A multiple-scale perturbation approach to mode coupling in periodic plates.
In this paper, guided ultrasonic wave propagation is analyzed in an elastic plate with sinusoidal surface corrugations. The corrugated area acts as a finite-length grating which corresponds to a 1-D phononic crystal (PC). The multiple-scale perturbation technique is used to derive coupled-mode equations describing the amplitudes of interacting modes. These equations are solved exactly for the two-point boundary-value problem of the PC. The study involves the coupling of the incident symmetric Lamb wave S(0) to the reflected antisymmetric Lamb wave A(0). The influences of the depth of corrugation and length of the PC are studied. Theoretical results are compared with experimental measurements.


Rainbows by elliptically deformed drops. I. Möbius shift for high-order rainbows.
Using ray theory, the Möbius shift of the (p-1)-order rainbow angle for a particle having an elliptical cross section is obtained to first order in the ellipticity as a function of the tilt of the ellipse with respect to the propagation direction of the incoming rays. The result is then adapted to the geometry of scattering of light rays from the sun by a falling water drop as a function of sun height angle. The variation in the angular spacing between the supernumeraries is determined as a function of location along the rainbow arc, the conditions under which the rainbow angle is insensitive to drop flattening were determined, and the dependence of the Möbius shift on the drop refractive index is shown for rainbows up to fourth order (p=5).


Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ.
γ-Secretase inhibitors have been considered promising drug candidates against Alzheimer's disease (AD) due to their ability to reduce amyloid-β (Aβ) production. However, clinical trials have been halted due to lack of clinical efficacy and/or side effects. Recent in vitro studies suggest that low doses of γ-secretase inhibitors may instead increase Aβ production. Using a stem cell-derived human model of cortical neurons and low doses of the γ-secretase inhibitor DAPT, the effects on a variety of Aβ peptides were studied using mass spectrometry. One major focus was to develop a novel method for specific detection of oligomeric Aβ (oAβ), and this was used to study the effects of low-dose γ-secretase inhibitor treatment on intracellular oAβ accumulation. Low-dose treatment (2 and 20nM) with DAPT increased the secretion of several Aβ peptides, especially Aβx-42. Furthermore, using the novel method for oAβ detection, we found that 2nM DAPT treatment of cortical neurons resulted in increased oAβ accumulation. Thus, low dose-treatment with DAPT causes both increased production of long, aggregation-prone Aβ peptides and accumulation of intracellular Aβ oligomers, both believed to contribute to AD pathology.


Nutritional supplementation for hip fracture aftercare in older people.
Fractures of the hip are an important cause of later ill health and mortality in older people. People with hip fractures are often malnourished at the time of fracture, and have poor food intake in hospital. This review assesses the effects of nutritional interventions in older people recovering from hip fracture. We searched the Cochrane Musculoskeletal Injuries Group Specialised Register, the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 3, 2004), MEDLINE (1966 to October week 1 2004), Nutrition Abstracts and Reviews, EMBASE, BIOSIS, CINAHL, HEALTHSTAR, the National Research Register and reference lists. We contacted investigators and handsearched four nutrition journals. Randomised and quasi-randomised trials of nutritional interventions for mainly older people (aged over 65 years) with hip fracture. Both authors independently selected trials, extracted data and assessed trial quality. We sought additional information from all trialists, and pooled data for primary outcomes. Eighteen randomised trials involving 1306 participants were included. Overall trial quality was poor; specifically in terms of allocation concealment, assessor blinding and intention-to-treat analysis. This, and the limited availability of outcome data, mean that the following results must be interpreted with caution. Eight trials evaluated oral multinutrient feeds: these provided non-protein energy, protein, some vitamins and minerals. Oral feeds had no statistically significant effect on mortality (15/161 versus 17/176; relative risk (RR) 0.89, 95% confidence interval (CI) 0.47 to 1.68) but may reduce 'unfavourable outcome' (combined outcome of mortality and survivors with complications) (14/66 versus 26/73; RR 0.52, 95% CI 0.32 to 0.84). Four trials examining nasogastric multinutrient feeding showed no evidence of an effect on mortality (RR 0.99, 95% CI 0.50 to 1.97), but the studies were heterogeneous regarding case mix. There was insufficient information for other outcomes. The specific effect of protein given in an oral feed was tested in three trials. There was no evidence for an effect on mortality (RR 1.38, 95% CI 0.82 to 2.34). Protein supplementation may have reduced the number of long term complications and days spent in rehabilitation wards. Two trials, testing intravenous thiamin (vitamin B1) and other water soluble vitamins, or 1-alpha-hydroxycholecalciferol (an active form of vitamin D) respectively, produced no evidence of effect for either vitamin supplement. While some evidence exists for the effectiveness of oral protein and energy feeds, overall the evidence for the effectiveness of nutritional supplementation remains weak. Future trials are required which overcome the defects of the reviewed studies, particularly inadequate size, methodology and outcome assessment.


Dyslipidemias and stroke prevention: Recommendations of the Study Group of Cerebrovascular Diseases of the Spanish Society of Neurology.
We present an update of the Spanish Society of Neurology's recommendations for prevention of both primary and secondary stroke in patients with dyslipidaemia. We performed a systematic review to evaluate the main aspects of the management of dyslipidaemias in primary and secondary stroke prevention and establish a series of recommendations. In primary prevention, the patient's vascular risk should be determined in order to define target values for low-density lipoprotein cholesterol. In secondary prevention after an atherothrombotic stroke, a target value <55 mg/dL is recommended; in non-atherothombotic ischaemic strokes, given the unclear relationship with dyslipidaemia, target value should be established according to the vascular risk group of each patient. In both primary and secondary prevention, statins are the drugs of first choice, and ezetimibe and/or PCSK9 inhibitors may be added in patients not achieving the target value.


Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease.
The molecular mechanisms behind human liver disease progression to cirrhosis remain elusive. Nuclear receptor small heterodimer partner (SHP/Nr0b2) is a hepatic tumor suppressor and a critical regulator of liver function. SHP expression is diminished in human cirrhotic livers, suggesting a regulatory role in human liver diseases. The goal of this study was to identify novel SHP-regulated genes that are involved in the development and progression of chronic liver disease. To achieve this, we conducted the first comprehensive RNA sequencing (RNA-seq) analysis of Shp(-/-) mice, compared the results with human hepatitis C cirrhosis RNA-seq and nonalcoholic steatohepatitis (NASH) microarray datasets, and verified novel results in human liver biospecimens. This approach revealed new gene signatures associated with chronic liver disease and regulated by SHP. Several genes were selected for validation of physiological relevance based on their marked upregulation, novelty with regard to liver function, and involvement in gene pathways related to liver disease. These genes include peptidoglycan recognition protein 2, dual specific phosphatase-4, tetraspanin 4, thrombospondin 1, and SPARC-related modular calcium binding protein-2, which were validated by qPCR analysis of 126 human liver specimens, including steatosis, fibrosis, and NASH, alcohol and hepatitis C cirrhosis, and in mouse models of liver inflammation and injury. This RNA-seq analysis identifies new genes that are regulated by the nuclear receptor SHP and implicated in the molecular pathogenesis of human chronic liver diseases. The results provide valuable transcriptome information for characterizing mechanisms of these diseases.


A High Stability Time Difference Readout Technique of RTD-Fluxgate Sensors.
The performance of Residence Times Difference (RTD)-fluxgate sensors is closely related to the time difference readout technique. The noise of the induction signal affects the quality of the output signal of the following circuit and the time difference detection, so the stability of the sensor is limited. Based on the analysis of the uncertainty of the RTD-fluxgate using the Bidirectional Magnetic Saturation Time Difference (BMSTD) readout scheme, the relationship between the saturation state of the magnetic core and the target (DC) magnetic field is studied in this article. It is proposed that combining the excitation and induction signals can provide the Negative Magnetic Saturation Time (NMST), which is a detection quantity used to measure the target magnetic field. Also, a mathematical model of output response between NMST and the target magnetic field is established, which analyzes the output NMST and sensitivity of the RTD-fluxgate sensor under different excitation conditions and is compared to the BMSTD readout scheme. The experiment results indicate that this technique can effectively reduce the noise influence. The fluctuation of time difference is less than ±0.1 μs in a target magnetic field range of ±5 × 10⁴ nT. The accuracy and stability of the sensor are improved, so the RTD-fluxgate using the readout technique of high stability time difference is suitable for detecting weak magnetic fields.


Glycosaminoglycans in nerve injury: 1. Low doses of glycosaminoglycans promote neurite formation.
This study has shown that glycosaminoglycans added to the culture medium may affect neurite formation in SH-SY5Y neuroblastoma cells. The most effective glycosaminoglycans are heparin and COS 8, a preparation with low anticoagulant activity. Promotion of neuritogenesis was remarkable at concentrations as low as 10(-8) and 10(-10). When added at 10(-4) M both agents are inhibitory. Chondroitin-4 sulfate, dermatan sulfate, and heparan sulfate were also effective, the doses required were, however, as high as 10(-4) M for promoting and 10(-4) M for inhibiting neuritogenesis. Thereby low doses of glycosaminoglycans promote, while higher doses inhibit neurite formation. The effects were observed when neuritogenesis was promoted in neuroblastoma cultures either by deprivation of serum or by addition of retinoic acid, in the former case neuritogenesis occurred within 48 hr; in the latter, in 14 days. PC12 pheochromocytoma cells neuritogenesis was triggered by adding NGF to the culture medium. We have also observed that glycosaminoglycan supplementation to the culture medium lowered the quantity of NGF required to form neurites by PC12 cells. Glycosaminoglycans at the dose of 10(-8) M allow the formation of PC12 neurites even in presence of 1 ng/ml NGF, a dose that normally is ineffective.


