Basal-lateral and intracellular membrane populations of rat exorbital lacrimal gland.
With the goal of isolating and identifying plasma membrane vesicle populations from epithelial cells of the rat exorbital lacrimal gland, we have designed an analytical fractionation of homogenates of the gland parenchyma. This fractionation utilizes separation procedures based on three independent physical properties of subcellular particles: sedimentation coefficient, density, and density after interaction of membrane cholesterol with digitonin. A commonly accepted marker for basal-lateral membranes, Na-K-ATPase, is associated with at least two physically distinct membrane populations. One population can be identified as basal-lateral membrane fragments on the basis of its fractional and specific contents of Na-K-ATPase; it accounts for 50% of the total Na-K-ATPase activity, enriched 29-fold with respect to the initial homogenate. With these values we calculate that the sample of basal membranes has been purified 60-fold with respect to the initial homogenate. The remaining Na-K-ATPase activity appears to be associated, at three- to fivefold lower specific activities, with intracellular membrane populations. We speculate that these populations have been derived from the Golgi complex.


Aesthetic surgery of the face and neck.
The reader is presumed to have a basic understanding of facial anatomy and facial rejuvenation procedures. After reading this article, the reader should also be able to: 1. Identify the essential anatomy of the face as it relates to facelift surgery. 2. Describe the common types of facelift procedures, including their strengths and weaknesses. 3. Apply appropriate preoperative and postoperative management for facelift patients. 4. Describe common adjunctive procedures. Physicians may earn 1.0 AMA PRA Category 1 Credit by successfully completing the examination based on material covered in this article. This activity should take one hour to complete. The examination begins on page 464. As a measure of the success of the education we hope you will receive from this article, we encourage you to log on to the Aesthetic Society website and take the preexamination before reading this article. Once you have completed the article, you may then take the examination again for CME credit. The Aesthetic Society will be able to compare your answers and use these data for future reference as we attempt to continually improve the CME articles we offer. ASAPS members can complete this CME examination online by logging on to the ASAPS members-only website (http://www.surgery.org/members) and clicking on "Clinical Education" in the menu bar. Modern aesthetic surgery of the face began in the first part of the 20th century in the United States and Europe. Initial limited excisions gradually progressed to skin undermining and eventually to a variety of methods for contouring the subcutaneous facial tissue. This particular review focuses on the cheek and neck. While the lid-cheek junction, eyelids, and brow must also be considered to obtain a harmonious appearance, those elements are outside the scope of this article. Overall patient management, including patient selection, preoperative preparation, postoperative care, and potential complications are discussed.


Scientists' Views on the Ethics, Promises and Practices of Synthetic Biology: A Qualitative Study of Australian Scientific Practice.
Synthetic biology is a broad term covering multiple scientific methodologies, technologies, and practices. Pairing biology with engineering, synbio seeks to design and build biological systems, either through improving living cells by adding in new functions, or creating new structures by combining natural and synthetic components. As with all new technologies, synthetic biology raises a number of ethical considerations. In order to understand what these issues might be, and how they relate to those covered in ethics literature on synbio, we conducted an interview study with practicing synthetic biologists affiliated with a synthetic biology centre in Australia. Scientists identified a range of ethical challenges germane to the field, including precarious employment, pressures from industry, gender inequity, and the negative effects of the hyping of synbio. These challenges differed markedly from those identified in the ethics literature, whose treatment of the harms and benefits of synbio remains largely speculative and abstract. In our discussion of the pragmatic, every day ethical issues synthetic biologists face, we illustrate how issues of waste or research integrity play pivotal roles in everything from lived experiences in the laboratory, to long-term research trajectories guiding the field. In a confirmation of the ethical relevance of our participant's views on the field, we argue that the subjects they raise must be included in any ethical analysis of synbio as a field.


[Translumbar coronary angiography and aortography in a patient with Takayasu's arteritis].
Since its introduction by Dos Santos in 1929, arterial angiography by translumbar percutaneous approach has suffered some transformations. Nowadays it has been replaced by other percutaneous approaches and it is indicated only when these routes of access have failed due to aortoiliac or subclavian arteries obstruction. This report presents a patient with Takayasu's Arteritis with severe peripheral arterial obstruction and unstable angina, who underwent coronary arteriography and aortography by translumbar approach. A review of this technique is made.


A transcriptional activator is located in the coding region of the yeast PGK gene.
Expression of heterologous genes from the PGK promoter on high copy number plasmids in yeast is relatively poor compared to the intact PGK gene because of low steady-state RNA levels. In this paper we show that low levels of heterologous RNA are not due to instability of mRNA but result from inefficient transcription due to a defect in RNA synthesis. A comparison of RNA levels from homologous and heterologous transcription units allowed the identification of a positive activator for transcription within the PGK coding region which is required for efficient expression of the PGK gene. Deletion of this region, the "downstream activator sequence", causes a six to ten fold reduction in transcriptional efficiency from the PGK 5' noncoding region.


