dilating force was measured by a previously constructed strain gauge instrument equipped with exchangeable Pratt cervical dilators. The dilating resistance offered by the cervical canal was recorded on a polygraph at a constant paper speed. Control experiments in which the dilating instrument was allowed to meet artificial cellulose tissue showed that the peak value recorded was of importance for estimating cellulose tissue resistance. Measurements of the area under the curve were shown to be of minor importance in this system. Using this technique in clinical applications, it was also shown that peak resistance provides the most accurate measurement of human cervical resistance.


A comparative study of 2-deoxyglucose patterns of glomerular activation in the olfactory bulbs of C57 BL/6J and AKR/J mice.
We have studied the patterns of glomerular activation evoked in the olfactory bulbs of C57BL/6J and AKR/J mice by olfactory stimulations with amyl acetate or isovaleric acid. Patterns of glomerular activation were obtained with the 2-deoxyglucose method and subsequently compared using a computer-assisted image analysis. The mice of both inbred strains stimulated with amyl acetate or isovaleric acid were characterized by areas of high 2-deoxyglucose uptake in their glomerular layer. Statistical comparisons of the patterns demonstrated that they were odor-specific. Although C57BL/6J mice have been found to be specifically anosmic to isovaleric acid, our findings indicate that their olfactory system is topographically activated by olfactory stimulations with this odorant. However, patterns of glomerular activity evoked by isovaleric acid stimulations are not similar in the two studied strains.


Mothers' willingness to accept and pay for vaccines to their children in western Iran: a contingent valuation study.
The clients' willingness to accept (WTA) and willingness to pay (WTP) for a given good or service can help elicit the monetary value of that good or service. This study aims to assess the WTA and WTP of mothers attending primary health centers for vaccines to their children during 2019 in Kermanshah city, western Iran. We conducted a cross-sectional study on a total of 667 mothers attending primary health centers for vaccines to their children aged two to 18 months. A multistage sampling technique was employed to involve the mothers in the study, and data were collected using a self-administrated open-ended questionnaire. The multivariate linear regression model was used to identify the factors associated with the mothers' WTP and WTA for vaccines to their children. The study indicated that 94.2 and 93.1% of the mothers respectively had WTA and WTP values greater than zero, with their corresponding mean values of US$ 6.8 and US$ 4.4. The mothers in the higher monthly household income category, mothers born in the urban areas, and being a female child showed statistically significant positive associations with the mothers' WTA for the vaccines. While there was a statistically significant positive relationship between monthly household income and the mothers' WTP; a statistically significant negative relationship exists between the mothers' age and their WTP for the vaccine to their children. The findings indicated the mothers' WTA to WTP ratio of greater than one for the vaccines to their children. The most important factor associated with the mothers' WTA and WTP was the monthly household income. Thus, improving the socio-economic standards of women in the study area might contribute to reinforcing their immunization services seeking behavior to their children.


Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi's sarcoma-associated herpesvirus infection.
Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with B-cell lymphomas including primary effusion lymphoma and multicentric Castleman's disease. KSHV establishes latency within B cells by modulating or mimicking the antiapoptotic Bcl-2 family of proteins to promote cell survival. Our previous BH3 profiling analysis, a functional assay that assesses the contribution of Bcl-2 proteins towards cellular survival, identified two Bcl-2 proteins, cellular Mcl-1 and viral KsBcl-2, as potential regulators of mitochondria polarization within a latently infected B-cell line, Bcbl-1. In this study, we used two novel peptide inhibitors identified in a peptide library screen that selectively bind KsBcl-2 (KL6-7_Y4eK) or KsBcl-2 and Mcl-1 (MS1) in order to decipher the relative contribution of Mcl-1 and KsBcl-2 in maintaining mitochondrial membrane potential. We found treatment with KL6-7_Y4eK and MS1 stimulated a similar amount of cytochrome c release from mitochondria isolated from Bcbl-1 cells, indicating that inhibition of KsBcl-2 alone is sufficient for mitochondrial outer membrane permiabilzation (MOMP) and thus apoptosis during a latent B cell infection. In turn, this study also identified and provides a proof-of-concept for the further development of novel KsBcl-2 inhibitors for the treatment of KSHV-associated B-cell lymphomas via the targeting of latently infected B cells.