Association between Dietary Intake and Lipid-Lowering Therapy: Prospective Analysis of Data from Australian Diabetes, Obesity, and Lifestyle Study (AusDiab) Using a Quantile Regression Approach.
Lipid-lowering therapy (LLT) should be accompanied by dietary guidance for cardiovascular risk reduction; however, current evidence suggests sub-optimal dietary behaviors in those on LLT. We examined the associations between the dietary intake of key food groups (vegetables, fruit, cereal, protein, and dairy) and LLT use in Australian adults using quantile regression. We used data from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), a prospective population-based study of adults aged ≥25 years, conducted over 5 years (1999-2005). Measurements included a 121-item food frequency questionnaire and LLT use. LLT use was categorized as: LLT users (n = 446), commenced LLT (n = 565), ceased LLT (n = 71), and non-users (n = 4813). Less than 1% of the cohort met recommended intakes of all food groups at the baseline and follow up. The median daily dietary intake at the follow up among LLT users was 2.2 serves of vegetables, 1.4 serves of fruit, 2.8 serves of cereal, 2.0 serves of protein, and 1.4 serves of dairy. Adjusted analysis showed no differences across the quantiles of intake of key food groups in LLT users and commenced LLT compared to non-users. The LLT medication status is not associated with any difference in meeting recommended intakes of key foods.


Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease.
The neuroprotective effect of autophagy activation by rapamycin and trehalose was studied in a mouse model of Parkinson's disease (PD) induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both rapamycin (10 mg/kg/day, 7 days) and trehalose (2% in drinking water, 7 days) increased the expression of LC3-II (a marker of autophagy activation) in the frontal cortex and striatum of normal C57Bl/6J mice, with signs of an additive effect. Autophagy stimulation in the striatum was confirmed by a lysosomal osmotic test. In the model of MPTP-induced PD, the two drugs were applied starting from the 2nd day after subchronic daily MPTP administration (20 mg/kg/day, 4 days). A marked increase in LC3-II expression in the striatum was detected under the action of trehalose and in the S. nigra after combined treatment with rapamycin and trehalose. The drugs had a positive effect for recovery of dopaminergic neurons and neuroprotection after MPTP-induced PD-like injury. The therapeutic effect was proven by active restoration of tyrosine hydroxylase (TH) content in the striatum and S. nigra and by improved cognition measured by the passive avoidance learning task. The results revealed the additive effect of the combined treatment with rapamycin and trehalose on dopaminergic deficits (according to the levels of TH expression in the nigrostriatal system) but not on the behavioral performance in the mouse PD model. Thus, the autophagy activation through different pathways by the combination of rapamycin and trehalose reverses both neuronal dopaminergic and behavioral deficits in vivo and seems to be a promising therapy for PD-like pathology.


Impact of Removal of Lymph Nodes on Survival in Stage I-III Gastric Signet-Ring Cell Cancer: The More, the Better?
There is an ongoing debate over the prognostic value of the number of examined lymph nodes (ELNs) in cases of gastric signet-ring cell cancer (GSRCC). In this study, we sought to evaluate the correlation between the number of ELNs and the prognosis of GSRCC and identify the optimal number of ELNs. A total of 1020 patients diagnosed with GSRCC between 2011 and 2018 in the National Cancer Center database were identified. Clinicopathological characteristics were retrospectively collected, and optimal cutoff values of ELNs were calculated by using X-tile. The impact of different ELNs on overall survival (OS) was compared by using Kaplan-Meier curves. We used univariate and multivariate Cox and subgroup analyses to explore the relationship between ELNs and OS. Furthermore, nonlinear correlations were investigated by using restricted cubic splines (RCSs). X-tile showed that the optimal cutoff value of ELNs was 22. The 5-year OS was higher for patients with ELNs > 22 (vs. ELNs ≤ 22, 66.9% vs. 74.9%, P = 0.026). Multivariate Cox analyses showed that high ELNs were associated with superior OS (hazard ratio = 0.56, 95% confidence interval 0.43-0.74, P < 0.001). In subgroup analyses, the significant association between tumor size > 4 cm, and TNM III stage was still observed. The RCS regression model showed a U-shaped dose-response nonlinear relationship between ELNs and OS; the inflection point, as well as the lowest risk points, corresponded to 44-52 ELNs. A U-shaped, nonlinear correlation with inflection points of 44-52 ELNs between ELNs and prognosis in GSRCC was identified.


Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism.
We analyzed survival effects for 15 different pairs of clinically relevant anti-cancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy™ II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.


Racial differences in heart failure therapeutics.
Heart failure in African Americans has a phenotype that is distinct from that in non-African Americans and that demonstrates increased importance of hypertensive etiologies. Trial data demonstrate that African Americans receive significant benefit from beta blockade. Despite differences in the heart failure phenotype, therapy of heart failure in African Americans remains largely the same as in white heart failure cohorts, with the notable exception of the added benefits provided by combination of hydralazine and isosorbide dinitrate (HYD-ISDN), now regarded as highly indicated therapy by both the Heart Failure Society of America and the American College of Cardiology/American Heart Association heart failure guideline committees. HYD-ISDN in fixed combination is the first cardiovascular drug approved for a single ethnic or racial subset--self-designated African Americans.


Data value and care value in the practice of health systems: A case study in Uganda.
In anthropology, interest in how values are created, maintained and changed has been reinvigorated. In this case study, we draw on this literature to interrogate concerns about the relationship between data collection and the delivery of patient care within global health. We followed a pilot study conducted in Kayunga, Uganda that aimed to improve the collection of health systems data in five public health centres. We undertook ethnographic research from July 2015 to September 2016 in health centres, at project workshops, meetings and training sessions. This included three months of observations by three fieldworkers; in-depth interviews with health workers (n = 15) and stakeholders (n = 5); and six focus group discussions with health workers. We observed that measurement, calculation and narrative practices could be assigned care-value or data-value and that the attempt to improve data collection within health facilities transferred 'data-value' into health centres with little consideration among project staff for its impact on care. We document acts of acquiescence and resistance to data-value by health workers. We also describe the rare moments when senior health workers reconciled these two forms of value, and care-value and data-value were enacted simultaneously. In contrast to many anthropological accounts, our analysis suggests that data-value and care-value are not necessarily conflicting. Actors seeking to make changes in health systems must, however, take into account local forms of value and devise health systems interventions that reinforce and enrich existing ethically driven practice.


Emerging strategies to overcome resistance to endocrine therapy for breast cancer.
Endocrine therapy of breast cancer is perhaps the oldest form of effective and well-tolerated targeted cancer systemic treatment, in both the adjuvant and metastatic disease settings. The most commonly used endocrine therapy agents are selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor downregulators. De novo or acquired resistance to these agents is a significant clinical problem. Preclinical and clinical investigations to understand this resistance have yielded significant advances in understanding cell signaling and the possible mechanisms of resistance. These mechanisms of resistance are as diverse as the biology of breast cancer and can arise from alterations in any of the cell signaling pathway components. A growing understanding of these mechanisms has provided rationale for development of strategies to overcome the resistance. Many of these mechanisms of resistance involve adaptive upregulation of alternate signaling pathways, such as growth factor signaling, and cross talk between estrogen receptor and growth factor signaling. Clinical trials are focusing on cotargeting these alternate pathways along with estrogen receptor signaling. It is becoming evident that, as with all cancer therapy, strategies to overcome resistance need to be individualized, and it is important to identify biomarkers to guide the use of these strategies. This manuscript systemically reviews the recent preclinical and clinical trials on the novel and pathway-driven agents that have shown significant promise in enhancing the efficacy and overcoming the resistance in the hormonal treatment of breast cancer. Future directions including biomarker selection and the role of next generation sequencing will be discussed.


Aerosol penetrance: a sensitive index of peripheral airways obstruction.
Early injury of the small airways has been demonstrated in asymptomatic smokers. Ventilatory tests including the maximum midexpiratory flow rate and closing volume have been useful in clinical detection of small airways disease in symptomatic subjects. In the present study, airway "obstruction" was assessed aerodynamically by gamma camera measurements of chest radioactivity following the inhalation of 131I-labeled aerosol (aerodynamic mass median diameter 3 mum). Studies were performed in normal subjects, asymptomatic smokers, and patients with chronic obstructive lung disease. An aerosol penetrance index (AeP) was devised from determinations which involved 1) an analysis of central (inner zone) and peripheral (outer zone) deposition of aerosol in the lung and 2) a ratio of initial counts to 24-h counts in the periphery (outer zone) of the lung. AeP values were 41.5 +/- 11.5 for the normal group, 20.9 +/- 7.6 for the smoker group, and 10.6 +/- 5.2 for the subjects with chronic obstructive airway disease. AeP was significantly reduced in the smokers indicating that the AeP is a sensitive index of early peripheral airways obstruction.


SARS-COV-2 induced Diarrhea is inflammatory, Ca 2+ Dependent and involves activation of calcium activated Cl channels.
Diarrhea occurs in 2-50% of cases of COVID-19 (∼8% is average across series). The diarrhea does not appear to account for the disease mortality and its contribution to the morbidity has not been defined, even though it is a component of Long Covid or post-infectious aspects of the disease. Even less is known about the pathophysiologic mechanism of the diarrhea. To begin to understand the pathophysiology of COVID-19 diarrhea, we exposed human enteroid monolayers obtained from five healthy subjects and made from duodenum, jejunum, and proximal colon to live SARS-CoV-2 and virus like particles (VLPs) made from exosomes expressing SARS-CoV-2 structural proteins (Spike, Nucleocapsid, Membrane and Envelope). Results: 1) Live virus was exposed apically for 90 min, then washed out and studied 2 and 5 days later. SARS-Cov-2 was taken up by enteroids and live virus was present in lysates and in the apical>>basolateral media of polarized enteroids 48 h after exposure. This is the first demonstration of basolateral appearance of live virus after apical exposure. High vRNA concentration was detected in cell lysates and in the apical and basolateral media up to 5 days after exposure. 2) Two days after viral exposure, cytokine measurements of media showed significantly increased levels of IL-6, IL-8 and MCP-1. 3) Two days after viral exposure, mRNA levels of ACE2, NHE3 and DRA were reduced but there was no change in mRNA of CFTR. NHE3 protein was also decreased. 4) Live viral studies were mimicked by some studies with VLP exposure for 48 h. VLPs with Spike-D614G bound to the enteroid apical surface and was taken up; this resulted in decreased mRNA levels of ACE2, NHE3, DRA and CFTR. 4) VLP effects were determined on active anion secretion measured with the Ussing chamber/voltage clamp technique. S-D614G acutely exposed to apical surface of human ileal enteroids did not alter the short-circuit current (Isc). However, VLPS-D614G exposure to enteroids that were pretreated for ∼24 h with IL-6 plus IL-8 induced a concentration dependent increase in Isc indicating stimulated anion secretion, that was delayed in onset by ∼8 min. The anion secretion was inhibited by apical exposure to a specific calcium activated Cl channel (CaCC) inhibitor (AO1) but not by a specific CFTR inhibitor (BP027); was inhibited by basolateral exposure to the K channel inhibit clortimazole; and was prevented by pretreatment with the calcium buffer BAPTA-AM. 5) The calcium dependence of the VLP-induced increase in Isc was studied in Caco-2/BBe cells stably expressing the genetically encoded Ca2+ sensor GCaMP6s. 24 h pretreatment with IL-6/IL-8 did not alter intracellular Ca2+. However, in IL-6/IL-8 pretreated cells, VLP S-D614G caused appearance of Ca 2+ waves and an overall increase in intracellular Ca 2+ with a delay of ∼10 min after VLP addition. We conclude that the diarrhea of COVID-19 appears to an example of a calcium dependent inflammatory diarrhea that involves both acutely stimulated Ca2+ dependent anion secretion (stimulated Isc) that involves CaCC and likely inhibition of neutral NaCl absorption (decreased NHE3 protein and mRNA and decreased DRA mRNA).