Supporting student mental health nurses in clinical placement through virtual in-practice support (VIPS): Innovation uptake and the 'VIPS' project.
The integration of technology in nurse education has become an essential element of academic practice. Yet innovation uptake between academic institutions across the four countries of the UK and their clinical practice partners has proved problematic, leading to a slow introduction of digitally enhanced teaching and learning innovations, particularly in the area of clinical decision making and leadership. The Virtual in Practice Support (VIPS) project involved two academic institutions working with the same mental health care service partner aiming to maximise student clinical placement learning. Student nurses in their final year of training were invited to take part in testing the viability of distance e-tutoring (via computer access to academic nurse lecturers) for facilitated critical reflection. An evaluation of the use of video linked conference sessions, set up for students to undertake a group based online (i.e. virtual) group tutorial is presented. All participants completed an evaluation data sheet using a five point Likert scale and free text evaluation feedback form completed at the end of each online tutorial session. Students were also invited to a focus group and all tutors were interviewed at the completion of the project. The VIPS project findings highlight; i) the importance of a clear project vision for innovation uptake ii) consequences of working with innovation champions and iii) how technology can be used to maximise student learning across geographical distance through online facilitated group critical discussion. VIPS' participants were able to articulate positive outcomes as a result of engaging in a multi-institutional project that capitalised on the richness of nursing clinical practice learning experience for both the students and the academics involved as innovation champions.


Antiangiogenic and radiotherapy for cancer treatment.
Tumor growth and progression depends on tumor angiogenesis, the growth of tumor blood vessels, therefore, targeting tumor angiogenesis is a very promising approach for controlling tumor growth and/or causing regression. Tumor blood vessels have been recognized as a critical component of radiation response to the point of being independent of tumor oxygenation during radiation. An anti-angiogenic approach has been considered less likely to develop drug resistance. But recent findings suggest that anti-angiogenesis causes hypoxia that selects tumor cells (due to genetic instability) that are less dependent on blood supply and leads to drug resistance. The approach of combination of anti-angiogenesis with ionizing radiation by targeting both endothelial and tumor cells should minimize this possibility. The combination may produce a synergistic anti-tumor effect.


Quantification of lumbar function. Part 1: Isometric and multispeed isokinetic trunk strength measures in sagittal and axial planes in normal subjects.
The goals of this study were to: evaluate the repeatability of a method of measuring trunk strength; measure isometric and isokinetic strength of trunk flexors, extensors and rotators; explore relationships among these muscle groups; and compare a torque to body weight adjustment measure versus lean body weight. One hundred twenty-five normal subjects (62 males, 63 females) were tested using a Cybex prototype trunk extension-flexion system. Sixty-seven subjects (25 males, 42 females) were tested using a prototype torso rotation unit. Fifty were tested on both devices. Results demonstrated that the strength data were reliable, with strength being greatest in extension. The following were also learned-torque output declined slightly with increased speed; extensor-flexor strength remained consistent from 18 to 44 years; extension-flexion ratios exceeded 1.1:1; left to right rotation ratios remained 1:1; there was no significant difference between torque adjusted to body weight or to lean body weight.


Short-term and long-term survival of kidney allograft: cure model analysis.
Kidney allograft failure is a major concern in kidney transplant recipients. We separately assessed risk factors for long-term and short-term survival of death-censored kidney allograft. This study included 397 kidney recipients who underwent surgery in Afzalipour Hospital, Kerman, Iran, from 2004 to 2010. The Cox mixture cure model was used to fit independent variables for prediction of graft survival in short-term and long-term. Allograft failure occurred in 43 kidney transplant recipients (10.8%). Among the long-term survivors, hypertension (odds ratio, 3.35; 95% confidence interval [CI], 1.6 to 6.7), a serum creatinine level greater than 1.6 at hospital discharge (odds ratio, 15.1; 95% CI, 7.2 to 31.9), and donor age (odds ratio, 1.14; 95% CI, 1.09 to 1.18) were significant predictors of allograft failure. Overweight, obesity, and male donor were associated with better survival. In short-term survivors, a high body mass index (hazard ratio, 3.59; 95% CI, 1.2 to 10.7) and longer duration of pretransplant dialysis (hazard ratio, 2.4; 95% CI, 1.07 to 5.7) were associated with graft failure, while the risk of allograft failure decreased in recipients who received kidney transplants from living donors versus deceased donors (hazard ratio, 0.3; 95% CI: 0.11 to 0.78) and with each 1-year increase in donor age (hazard ratio, 0.91; 95% CI, 0.86 to 0.96). Many efforts have been made to improve short-term survival of kidney allograft. The cure analysis extends the knowledge by showing that control of which variables can improve both long-term and short-term survival rates.