A designed heme-[4Fe-4S] metalloenzyme catalyzes sulfite reduction like the native enzyme.
Multielectron redox reactions often require multicofactor metalloenzymes to facilitate coupled electron and proton movement, but it is challenging to design artificial enzymes to catalyze these important reactions, owing to their structural and functional complexity. We report a designed heteronuclear heme-[4Fe-4S] cofactor in cytochrome c peroxidase as a structural and functional model of the enzyme sulfite reductase. The initial model exhibits spectroscopic and ligand-binding properties of the native enzyme, and sulfite reduction activity was improved-through rational tuning of the secondary sphere interactions around the [4Fe-4S] and the substrate-binding sites-to be close to that of the native enzyme. By offering insight into the requirements for a demanding six-electron, seven-proton reaction that has so far eluded synthetic catalysts, this study provides strategies for designing highly functional multicofactor artificial enzymes.


Submillimeter resolution CT scanning of orbital diseases.
continuous improvement in image quality produced by CT scanning has occurred since 1972 when the resolution element of the new EMI scanner was 3.0 X 3.0 X 12 mm. We are now working with a fourth generation machine with a resolution element of 0.75 X 0.75 X 2.0 mm. This hundred fold improvement in spatial resolution has had important clinical impact in analyzing diseases of the orbit.


Differential responses of tiger swallowtail subspecies to secondary metabolites from tulip tree and quaking aspen.
Two subspecies of the eastern tiger swallowtail butterfly, Papilio glaucus, exhibit reciprocal inabilities to survive and grow on each other's preferred foodplant. P. g. canadensis R. & J. performs well on quaking aspen (Populus tremuloides Michx.) but not on tulip tree (Liriodendron tulipifera L.); P. g. glaucus L. performs well on tulip tree but not on quaking aspen. This study was designed to test the hypothesis that secondary metabolites in tulip tree and quaking aspen are responsible for these differential utilization abilities. We extracted and fractionated leaf constituents into different chemical classes, applied them to a mutually acceptable diet (black cherry, Prunus serotina, leaves), and bioassayed them against neonate larvae (survival) and penultimate instar larvae (survival, growth, digestibility and conversion efficiencies). For each plant species, one fraction in particular showed activity against the unadapted subspecies. One tulip tree fraction dramatically reduced survival of P. g. canadensis neonates, and reduced consumption rates, growth rates, and ECI's of fourth instar larvae. The tulip tree constituents most likely responsible for these effects are sesquiterpene lactones. One quaking aspen fraction greatly lowered survival of P. g. glaucus neonates, and decreased survival, consumption rates, growth rates and ECD's of fourth instar larvae. The compounds responsible for these results are probably simple phenols or phenolic glycosides. Surprisingly, P. g. glaucus and P. g. canadensis showed slightly poorer performance on the active tulip tree and quaking aspen fractions, respectively, indicating that even adapted insects incur a metabolic cost in the processing of their host's phytochemicals.


Technetium-99m scintigraphy to visualize T-cell homing in vivo: a preclinical study.
The knowledge of lymphocyte distribution is very usefulness in monitoring therapeutic treatments. We present here a method employed in clinical practice, the scintigraphy, to study in the rat the physiologic lymphocyte traffic. Rat T cells labeled with 99mTc were injected in syngeneic animals, and their fate was studied by serial scintigraphic scanning. Sorted naïve CD4+ CD45RC(bright) T cells homed to lymphoid organs and accumulated in spleen. CD4+ CD45RC(dim) memory lymphocytes first reached the liver and the lungs and recirculated. The results obtained by using the scintigraphic method to in vivo study the lymphocyte homing in rats are comparable to those obtained with previously used experimental methods. We consider the scintigraphic method a useful tool to in vivo track lymphocytes and to address therapeutic treatment in men.