Nonequilibrium self-assembly of linear fibers: microscopic treatment of growth, decay, catastrophe and rescue.
Many of the large structures of cells are constructed from fibers. These fibers self-assemble from individual proteins in a far-from-equilibrium fashion. Nonequilibrium self-assembly results in a highly dynamic process at the subcellular level that can be regulated and tuned to carry out many of the biological functions of the cell: growth, division and locomotion. We construct and analyze a nonequilibrium model of the dynamic end of a biological fiber that possesses site-resolved resolution. We solve for the steady states of this nonequilibrium system using a variational method. The results are compared to exact numerical solutions for systems with modest size. Using an effective reaction coordinate, we construct an effective potential from the steady-state distribution. The stochastic transitions of the system can be analyzed in this representation. We then apply this method to model microtubule systems. Predictions for macroscopic catastrophe, rescue and dynamic instability in the steady states are analyzed. We find that the length of the cap of the microtubule is small. The relations between the catastrophe/rescue rate and the growth rate are also discussed.


Oxaprozin: kinetic and dynamic profile in the treatment of pain.
Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal anti-inflammatory drug (NSAID) which is effective in models of inflammation, pain and pyrexia. It is effective and well tolerated in the clinical management of adult rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis, soft tissue disorders and post operative dental pain. Oxaprozin has a high oral bioavailability (95%), with peak plasma concentrations at 3 to 5 hours after dosing. It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes. Oxaprozin's strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder, since it exhibits actions such as inhibition of COX-1 and COX-2 isoenzymes, inhibition of nuclear translocation of NF-kappaB and of metalloproteases, and modulates the endogenous cannabinoid system. This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain, in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period. Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain. Oxaprozin and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF-36 quality of life component. The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti-rheumatic agents such as aspirin, diclofenac, ibuprofen, indomethacin etc. in several different painful musculoskeletal conditions.


Validation of a quantitative trait locus for the white-core expression rate of grain on chromosome 6 in a brewing rice cultivar and development of DNA markers for marker-assisted selection.
Sake-brewing cultivars among varieties of Japanese rice (Oryza sativa L.) have traits adapted to the sake-brewing process, such as a high white-core expression rate (WCE). Our previous study detected putative quantitative trait loci (QTLs) associated with a high WCE derived from Yamadanishiki, a popular brewing rice cultivar. Because the occurrence of white-core grains depends on air temperature and the position of the grain on the panicle, phenotyping of WCE must consider these variable conditions. In this study, qWCE6, a QTL for the WCE on chromosome 6, was validated for the first time, and the phenotyping method examined for its suitability in fine-mapping. A clear tendency towards high WCE was observed in late-heading substituted lines which headed under low daily mean temperature at the experimental location. White-core grains were often expressed by the primary spikelets on the upper panicle, producing a high percentage of superior grains. The segregating population for qWCE6 in late heading revealed a distinct difference in WCE between the Koshihikari and Yamadanishiki homozygous alleles at qWCE6 as determined from that locality. Further, two insertion/deletion markers were developed for the marker-assisted selection of qWCE6. Our results will be useful for informing the breeding of sake-brewing rice cultivars.


Repeated dosing of Uniphyl tablets under fed and fasting conditions: comparison of serum theophylline levels, pulmonary function, and asthma symptoms.
In order to determine the effects of repeated administration under fed and fasting conditions on the bioavailability and clinical efficacy of Uniphyl tablets, 22 adult asthmatics took the drug immediately following their evening meal for seven consecutive days and under fasting conditions for an additional seven consecutive days. For each patient, the daily theophylline dose remained constant throughout the study. Peak and trough serum theophylline concentrations (STC), spirometry, asthma symptoms, side effects and use of beta-agonist inhalers were recorded daily at 0730 and 1900 hours. The mean daily theophylline dose was 818.2 +/- 213.0 mg. The mean peak STC when Uniphyl was taken with food was 14.4 +/- 4.5 mg/L and was 13.1 +/- 3.6 mg/L when taken under fasting conditions (P less than .05). The trough STC was 7.4 +/- 2.8 mg/L with food and 6.9 +/- 2.1 mg/L while fasting (NS). There were no significant differences between the two dosing conditions in terms of spirometry, asthma symptom scores, side effects or use of beta-agonist inhalers. There was no significant difference between the patients' morning and evening FEV1 under either dosing condition. Since the differences in STC between fed and fasting conditions were not clinically significant, we conclude that there is no need to restrict patients to a rigid relationship between Uniphyl dosing and meal conditions. On the basis of patient preference and compatibility with a normal lifestyle, we recommend that patients should generally be instructed to take the drug with or shortly following their evening meal.


Dissipative structures in a two-cell system: Numerical and experimental approaches.
It has been shown that the coupling between the photoreduction of the oxidized form of dichloroindophenol (an artificial electron acceptor) by thylakoids and the incident light intensity can lead to the appearance of multiple steady states when the system is operated under open conditions. In the present work, a numerical study and experimental evidence are presented on the occurrence of dissipative structures in an arrangement of two continuously stirred tank reactors with mutual mass exchange of dichloroindophenol through an inert membrane. The stable spatial structures are generated by the creation of transient internal and external asymmetries. A nontrivial hysteresis effect between symmetric and asymmetric stable steady states has been observed.


[Beta adrenergic receptors in circulating lymphocytes of patients with chronic heart failure].
Severe decompensated chronic heart failure is associated to increased levels of circulating catecholamines and decreased density of myocardial beta-adrenergic receptors. In 14 patients with stable, class II-III heart failure we studied circulating lymphocytes to determine the number of beta adrenergic receptors, the dissociation constant of 3H dihydroalprenolol (kd) and the intracellular content of cyclic AMP (AMPc). Results (mean +/- SEM) were compared to those obtained in 10 healthy controls. The number of beta receptors was significantly decreased (105 +/- 16 vs 185 +/- 24, fmol/mg of membrane protein, p less than 0.01). No differences were found in Kd (1.65 +/- 0.2 vs. 1.36 +/- 0.28 nm) nor the level of AMPc (7.9 +/- 2.1 vs 7.1 +/- 2.9 pmol/mg protein), respectively. The decreased number of beta adrenergic receptors in the circulating lymphocytes may be related to the increased level of circulating catecholamines that have been shown to be present during exercise in these patients.


[Comparative evaluation using in vitro dissolution tests of various sustained release theophylline preparations].
The author's aim was to compare the dissolution properties of the two newly developed sustained release "A" and "B" tablets containing 3,000 mg and 150 mg theophyllin respectively with the similar foreign preparations on the market. The referent preparations are as follows: Theo-Dur (Astra) and Theo-Dur (Recordati) tablets; Euphyllin and Euphyllin minor (Byk Gulden) retard capsules; Euphyllin retard (Byk Gulden) filmcoated tablets and Aminophyllinum-retard (Lek-Ljubljana) tablets. The dissolution tests were carried out by means of the rotating basket apparatus. The "half-change" method was used for testing the dissolution of the preparations. Evaluating the preparations the optimal dissolution rate found in the literature was taken into consideration. The results of the "B" tablet containing 150 mg theophylline were in good agreement with the findings of the preparations on the market and those indicated in the literature. The "A" tablet containing 300 mg active substance showed significantly slower dissolution rate as the comparative preparation did and as it is regarded optimal by the literature.


Time series analysis of benzo[A]pyrene-induced transcriptome changes suggests that a network of transcription factors regulates the effects on functional gene sets.
Chemical carcinogens may cause a multitude of effects inside cells, thereby affecting transcript levels of genes by direct activation of transcription factors (TF) or indirectly through the formation of DNA damage. As the temporal profiles of these responses may be profoundly different, examining time-dependent changes may provide new insights in TF networks related to cellular responses to chemical carcinogens. Therefore, we investigated in human hepatoma cells gene expression changes caused by benzo[a]pyrene at 12 time points after exposure, in relation to DNA adduct and cell cycle. Temporal profiles for functional gene sets demonstrate both early and late effects in up- and downregulation of relevant gene sets involved in cell cycle, apoptosis, DNA repair, and metabolism of amino acids and lipids. Many significant transcription regulation networks appeared to be around TF that are proto-oncogenes or tumor suppressor genes. The time series analysis tool Short Time-series Expression Miner (STEM) was used to identify time-dependent correlation of pathways, gene sets, TF networks, and biological parameters. Most correlations are with DNA adduct levels, which is an early response, and less with the later responses on G1 and S phase cells. The majority of the modulated genes in the Reactome pathways can be regulated by several of these TF, e.g., 73% by nuclear factor-kappa B and 34-42% by c-MYC, SRF, AP1, and E2F1. All these TF can also regulate one or more of the others. Our data indicate that a complex network of a few TF is responsible for the majority of the transcriptional changes induced by BaP. This network hardly changes over time, despite that the transcriptional profiles clearly alter, suggesting that also other regulatory mechanisms are involved.