Gynecological cancers in developing countries: the challenge of chemotherapy in low-resources setting.
The epidemiologic pattern of cancers in developing countries differs in many aspects from that of industrialized nations. Cancer natural history, microbiologic environment, patient's immune system, and drug availability may differ as well. Four of five new cases of cervical cancer and most of cervical cancer deaths occur in developing countries. Where chemoradiation and supportive care facilities are unavailable, it would be logical to consider an inexpensive effective drug. In locally advanced cases, neoadjuvant chemotherapy followed by surgery should be considered the treatment of choice. For ovarian cancer, it may be reasonable to maintain a secure supply of platinum and/or taxanes. For endometrial cancer, platinum compounds are proved active chemotherapic single agents. Oral medroxyprogesterone acetate (MPA) may represent a good chance for treating an advanced or recurrent disease. For vulvar/vaginal cancer, the role of chemotherapy alone is currently considered limited, and it is mostly used as palliative treatment in advanced or recurrent cases. Whenever possible, standard western chemotherapic regimens should be applied in developing countries as well. When standard therapies are unavailable, drugs of choice should be easily accessible, inexpensive, and effective. The most commonly used drugs are cisplatin, cyclophosphamide, and MPA.


Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer.
Epidemiological studies have indicated that high iodine intake might be a risk factor for papillary thyroid cancer (PTC), which commonly harbors the oncogenic T1799A BRAF mutation. The objective of the study was to investigate the relationship between BRAF mutation in PTC and iodine intake in patients. We analyzed and compared the prevalences of the T1799A BRAF mutation in classical PTC of 1032 patients from five regions in China that uniquely harbor different iodine contents in natural drinking water, ranging from normal (10-21 microg/liter) to high (104-287 microg/liter). The BRAF mutation was identified by direct DNA sequencing. The prevalence of BRAF mutation was significantly higher in any of the regions with high iodine content than any of the regions with normal iodine content. Overall, BRAF mutation was found in 387 of 559 PTC with high iodine content (69%) vs. 252 of 473 PTC with normal iodine content (53%), with an odds ratio of 1.97 (95% confidence interval 1.53-2.55) for the association of BRAF mutation with high iodine content (P < 0.0001). In addition, clinicopathological correlation analysis, the largest one of its type ever, showed that BRAF mutation was significantly associated with extrathyroidal invasion, lymph node metastasis, and advanced tumor stages of PTC. High iodine intake seems to be a significant risk factor for the occurrence of BRAF mutation in thyroid gland and may therefore be a risk factor for the development of PTC. This large study also confirmed the association of BRAF mutation with poorer clinicopathological outcomes of PTC.


Choroid plexus cyst in the lateral ventricle causing obstructive symptoms in an adult.
This case of a rare symptomatic choroid plexus cyst in the lateral ventricle, which presented with papilledema and decreased vision, is the first such lesion found in an adult. Five earlier reported cases, all in children, are discussed, as are the limitations of computerized tomographic (CT) scanning and the need for further radiological studies to establish the diagnosis preoperatively. Metrizamide ventriculography with CT scanning is used to define the lesion and plan an operative approach.


Red wine polyphenols correct vascular function injured by chronic carbon tetrachloride intoxication.
The aim of the study was to evaluate the effect of red wine polyphenols extract Provinols™ on the development of cardiovascular injury in the model of carbon tetrachloride (CCl4) intoxication. We followed the thoracic aorta vasoactivity and left ventricle nitric oxide (NO) synthase activity in male Wistar rats. In the preventive experiment lasting for 12 weeks the control group, the group receiving CCl4 (0.5 ml/kg) two times a week subcutaneously, the group receiving Provinols™ (30 mg/kg/day) in drinking water and the group receiving CCl4+Provinols™ was used. In the recovery experiment, the initial 12 weeks of CCl4 treatment were followed by 3 weeks of spontaneous recovery or recovery with Provinols™. CCl4-intoxication resulted in the injury of vasoactivity which was demonstrated by the inhibition of acetylcholine-induced relaxation as well as noradrenaline-induced contraction. In the preventive as well as recovery experiment administration of polyphenols refreshed endothelium-dependent relaxant response and normalized inhibited contraction to adrenergic stimuli. Provinols™ treatment significantly increased NO-synthase activity in all groups. The results revealed beneficial effects of red wine polyphenols on vascular function injured by chronic CCl4 intoxication. The correction of endothelial function seems to be attributed to the activation of NO pathway by polyphenols.