Characterization of the virE locus of Agrobacterium tumefaciens plasmid pTiC58.
The virE locus that is responsible for the efficiency of infection by Agrobacterium tumefaciens (T. Hirooka and C. Kado, J. Bacteriol. 168:237-243, 1986) is located next to the right boundary of the virulence (Vir) region of the nopaline plasmid pTiC58. This locus is very similar to the virE locus of octopine type Ti plasmids on the basis of nucleotide and amino acid sequence comparisons as well as genetic complementation analyses. The nucleotide sequence of virE revealed three open reading frames, arranged as an operon, with a potential coding capacity for proteins of 9, 7.1, and 63.5 kilodaltons. The promoter region of virE was analyzed by using gene fusions to promoterless cat and lux genes. Two different promoters were detected, one which operates in A. tumefaciens and one which operates in Escherichia coli. virE is transcribed from left to right toward the T region. In A. tumefaciens, the expression of virE was induced by acetosyringone and required the presence of pTiC58.


Transcriptomics approach to investigate zebrafish heart regeneration.
In mammals, after a myocardial infarction episode, the damaged myocardium is replaced by scar tissue with negligible cardiomyocyte proliferation. Zebrafish, in contrast, display an extensive regenerative capacity, as they are able to restore completely lost cardiac tissue after partial ventricular amputation. Although questions about the early signals that drive the regenerative response and the relative role of each cardiac cell type in this process still need to be answered, the zebrafish is emerging as a very valuable tool to understand heart regeneration and to devise strategies that may be of potential value to treat human cardiac disease. Here, we performed a genome-wide transcriptome profile analysis focusing on the early time points of zebrafish heart regeneration and compared our results with those of previously published data. Our analyses confirmed the differential expression of several transcripts and identified additional genes whose expression is differentially regulated during zebrafish heart regeneration. We validated the microarray data by conventional and/or quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). For a subset of these genes, their expression pattern was analyzed by in-situ hybridization and shown to be upregulated in the regenerating area of the heart. Our results offer new insights into the biology of heart regeneration in the zebrafish and, together with future experiments in mammals, may be of potential interest for clinical applications.


Eburicoic Acid, a Triterpenoid Compound from Antrodia camphorata, Displays Antidiabetic and Antihyperlipidemic Effects in Palmitate-Treated C2C12 Myotubes and in High-Fat Diet-Fed Mice.
This study was designed to investigate the antidiabetic and antihyperlipidemic effects and mechanisms of eburicoic acid (TRR); one component of Antrodia camphorata in vitro and in an animal model for 14 weeks. Expression levels of membrane glucose transporter type 4 (GLUT4); phospho-5'-adenosine monophosphate-activated protein kinase (AMPK)/total AMPK; and phospho-Akt/total-Akt in insulin-resistant C2C12 myotube cells were significantly decreased by palmitate; and such decrease was prevented and restored by TRR at different concentrations. A group of control (CON) was on low-fat diet over a period of 14 weeks. Diabetic mice; after high-fat-diet (HFD) induction for 10 weeks; were randomly divided into six groups and were given once a day oral gavage doses of either TRR (at three dosage levels); fenofibrate (Feno) (at 0.25 g/kg body weight); metformin (Metf) (at 0.3 g/kg body weight); or vehicle (distilled water) (HF group) over a period of 4 weeks and still on HFD. Levels of glucose; triglyceride; free fatty acid (FFA); insulin; and leptin in blood were increased in 14-week HFD-fed mice as compared to the CON group; and the increases were prevented by TRR, Feno, or Metf as compared to the HF group. Moreover, HFD-induction displayed a decrease in circulating adiponectin levels, and the decrease was prevented by TRR, Feno, or Metf treatment. The overall effect of TRR is to decrease glucose and triglyceride levels and improved peripheral insulin sensitivity. Eburicoic acid, Feno, and Metf displayed both enhanced expression levels of phospho-AMPK and membrane expression levels of GLUT4 in the skeletal muscle of HFD-fed mice to facilitate glucose uptake with consequent enhanced hepatic expression levels of phospho-AMPK in the liver and phosphorylation of the transcription factor forkhead box protein O1 (FOXO1) but decreased messenger RNA (mRNA) of phosphenolpyruvate carboxykinase (PEPCK) to inhibit hepatic glucose production; resulting in lowered blood glucose levels. Moreover; TRR treatment increased hepatic expression levels of the peroxisome proliferator-activated receptor α (PPARα) to enhance fatty acid oxidation; but displayed a reduction in expressions of hepatic fatty acid synthase (FAS) but an increase in fatty acid oxidation PPARα coincident with a decrease in hepatic mRNA levels of sterol response element binding protein-1c (SREBP-1c); resulting in a decrease in blood triglycerides and amelioration of hepatic ballooning degeneration. Eburicoic acid-treated mice reduced adipose expression levels of lipogenic FAS and peroxisome proliferator-activated receptor γ (PPARγ) and led to decreased adipose lipid accumulation. The present findings demonstrated that TRR exhibits a beneficial therapeutic potential in the treatment of type 2 diabetes and hyperlipidemia.


Donation after cardiac death liver transplantation is associated with increased risk of end-stage renal disease.
Limited organ supply has led to greater use of liver allografts with higher donor risk indices (DRI) and/or donated after cardiac death (DCD). DCD status is associated with acute kidney injury after liver transplantation; however, less is known about the association between donor quality and end-stage renal disease (ESRD). Using SRTR data, we assembled a cohort of liver transplant recipients from 2/2002 to 12/2010. We fit multivariable Cox regression models for ESRD. Model 1 included total DRI; model 2 included components of DRI, including DCD, as separate variables. Forty thousand four hundred and sixty-three liver transplant recipients were included. Median DRI was 1.40 (IQR 1.14, 1.72); 1822 (5%) received DCD livers. During median follow-up of 3.93 years, ESRD occurred in 2008 (5%) and death in 11 075 (27%) subjects. There was a stepwise increase in ESRD risk with higher DRI (DRI ≥1.14 and <1.40: HR 1.17, P = 0.06; DRI ≥1.40 and <1.72: HR 1.29, P = 0.003; DRI ≥1.72: HR 1.39, P < 0.001, compared with DRI <1.14). Adjusting for DRI components separately, DCD status was most strongly associated with ESRD (HR 1.40, P = 0.008). Higher DRI is associated with ESRD after liver transplantation, driven in part by DCD status. Donor quality is an important predictor of long-term renal outcomes in liver transplant recipients.


3D bioprinting of heterogeneous bi- and tri-layered hollow channels within gel scaffolds using scalable multi-axial microfluidic extrusion nozzle.
One of the primary focuses in recent years in tissue engineering has been the fabrication and integration of vascular structures into artificial tissue constructs. However, most available methodologies lack the ability to create multi-layered concentric conduits inside natural extracellular matrices (ECMs) and gels that replicate more accurately the hierarchical architecture of biological blood vessels. In this work, we present a new microfluidic nozzle design capable of multi-axial extrusion in order to 3D print and pattern bi- and tri-layered hollow channel structures. This nozzle allows, for the first time, for these structures to be embedded within layers of gels and ECMs in a fast, simple and low-cost manner. By varying flow rates (1-6 ml min-1), printspeeds (1-16 m min-1), and material concentration (25-175 mM and 1.5%-2.5% for calcium chloride and alginate, respectively) we are able to accurately determine the operational printing range as well as achieve a wide range of conduit dimensions (0.69-2.31 mm) that can be printed within a few seconds. Our scalable design allows for multi-axial extrusion and versatility in material incorporation in order to create heterogeneous structures. We demonstrate the ability to print distinct concentric layers of different cell types, namely endothelial cells and fibroblasts. By incorporating various layers of different cell-friendly materials (such as collagen and fibrin) alongside materials with high mechanical strength (i.e. alginate), we were able to increase long-term cell viability and growth without compromising the structural integrity. In this way, we can improve cellular adhesion in our biocompatible constructs as well as allow them to remain structurally sound. We are able to realize complex heterogeneous, hierarchical architectures that have strong potential for use not only in vascular tissue applications, but also in other artificially fabricated tubular or fiber-like structures such as skeletal muscle or nerve conduits.


Role of migratory birds in introduction and range expansion of Ixodes scapularis ticks and of Borrelia burgdorferi and Anaplasma phagocytophilum in Canada.
During the spring in 2005 and 2006, 39,095 northward-migrating land birds were captured at 12 bird observatories in eastern Canada to investigate the role of migratory birds in northward range expansion of Lyme borreliosis, human granulocytic anaplasmosis, and their tick vector, Ixodes scapularis. The prevalence of birds carrying I. scapularis ticks (mostly nymphs) was 0.35% (95% confidence interval [CI] = 0.30 to 0.42), but a nested study by experienced observers suggested a more realistic infestation prevalence of 2.2% (95% CI = 1.18 to 3.73). The mean infestation intensity was 1.66 per bird. Overall, 15.4% of I. scapularis nymphs (95% CI = 10.7 to 20.9) were PCR positive for Borrelia burgdorferi, but only 8% (95% CI = 3.8 to 15.1) were positive when excluding nymphs collected at Long Point, Ontario, where B. burgdorferi is endemic. A wide range of ospC and rrs-rrl intergenic spacer alleles of B. burgdorferi were identified in infected ticks, including those associated with disseminated Lyme disease and alleles that are rare in the northeastern United States. Overall, 1.4[corrected]% (95% CI = 0.3 [corrected] to 0.41) of I. scapularis nymphs were PCR positive for Anaplasma phagocytophilum. We estimate that migratory birds disperse 50 million to 175 million I. scapularis ticks across Canada each spring, implicating migratory birds as possibly significant in I. scapularis range expansion in Canada. However, infrequent larvae and the low infection prevalence in ticks carried by the birds raise questions as to how B. burgdorferi and A. phagocytophilum become endemic in any tick populations established by bird-transported ticks.


Soft and Stretchable Sensor Using Biocompatible Electrodes and Liquid for Medical Applications.
This article introduces a soft and stretchable sensor composed of silicone rubber integrating a conductive liquid-filled channel with a biocompatible sodium chloride (NaCl) solution and novel stretchable gold sputtered electrodes to facilitate the biocompatibility of the sensor. By stretching the sensor, the cross section of the channel deforms, thus leading to a change in electrical resistance. The functionalities of the sensor have been validated experimentally: changes in electrical resistance are measured as a function of the applied strain. The experimentally measured values match theoretical predictions, showing relatively low hysteresis. A preliminary assessment on the proposed sensor prototype shows good results with a maximum tested strain of 64%. The design optimization of the saline solution, the electrodes, and the algebraic approximations derived for integrating the sensors in a flexible manipulator for surgery has been discussed. The contribution of this article is the introduction of the biocompatible and stretchable gold sputtered electrodes integrated with the NaCl-filled channel rubber as a fully biocompatible solution for measuring deformations in soft and stretchable medical instruments.


Systematic review and meta-analysis of mass spectrometry proteomics applied to ocular fluids to assess potential biomarkers of age-related macular degeneration.
Age-related macular degeneration (AMD) is a significant cause of severe vision loss. The main purpose of this study was to identify mass spectrometry proteomics-based potential biomarkers of AMD that contribute to understanding the mechanisms of disease and aiding in early diagnosis. This study retrieved studies that aim to detect differences relate to proteomics in AMD patients and healthy control groups by mass spectrometry (MS) proteomics approaches. The search process was accord with PRISMA guidelines (PROSPERO database: CRD42023388093). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes Pathway Analysis (KEGG) were performed on differentially expressed proteins (DEPs) in the included articles using the DAVID database. DEPs were included in a meta-analysis when their effect size could be computed in at least two research studies. The effect size of measured proteins was transformed to the log2-fold change. Protein‒protein interaction (PPI) analysis was conducted on proteins that were statistically significant in the meta-analysis using the String online database. Eleven studies fulfilled the inclusion criteria, and 161 DEPs were identified. The GO analysis showed that AMD is significantly related to proteolysis, extracellular exosome and protein binding. In KEGG, the most significant pathway was the complement and coagulation cascades. Meta-analysis results suggested that eight proteins were statistically significant, and according to PPI results, the most significant four proteins were serotransferrin (TF), apolipoprotein A1 (APOA1), complement C3 (C3) and lipocalin-1 (LCN1). Four possible biomarkers, TF, APOA1, C3 and LCN1, were found to be significant in the pathogenesis of AMD and need to be further validated. Further studies should be performed to evaluate diagnostic and therapeutic value of these proteins.


Recognition and referral of girls with Attention Deficit Hyperactivity Disorder: case vignette study.
Compared with boys, girls with Attention Deficit Hyperactivity Disorder (ADHD) are under-recognized. Parents commonly discuss concerns with teachers, who play an important role in the recognition and referral of children with ADHD. We investigated whether the predominating subtype of symptomatology influences teacher recognition of affected girls. A total of 212 teachers from 40 randomly selected primary schools in England participated in a postal questionnaire study. The questionnaire consisted of a case vignette (based on DSM-IV criteria) describing a girl with either combined or predominantly inattentive subtype ADHD. Each school received an equal number of each type of vignette for distribution. Further questions elicited teachers' conceptualization of the girl's difficulties and need for specialist referral, their views on treatment modalities and demographic data. Most (98%) teachers recognized the presence of a problem but mainly conceptualized the girl's behaviour as reflecting attentional (89%) or emotional (62%) difficulties. Teachers were less likely to correctly identify a girl with inattentive than combined subtype ADHD (14% vs. 43%) or recommend clinical referral (50% vs. 59%) for her. Few (15%) teachers thought that medication might be helpful for a girl meeting diagnostic criteria for ADHD. Teachers are able to recognize ADHD-related behaviours and impairments but conceptualize these as reflecting attentional or emotional difficulties rather than as relating to a disorder (ADHD). Teachers' conceptualization of ADHD and views about medication are important factors that could affect accurate recognition and referral. Improving teachers' knowledge about ADHD, especially the inattentive subtype, could assist in tackling gender-related barriers to care.


D1 dopamine receptor dDA1 is required in the mushroom body neurons for aversive and appetitive learning in Drosophila.
Drosophila has robust behavioral plasticity to avoid or prefer the odor that predicts punishment or food reward, respectively. Both types of plasticity are mediated by the mushroom body (MB) neurons in the brain, in which various signaling molecules play crucial roles. However, important yet unresolved molecules are the receptors that initiate aversive or appetitive learning cascades in the MB. We have shown previously that D1 dopamine receptor dDA1 is highly enriched in the MB neuropil. Here, we demonstrate that dDA1 is a key receptor that mediates both aversive and appetitive learning in pavlovian olfactory conditioning. We identified two mutants, dumb1 and dumb2, with abnormal dDA1 expression. When trained with the same conditioned stimuli, both dumb alleles showed negligible learning in electric shock-mediated conditioning while they exhibited moderately impaired learning in sugar-mediated conditioning. These phenotypes were not attributable to anomalous sensory modalities of dumb mutants because their olfactory acuity, shock reactivity, and sugar preference were comparable to those of control lines. Remarkably, the dumb mutant's impaired performance in both paradigms was fully rescued by reinstating dDA1 expression in the same subset of MB neurons, indicating the critical roles of the MB dDA1 in aversive as well as appetitive learning. Previous studies using dopamine receptor antagonists implicate the involvement of D1/D5 receptors in various pavlovian conditioning tasks in mammals; however, these have not been supported by the studies of D1- or D5-deficient animals. The findings described here unambiguously clarify the critical roles of D1 dopamine receptor in aversive and appetitive pavlovian conditioning.


Hexavalent chromium-induced erythrocyte membrane phospholipid asymmetry.
Hexavalent (VI) chromium is a global contaminant with cytotoxic activity. Chromium (VI) induces oxidative stress, inflammation, cell proliferation, malignant transformation and may trigger carcinogenesis and at the same time apoptosis. The toxic effects of chromium (VI) at least partially result from mitochondrial injury and DNA damage. Erythrocytes lack mitochondria and nuclei but may experience an apoptosis-like suicidal cell death, i.e. eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Eryptosis may result from increase of cytosolic Ca(2+) activity, ATP depletion and/or ceramide formation. The present study explored, whether chromium (VI) triggers eryptosis. Fluo-3-fluorescence was employed to determine cytosolic Ca(2+)-concentration, forward scatter to estimate cell volume, binding of fluorescent annexin V to detect phosphatidylserine exposure, hemoglobin concentration in the supernatant to quantify hemolysis, luciferin-luciferase to determine cytosolic ATP concentration and fluorescent anti-ceramide antibodies to uncover ceramide formation. A 48 h exposure to chromium (VI) (≥10 μM) significantly increased cytosolic Ca(2+)-concentration, decreased ATP concentration (20 μM), decreased forward scatter, increased annexin V-binding and increased (albeit to a much smaller extent) hemolysis. Chromium (VI) did not significantly modify ceramide formation. The effect of 20 μM chromium (VI) on annexin V binding was partially reversed in the nominal absence of Ca(2+). The present observations disclose a novel effect of chromium (VI), i.e. Ca(2+) entry and cytosolic ATP depletion in erythrocytes, effects resulting in eryptosis with cell shrinkage and cell membrane scrambling.


[Assessment of the effectiveness of inactivated influenza vaccines for adults].
In 9 controlled epidemiological observations (1977-1984) the effectiveness of modern Soviet whole-virion vaccines was studied in organized groups of adults and at industrial enterprises. During the epidemic outbreaks of influenza of different etiology and intensity morbidity rate in influenza and acute respiratory diseases was shown to decrease 1.1-2.2 times among the vaccinees, depending on the correspondence of epidemic and vaccine influenza strains. The absence of influenza virus B in inactivated influenza vaccines was the reason for their low effectiveness during influenza outbreaks of mixed etiology B + A (H1N1).


Factors underlying chronic inflammation in rheumatoid arthritis.
Rheumatoid arthritis (RA)is a debilitating chronic inflammatory disease whose characteristic pathology includes swollen, painful, and deformed joints. In recent decades, both clinical and basic scientific research have tried to determine the factors involved in the pathogenesis of this common disease. Although the cause of RA is still unknown, several factors that contribute to RA have been identified. Among these are the discoveries of: susceptibility genes, disease-causing immune cells, and cytokine and signal transduction networks involved in promoting persistence of inflammation. Various therapeutic strategies, including anti-tumor necrosis factor therapy, have been developed to target one or more of these factors. Although none of these therapeutic strategies can actually cure the disease, some of these novel agents have proven to be more effective than others. This implies that the success of a therapy is very much dependent on the therapeutic targets chosen. Therefore, improved understanding of the cellular and molecular events occurring in the rheumatoid joint during the pathogenesis of the disease is particularly important if we are to better combined therapeutic strategies. In this article we summarize current understanding of the factors that contribute to disease pathogenesis in RA and identify cellular and molecular events that could drive the development of the disease and represent potential new therapeutic targets.


Health care reform: the Clinton proposal and congressional counterproposals--Part II.
Note: Part I of this Article appears in the January 1994 issue of the JOURNAL OF HEALTH AND HOSPITAL LAW (V. 27, No. 1). Part II continues discussion of the potential effects of reform for the structure and financial security of various types of health care providers; identifies some possible effects of reform on health care facility operations; and describes proposed amendments to existing law appearing in various reform proposals.


Uterine Metastasis From Gastric Adenocarcinoma Masquerading as Physiologic Endometrial Uptake in FDG PET/CT.
A 44-year-old woman with newly diagnosed gastric adenocarcinoma by gastroscopy underwent F-FDG PET/CT to evaluate possible metastasis. The images demonstrated intense activity in the region of uterine corpus, as well as greater gastric curvature. Physiologic uptake of endometrium was initially suspected, given the rarity with which extragenital cancers metastasize to the uterus. Ultimately, the endometrium proved to be mucinous adenocarcinoma of gastric origin based on its shared histological features and compatible immunostaining profile.


Lung cancer trends: smoking, obesity, and sex assessed in the Staten Island University's lung cancer patients.
The incidence of lung cancer in the United States decreased by 1.8% from 1991 to 2005 while it increased by 0.5% in females. We assessed whether nonsmokers afflicted with lung cancer at Staten Island University Hospital are disproportionately female in comparison to national averages. We also evaluated different factors including race, histology, and body mass index (BMI) in correlation with smoking history. A retrospective chart review was conducted from 2005 to 2011 on 857 patients. Patients were divided into two groups according to their smoking status: current or ever-smokers, and former or never-smokers. A chi-square test for categorical data and multivariate logistic regression analyses was used to study the relation between BMI and the other clinical and demographic data. Forty-nine percent of patients were men and 51% were women with a mean age at diagnosis of 67.8 years. Current smokers were most common (50.2%) followed by ever-smokers (18.2%), former smokers (15.8%) and never-smokers (15.6%). Forty eight percent had stage IV lung cancer upon presentation. Never-smokers with lung cancer were 24 times more likely to be females. However, the proportion of female former smokers (31.6%) was lower than the proportion of male former smokers (68.4%) (P=0.001). There was no significant association between American Joint Committee on Cancer (AJCC) stage, sex, race, and histological type in the two smoking groups. Current/ever-smokers tended to be younger at age of diagnosis (P=0.0003). BMI was lower in the current/ever-smokers (26.8 kg/m(2)) versus former/never-smokers (28.8) in males (P=0.0005). BMI was significantly higher in males (30.26) versus females (25.25) in the never-smoker category (P=0.004). Current smokers, compared to others, had a lower BMI in males (26.4 versus 28.3; P=0.0001) and females (25.5 versus 26.9; P=0.013) but the mean BMI for all groups was in the overweight/obese range. Our population of lung cancer patients although demographically distinct, reflects a similar proportion of afflicted nonsmokers to the national population. Smoking is a major risk factor for lung cancer, but there is also a possible direct correlation with BMI that would support obesity as a potential risk factor for lung cancer.


Stratum corneum compliance enhances tactile sensitivity through increasing skin deformation: A study protocol for a randomized controlled trial.
Tactile sensation plays a crucial role in object manipulation, communication, and even emotional well-being. It has been reported that the deformability of skin (also described as skin compliance) that shows a large mechanical response to stimuli is associated with high tactile sensitivity. However, although the compliance of the stratum corneum, the outermost layer of skin, can change daily due to skin care and environmental factors, few studies have quantified the effect of the stratum corneum on tactile sensation. We investigated the changes in tactile sensitivity resulting from skin hydration and identified corresponding alterations in the compliance of the stratum corneum. A randomized controlled trial was conducted. Participants were randomly assigned to an intervention group (n = 20) that had a moisturizing cream applied to their cheeks or a control group (n = 19) that had Milli-Q water applied to their cheeks. Tactile discrimination performance was assessed using psychophysical techniques before and after application. The water content, mechanical response characteristics, and penetration of PEG/PPG-17/4 dimethyl ether from the cream in the stratum corneum were evaluated to identify hydration effects. Skin deformations occurring during tactile sensation were measured concurrently using a suction device employed for tactile stimulation. Tactile sensitivity was increased in participants who had cream applied to the skin surface, while no significant change was observed in participants who received Milli-Q water. The improved discrimination of tactile stimulus intensity was directly related to the magnitude of skin displacement. The higher water content of the stratum corneum due to cream application decreased the dynamic modulus of elasticity of the stratum corneum and increased the skin's extensibility in response to tactile stimuli. Hydrating the stratum corneum significantly enhances tactile sensitivity and is accompanied by an increase in skin extensibility, a factor in tactile intensity perception. The compliance of the thin stratum corneum layer plays a crucial role in tactile experiences that involve skin stretching.


Measurement of osteotomy force during endoscopic sinus surgery.
Greater understanding of the surgeon's task and skills are required to improve surgical technique and the effectiveness of training. Currently, neither the objective measurement of osteotomy forces during endoscopic sinus surgery (ESS) nor the validity of the properties of cadaver materials, are well documented. Measurement was performed of peak axial osteotomy force during ESS. A comparison was made of results with previously published cadaver data to validate the force properties of cadaver models. A prospective, consecutive cohort of 25 patients was compared with data from 15 cadaver heads. A modified Storz sinus curette measured osteotomy force from uncinate, bulla ethmoidalis, and ground lamella. Independent variables were osteotomy site, age, gender, indication for surgery, and side. Corresponding cadaver data were analyzed for the independent variables of osteotomy site, side, and gender and then compared with the live patient data. Mean osteotomy force in live patients was 9.6 N (95% CI, 8.9-10.4 N). Mean osteotomy force in the cadaver heads was 6.4 N (95% CI, 5.7-7.0 N). Ethmoid osteotomy of live patients required 3.2 N (95% CI, 2.1-4.3 N) more force than the cadaver heads (p = 0.0001). This relationship was statistically significant at the bulla ethmoidalis (p = 0.002) and the ground lamella (p = 0.0001) but not at the uncinate (p = 0.068). Osteotomy in female live subjects required 1.6 N (95% CI, 0.1-3.1 N) more force than male live subjects (p = 0.03). Cadaver tissue may underestimate the mean osteotomy force required in osteotomy of living ethmoid sinus lamellae by a factor of 1.5 times. Caution may be required in extrapolating force estimates from cadaver tissue to those required in living patients.


'BeSAFE', effect-evaluation of internet-based, tailored safety information combined with personal counselling on parents' child safety behaviours: study design of a randomized controlled trial.
Injuries in or around the home are the most important cause of death among children aged 0-4 years old. It is also a major source of morbidity and loss of quality of life. In order to reduce the number of injuries, the Consumer Safety Institute introduced the use of Safety Information Leaflets in the Netherlands to provide safety education to parents of children aged 0-4 years. Despite current safety education, necessary safety behaviours are still not taken by a large number of parents, causing unnecessary risk of injury among young children. In an earlier study an E-health module with internet-based, tailored safety information was developed and applied. It concerns an advice for parents on safety behaviours in their homes regarding their child. The aim of this study is to evaluate the effect of this safety information combined with personal counselling on parents' child safety behaviours. Parents who are eligible for the regular well-child visit with their child at child age 5-8 months are invited to participate in this study. Participating parents are randomized into one of two groups: 1) internet-based, tailored safety information combined with personal counselling (intervention group), or 2) personal counselling using the Safety Information Leaflets of the Consumer Safety Institute in the Netherlands for children aged 12 to 24 months (control group). All parents receive safety information on safety topics regarding the prevention of falling, poisoning, drowning and burning. Parents of the intervention group will access the internet-based, tailored safety information module when their child is approximately 10 months old. After completion of the assessment questions, the program compiles a tailored safety advice. The parents are asked to devise and inscribe a personal implementation intention. During the next well-child visit, the Child Health Clinic professional will discuss this tailored safety information and the implementation intention with the parents. The control group will receive usual care, i.e. the provision of Safety Information Leaflets during their well-child visit at the child's age of 11 months. It is hypothesized that the intervention, internet-based, tailored safety information combined with personal counselling results in more parents' child safety behaviours. Current Controlled Trials NTR1836.


Dose verification to cochlea during gamma knife radiosurgery of acoustic schwannoma using MOSFET dosimeter.
Dose verification to cochlea using metal oxide semiconductor field effect transistor (MOSFET) dosimeter using a specially designed multi slice head and neck phantom during the treatment of acoustic schwannoma by Gamma Knife radiosurgery unit. A multi slice polystyrene head phantom was designed and fabricated for measurement of dose to cochlea during the treatment of the acoustic schwannoma. The phantom has provision to position the MOSFET dosimeters at the desired location precisely. MOSFET dosimeters of 0.2 mm x 0.2 mm x 0.5 μm were used to measure the dose to the cochlea. CT scans of the phantom with MOSFETs in situ were taken along with Leksell frame. The treatment plans of five patients treated earlier for acoustic schwannoma were transferred to the phantom. Dose and coordinates of maximum dose point inside the cochlea were derived. The phantom along with the MOSFET dosimeters was irradiated to deliver the planned treatment and dose received by cochlea were measured. The treatment planning system (TPS) estimated and measured dose to the cochlea were in the range of 7.4 - 8.4 Gy and 7.1 - 8 Gy, respectively. The maximum variation between TPS calculated and measured dose to cochlea was 5%. The measured dose values were found in good agreement with the dose values calculated using the TPS. The MOSFET dosimeter can be a suitable choice for routine dose verification in the Gamma Knife radiosurgery.


Development and testing of a questionnaire to measure older people's experience of the Transition Care Program in Australia.
Transition Care (TC) is a new program for older adults in Australia. At present, program quality is assessed using provider reports of compliance with key requirements established by the Australian Government Department of Health and Ageing. As part of the National Evaluation of the Transition Care Program, the authors developed a questionnaire to measure recipient experience of TC. Validity and reliability were assessed via interviews with 582 recipients or proxies 3 months after discharge from TC. Concordance between test-retest observations was high. Principal component analysis suggested three subscales were important: restoration, continuity of care and patient involvement. Recipients of TC in a residential care setting had lower mean scores on the restoration subscale compared to those who received services in the community. This study found that a standardised measure of recipient experience could inform quality improvement in TC and is feasible to administer via questionnaire.


Curcumin alleviates immune-complex-mediated glomerulonephritis in factor-H-deficient mice.
Complement factor H (Cfh) is a key regulator of the complement cascade and protects C57BL/6 mice from immune complex-mediated complement-dependent glomerulonephritis. In chronic serum sickness (CSS) there are increased deposits of immune complexes in the glomeruli with inflammation and a scarring phenotype. As cucurmin is an effective anti-inflammatory agent and reduces complement activation, we hypothesized that it should alleviate renal disease in this setting. To determine the effectiveness of curcumin, an apoferritin-induced CSS model in Cfh-deficient (Cfh(-/-)) mice was used. Curcumin treatment (30 mg/kg) given every day in parallel with apoferritin reduced glomerulonephritis and enhanced kidney function (blood urea nitrogen, 45·4 ± 7·5 versus 35·6 ± 5·1; albuminuria, 50·1 ± 7·1 versus 15·7 ± 7·1; glomerulonephritis, 2·62 + 0·25 versus 2 + 0·3, P < 0·05). In line with reduced IgG deposits in mice with CSS given curcumin, C9 deposits were reduced indicating reduced complement activation. Mice treated with curcumin had a significant reduction in the number of splenic CD19(+) B cells and the ratio of CD19 : CD3 cells (P < 0·05) with no change in the T-cell population. Myeloperoxidase assay showed reduced macrophages in the kidney. However, a significant reduction in the M2 subset of splenic macrophages by apoferritin was prevented by curcumin, suggesting a protective function. Curcumin treatment reduced mRNA expression of inflammatory proteins monocyte chemoattractant protein-1 and transforming growth factor-β and matrix proteins, fibronectin, laminin and collagen. Our results clearly illustrate that curcumin reduces glomerulosclerosis, improves kidney function and could serve as a therapeutic agent during serum sickness.


Weight-adjusted dosing of TNK-tissue plasminogen activator and its relation to angiographic outcomes in the thrombolysis in myocardial infarction 10B trial. TIMI 10B Investigators.
Fixed doses of thrombolytic agents are generally administered to patients of varying body weights, and the dose-response relation may be confounded by the variability in patient weight. We hypothesized that higher doses of TNK-tissue plasminogen activator (tPA) per unit body weight would be related to improved flow at 90 minutes after thrombolytic administration. A total of 886 patients with acute myocardial infarction were randomized to receive either a single bolus of 30, 40, or 50 mg of TNK-tPA or front-loaded tPA in the Thrombolysis In Myocardial Infarction (TIMI) 10B trial. The dose of TNK-tPA administered was divided by the patient's weight to arrive at the TNK-tPA dose (mg) per unit body weight (kg), and patients were stratified into tertiles based on mg/kg of TNK-tPA: low dose, 0.2 to 0.39 mg/kg; mid-dose, 0.40 to 0.51 mg/kg; high dose, 0.52 to 1.24 mg/kg. Flow in the culprit and nonculprit arteries was analyzed using the TIMI flow grades and the corrected TIMI frame count (CTFC). The median CTFC in culprit arteries differed between the tertiles (3-way p = 0.007), with the CTFC being 7.2 frames faster in high-dose than in low-dose patients (43.1 +/- 30.1, median 31.2, n = 171 vs 54.6 +/- 34.8, median 38.4, n = 166, 2-way p = 0.002). Patients in the mid- and high-dose tertiles achieved patency more frequently (TIMI grade 2 or 3 flow) by 60 minutes (p = 0.02), and the 90-minute percent diameter stenosis was less severe in patients in the high- versus low-dose tertile (p = 0.03). In nonculprit arteries, the CTFC was faster in high- than in low-dose tertiles (29.6 +/- 13.4, median 26.9, n = 130 vs 34.7 +/- 16.3, median 32.8, n = 108, 3-way p = 0.03, 2-way p = 0.008). In patients who underwent percutaneous transluminal coronary angioplasty (PTCA), the CTFC in culprit arteries after PTCA was fastest in the high- and mid-dose tertiles than in those receiving low doses (2-way p = 0.05). Thus, higher doses per unit body weight of TNK-tPA result in not only faster culprit artery flow, but also faster nonculprit, global, and post-PTCA flow, which may reflect earlier opening, reduced stunning, or improved microvascular function. The greater effectiveness of thrombolysis must be weighed against any increase in risk.


What Stops Fairness from Emerging in Assessment? The Forces on a Complex Adaptive System.
Workplace-based assessment occurs in authentic, dynamic clinical environments where reproducible, measurement-based assessments can often not be implemented. In these environments, research approaches that respect these multiple dynamic interactions, such as complexity perspectives, are encouraged. Previous research has shown that fairness in assessment is a nonlinear phenomenon that emerges from interactions between its components and behaves like a complex adaptative system. The aim of this study was to understand the external forces on the complex adaptive system which may disrupt fairness from emerging. We conducted online focus groups with a purposeful sample of nineteen academic leaders in the Netherlands. We used an iterative approach to collection, analysis and coding of the data and interpreted the results using a lens of complexity, focusing on how individual elements of fairness work in concert to create systems with complex behaviour. We identified three themes of forces which can disrupt fairness: forces impairing interactivity, forces impairing adaption and forces impairing embeddedness. Within each of these themes, we identified subthemes: assessor and student forces, tool forces and system forces. Consistent with complexity theory, this study suggests there are multiple forces which can hamper the emergence of fairness. Whilst complexity thinking does not reduce the scale of the challenge, viewing forces through this lens provides insight into why and how these forces are disrupting fairness. This allows for more purposeful, meaningful changes to support the use of fair judgement in assessment in dynamic authentic clinical workplaces.


Assessment of early neurocognitive functioning increases the accuracy of predicting chronic PTSD risk.
Post-traumatic stress disorder (PTSD) is a protracted and debilitating consequence of traumatic events. Identifying early predictors of PTSD can inform the disorder's risk stratification and prevention. We used advanced computational models to evaluate the contribution of early neurocognitive performance measures to the accuracy of predicting chronic PTSD from demographics and early clinical features. We consecutively enrolled adult trauma survivors seen in a general hospital emergency department (ED) to a 14-month long prospective panel study. Extreme Gradient Boosting algorithm evaluated the incremental contribution to 14 months PTSD risk of demographic variables, 1-month clinical variables, and concurrent neurocognitive performance. The main outcome variable was PTSD diagnosis, 14 months after ED admission, obtained by trained clinicians using the Clinician-Administered PTSD Scale (CAPS). N = 138 trauma survivors (mean age = 34.25 ± 11.73, range = 18-64; n = 73 [53%] women) were evaluated 1 month after ED admission and followed for 14 months, at which time n = 33 (24%) met PTSD diagnosis. Demographics and clinical variables yielded a discriminatory accuracy of AUC = 0.68 in classifying PTSD diagnostic status. Adding neurocognitive functioning improved the discriminatory accuracy (AUC = 0.88); the largest contribution emanating from poorer cognitive flexibility, processing speed, motor coordination, controlled and sustained attention, emotional bias, and higher response inhibition, and recall memory. Impaired cognitive functioning 1-month after trauma exposure is a significant and independent risk factor for PTSD. Evaluating cognitive performance could improve early screening and prevention.


Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study.
Plasma phospholipid transfer protein (PLTP) interacts with HDL particles and facilitates the transfer of phospholipids from triglyceride (TG)-rich lipoproteins to HDL. Overexpressing human PLTP in mice increases the susceptibility to atherosclerosis. In human plasma, high-active and low-active forms of PLTP exist. To elucidate the contribution of phospholipid transfer activity to changes in lipoprotein metabolism and atherogenesis, we developed mice expressing mutant PLTP, still able to associate with HDL but lacking phospholipid transfer activity. In mice heterozygous for the LDL receptor, effects of the mutant and normal human PLTP transgene (mutPLTP tg and PLTP tg, respectively) were compared. In PLTP tg mice, plasma PLTP activity was increased 2.9-fold, resulting in markedly reduced HDL lipid levels. In contrast, in mutPLTP tg mice, lipid levels were not different from controls. Furthermore, hepatic VLDL-TG secretion was stimulated in PLTP tg mice, but not in mutPLTP tg mice. When mice were fed a cholesterol-enriched diet, atherosclerotic lesion size in PLTP tg mice was increased more than 2-fold compared with control mice, whereas in mutPLTP tg mice, there was no change. Our findings demonstrate that PLTP transfer activity is essential for the development of atherosclerosis in PLTP transgenic mice, identifying PLTP activity as a possible target to prevent atherogenesis, independent of plasma PLTP concentration.


Silene latifolia: the classical model to study heteromorphic sex chromosomes.
This review summarizes older as well as recent data about the model dioecious plant Silene latifolia. This plant has been the subject of more than one hundred years of research efforts and its most conspicuous property is huge and well differentiated heteromorphic sex chromosomes, XX in females and XY in males. Due to this property the S. latifolia sex chromosomes have been often used for cytogenetic studies as well as for flow sorting and laser microdissection. Nowadays S. latifolia is the focus of genomic studies, molecular mapping, phylogenetic and population genetics analyses.


Use of radiation therapy for patients with soft-tissue and bone sarcomas.
Radiation therapy is recommended as an adjuvant to resection for intermediate- and high-grade soft-tissue sarcomas; its role in bone sarcomas is largely limited to select patients with Ewing sarcoma. Despite the integral role of radiation therapy in soft-tissue sarcoma management, its optimal timing--preoperative versus postoperative--is uncertain, with each timing scenario having advantages and disadvantages. Preparation for radiation therapy involves a detailed planning session to optimize and standardize patient positioning and determine the target volume. Side effects of radiation therapy may include skin changes, delayed wound healing and other wound complications, fatigue, reduced range of motion of the affected limb, pain, and bone fractures.


Identification of bovine liver mitochondrial NAD+ glycohydrolase as ADP-ribosyl cyclase.
The present investigation identifies bovine liver mitochondrial NADase (NAD+ glycohydrolase) as a member of the class of bifunctional ADP-ribosyl cyclases/cyclic ADP-ribose hydrolases, known to be potential second messenger enzymes. These enzymes catalyse the synthesis and degradation of cyclic ADP-ribose, a potent intracellular calcium-mobilizing agent. The mitochondrial enzyme utilized the NAD+ analogues nicotinamide guanine dinucleotide (NGD+) and nicotinamide hypoxanthine dinucleotide (NHD+) to form fluorescent cyclic purine nucleoside diphosphoriboses. ADP-ribosyl cyclase activity was also demonstrated using 32P-labelled NAD+ as substrate. The identity of NADase and ADP-ribosyl cyclase was supported by their co-migration in SDS/polyacrylamide gels. Cyclase activity was visualized directly within the gel by detecting the formation of fluorescent cyclic IDP-ribose from NHD+. The enzyme catalysed the hydrolysis of cyclic ADP-ribose to ADP-ribose. Moreover, in the presence of nicotinamide and cyclic ADP-ribose the enzyme synthesized NAD+. Both the ADP-ribosyl cyclase and NADase activities of the enzyme were strongly inhibited by reducing agents. Treatment of the NADase with dithiothreitol caused the apparent inactivation of the enzyme. Subsequent removal of the reducing agent and addition of oxidized glutathione led to a partial recovery of enzymic activity. The results support a model for pro-oxidant-induced calcium release from mitochondria involving cyclic ADP-ribose as a specific messenger, rather than the non-enzymic modification of proteins by ADP-ribose.


Sumatriptan injection and tablets in clinical practice: results of a survey of 707 migraineurs.
This report from the Gothenburg Migraine Clinic in Sweden describes the results of a telephone survey of over 700 patients using open-label sumatriptan tablets or sumatriptan injection for the treatment of migraine. The information is based on the patients' cumulative experience of more than 76,000 subcutaneous injections, 56,000 tablets 100 mg, and 20,000 tablets 50 mg. The results demonstrate that sumatriptan tablets were preferred by a greater proportion of patients than sumatriptan injection. However, sumatriptan injection was perceived as the most effective dosing form by the greatest proportion of patients. Among patients who found sumatriptan injection to be the most effective dosing form, the most frequently cited reasons were efficacy and speed of action. Among patients who found sumatriptan tablets to be the most effective dosing form, the most frequently cited reasons were fewer side effects and lack of experience with other dosing forms. Approximately half of sumatriptan users indicated that sumatriptan use was associated with decreases in the numbers of days with migraine, days at work with migraine, and days off work/normal activities due to migraine. When they worked during a migraine attack, patients estimated that they were 76% effective after taking sumatriptan compared with 47% effective with other medications and 49% effective with no medication. In general, side effects were reported less frequently among sumatriptan tablet users compared with injection users. Asked to compare sumatriptan with the best migraine treatment that they had used before, 94% of patients indicated that sumatriptan was better or much better than their previous therapies. These data provide important information from the clinical practice setting to complement the data from sumatriptan clinical trials.


Gonococcal strains from homosexual men have outer membranes with reduced permeability to hydrophobic molecules.
Loci designated penA, penB, and mtr contribute additively to penicillin G resistance in Neisseria gonorrhoeae; the mtr locus also confers resistance to hydrophobic dyes, detergents, and antibiotics, env mutations suppress the phenotypic expression of mtr and penB and are responsible for increased sensitivity to various hydrophobic molecules. We postulated that the host environment is important in the selection of gonococcal strains with these particular outer membrane phenotypes. Thus, mtr strains should predominate in environments that are high in hydrophobic molecules. To test this hypothesis we determined the outer membrane phenotype of 152 strains of N. gonorrhoeae. Rectal and urethral isolates from 58 homosexual men, urethral isolates from 55 heterosexual men, and cervical and rectal isolates from 39 heterosexual women were used in this study. Strains from 43 of the homosexual men were matched with those from heterosexual men with respect to auxotype and year and season of isolation. Cell envelope phenotype was determined for each strain on the basis of its resistance to various hydrophobic compounds. The identity of mtr strains was confirmed by genetic transformation. Among the matched pairs, mtr strains were significantly more prevalent among isolates from homosexual men than among those from heterosexual men (P = 0.03). Serogrouping by coagglutination demonstrated that 17 of 19 mtr strains versus 76 of 131 non-mtr strains belonged to coagglutination group WII (P = 0.01). Coagglutination group WII strains were also associated with homosexuality (P = 0.02). Gonococci were also tested for resistance to fecal lipids, mtr strains were more resistant to growth inhibition by fecal lipids than were non-mtr strains.


Safety of gadolinium during pregnancy.
A pregnant patient who underwent magnetic resonance imaging (MRI) because of an acute abdomen, was told that MRI contrast agents (ie, gadolinium-based contrast agents) are contraindicated during pregnancy. What is the risk to her baby? Current radiology practices and recommendations discourage the use of gadolinium-based contrast agents during pregnancy because their safety for the fetus has not yet been proven. In line, however, with the European Society of Radiology guidelines and based on the available evidence, gadolinium-based contrast agents appear to be safe in pregnancy. Gadolinium use should be considered when the diagnostic study is important for the health of the mother.


Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.
Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis.


[Diagnostic value of flow cytometry of bladder lavage in the surveillance of bladder tumors].
DNA index and proliferation index (% greater than 2 n) of 125 bladder washings were studied with flow cytometry. Cystoscopy was positive in 49 patients and negative in 56 patients with a previous history of bladder cancer. There were 20 control patients with a normal bladder. Flow cytometric data was compared with cystoscopic and cytologic data. In the group of 49 patients with a positive cystoscopy, conventional cytology was suspicious or positive in 70% (34/49) whereas flow cytometry was positive in only 43% of the cases (21/49). The diagnostic sensitivity of flow cytometry increased with grade elevation: 7% of grade 1 tumors, 43% of grade 2 and 77% of grade 3 had a positive flow cytometric examination. In the group of 56 patients with a negative cystoscopy, flow cytometry was positive in 36% of the cases and cytology in 6% of the cases. The diagnostic sensitivity of flow cytometry was rather disappointing in the study on bladder washings. Flow cytometric follow-up of bladder washings should be reserved preferentially to patients with a poor prognosis, i.e., superficial bladder cancer with an aneuploid DNA content.


Copeptin as a Prognostic Marker in Prolonged Targeted Temperature Management After Out-of-Hospital Cardiac Arrest.
The aim was to investigate blood concentrations of copeptin and the prognostication in 24 versus 48 hours of targeted temperature management (TTM) in patients resuscitated after out-of-hospital cardiac arrest. This is an exploratory biomarker substudy of the trial entitled; "Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital-cardiac-arrest: A randomized clinical trial." Patients were randomized to target temperature of 33°C ± 1°C for 24 (TTM24) or 48 (TTM48) hours. The primary outcome was copeptin concentrations compared with TTM at admission, 24, 48, and 72 hours (t24, t48, and t72) after reaching target temperature. Secondary outcomes were the association between copeptin and cerebral performance category (CPC) score after 6 months, and copeptin level between cerebral or noncerebral causes of death. Blood samples from 117 patients were analyzed from two Scandinavian sites. No significant differences in copeptin concentrations were found between TTM24 versus TTM48 at admission 211.3 μg/L (148-276.6) versus 179.8 μg/L (127-232.6) (p = 0.45), t24: 23.3 μg/L (16.5-30.2) versus 18.6 μg/L (13.3-23.9) (p = 0.25), t48: 28.8 μg/L (20.6-36.9) versus 19.7 μg/L (14.3-25.1) (p = 0.06), and t72: 23.3 μg/L (13.8-26.8) versus 31.6 μg/L (22-41.2) (p = 0.05). Copeptin concentrations were significantly higher in poor neurological outcome group at t24, t48, and t72 (p < 0.01), but not at admission (p = 0.19). The prognostic ability of copeptin (area under the receiver operating characteristic curve) was at admission: 0.59 (95% confidence intervals: 0.46-0.72), t24: 0.74 (0.63-0.86), t48: 0.8 (0.7-0.9), and t72: 0.76 (0.65-0.87). Copeptin levels were not significantly different in noncerebral compared with cerebral causes at admission: p = 0.41, t24: p = 0.52, t48: p = 0.15, and t72: p = 0.38. There were no differences in the level of copeptin in TTM24 versus TTM48. Blood concentrations of copeptin were associated with CPC at 6 months, and no association between levels of copeptin and cerebral versus noncerebral causes of death was observed.


Controlled Layer-by-Layer Etching of MoS₂.
Two-dimensional (2D) metal dichalcogenides like molybdenum disulfide (MoS2) may provide a pathway to high-mobility channel materials that are needed for beyond-complementary metal-oxide-semiconductor (CMOS) devices. Controlling the thickness of these materials at the atomic level will be a key factor in the future development of MoS2 devices. In this study, we propose a layer-by-layer removal of MoS2 using the atomic layer etching (ALET) that is composed of the cyclic processing of chlorine (Cl)-radical adsorption and argon (Ar)(+) ion-beam desorption. MoS2 etching was not observed with only the Cl-radical adsorption or low-energy (<20 eV) Ar(+) ion-beam desorption steps; however, the use of sequential etching that is composed of the Cl-radical adsorption step and a subsequent Ar(+) ion-beam desorption step resulted in the complete etching of one monolayer of MoS2. Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) indicated the removal of one monolayer of MoS2 with each ALET cycle; therefore, the number of MoS2 layers could be precisely controlled by using this cyclical etch method. In addition, no noticeable damage or etch residue was observed on the exposed MoS2.


Cytokeratin polypeptide expression during the histogenesis of guinea pig submandibular salivary gland.
The present study was directed towards the characterization of cell-specific histogenetic markers for the various epithelial elements of the adult and the developing guinea pig submandibular salivary gland. We have employed immunofluorescent labelling using three cytokeratin monoclonal antibodies, for which the polypeptide specificities towards guinea pig cytokeratins were determined. All the epithelial elements of the adult gland were positively labelled with two monoclonal antibodies, namely KG 8.13 ('broad spectrum' anti-cytokeratin) and antibody Ks B.18 (reactive with a simple cytokeratin-specific polypeptide of 49 X 10(3) Mr). Antibody KS 8.58 (reactive with a guinea pig cytokeratin polypeptide of 50 X 10(3) Mr) labelled the basal cells of the large ducts, as well as the myoepithelium. During development of the gland, the submandibular anlage and its primary and secondary branches with their terminal buds, were uniformly labelled with the three antibodies; however, the cytokeratin polypeptides reactive with antibody KS 8.58, which were apparently expressed in all cells of the developing ducts, gradually disappear from most of the ductal cells, starting at about 6 weeks of gestation, and remain only in the basal or reserve cells of the large ducts and the myoepithelium. These observations support the notion that the basal cells retain at least some of the properties of the embryonic glandular epithelium and could be considered as pluripotent reserve cells which may function as progenitors for other epithelial elements in the salivary glands epithelia.