Lonicera hypoglauca inhibits xanthine oxidase and reduces serum uric acid in mice.
Xanthine oxidase (XOD) catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid, and is a key enzyme in the pathogenesis of hyperuricemia. The ability of extracts of Lonicera hypoglauca (Caprifoliaceae) to inhibit XOD was investigated in this study. An ethanol extract (LH-crude) of the leaves of L. hypoglauca and its derived EtOAc soluble sub-fractions (LH-EA) significantly inhibited XOD activity, with IC50 values for LH-crude and LH-EA of 48.8 and 35.2 microg/mL. Moreover, LH-EA reduced serum urate levels IN VIVO in a potassium oxonate-induced hyperuricemic mouse model, by 70.1% and 93.7% of the hyperuricemic untreated group at doses of 300 and 500 mg/kg of LH-EA, respectively. Finally, we used bioactivity-guided fractionation to isolate a new bisflavonoid, loniceraflavone, which showed significant inhibition of XOD (IC50=0.85 microg/mL). These results suggest that L. hypoglauca and its extracts may have a considerable potential for development as an anti-hyperuricemia agent for clinical application.


Acetate acts as a protonophore and differentially affects bead movement and cell migration of the gliding bacterium Cytophaga johnsonae (Flavobacterium johnsoniae).
Cells of Cytophaga johnsonae (now Flavobacterium johnsoniae) are able to translocate on solid surfaces but are unable to swim in liquid media. Organelles that may be involved in this gliding motility have not been detected, and the mechanism(s) responsible remains unknown. The movement of latex beads attached to the cell surface is considered by some to be a manifestation of the gliding machinery. In this study, acetate (in nutrient-level quantity, 45 mM) was found to inhibit bead movement on cell surfaces, whilst formation and movement of groups of cells (rafts) and typical colony spread were not affected; generation time (in liquid culture) was only slightly increased. Since acetate is a weak acid and is recognized as a protonophore, various electron-transport-associated features were assessed in an effort to understand the differential effects of acetate on bead movement and cell motility. Selected protonophores and electron transport inhibitors were tested to compare their effects on cell translocation and metabolic activities with those of acetate. Although O2 consumption was not significantly affected in the presence of acetate and the protonmotive force decreased only minimally, ATP levels were markedly decreased. Arsenate and cyanide were also shown to inhibit bead movement but did not inhibit either movement of rafts of cells or colony spreading. Cyanide lowered O2 consumption, while arsenate did not; both compounds effected substantial decreases in cellular ATP content, but little or no decrease in protonmotive force. The inhibitory effects of these compounds on bead movement over cell surfaces contrasted with the continued ability of cells to form rafts, to glide and to form spreading colonies and led to the conclusion that bead movement is not a complete correlate of the gliding machinery of C. johnsonae. In addition, it seems likely that bead movement is more affected by the level of cellular ATP than it is by the protonmotive force, which has been assumed to provide the energy (derived from the transmembrane gradients) for the gliding machinery.


Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial.
Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. GlaxoSmithKline.


Role of sinoaortic afferents in modulating BP and pulse-interval spectral characteristics in unanesthetized cats.
Sinoaortic denervation (SAD) is accompanied by an increase in blood pressure (BP) and a reduction in pulse-interval (PI) variance. Little is known, however, about the effect of SAD on the complex BP and PI variability pattern, which is identified by spectral analysis. In nine unanesthetized cats in which intra-arterial BP was monitored before and 7-10 days after SAD, spectral powers (estimated by fast Fourier transform) were calculated for the low frequency (LF, 0.025-0.07 Hz), midfrequency (MF, 0.07-0.14 Hz), and high frequency (HF, 0.14-0.60 Hz) band. The very low frequency (VLF) BP and PI components (VLF less than 0.025 Hz) were also estimated. SAD increased systolic BP variance and decreased PI variance. The reduction of PI variance was paralleled by significant and marked reductions in all PI powers including the VLF components. In contrast, the increase in systolic BP variance was accompanied by a marked increase in LF power, a decrease in MF power, and no change in HF power. The VLF BP components increased after SAD for frequencies between 0.025 and 0.0012 Hz, whereas a sudden marked reduction was observed below 0.0012 Hz. Similar results were obtained for diastolic BP powers. Thus the reduction in PI variance induced by SAD is paralleled by a reduction in all PI fluctuations identified by spectral analysis. This is not the case for the SAD-related increase in BP variance, which is accompanied by an increase, no change, or even a reduction in the different BP spectral components.(ABSTRACT TRUNCATED AT 250 WORDS)


Improved growth of pea, lettuce, and radish plants using the slow release of hydrogen sulfide from GYY-4137.
Hydrogen sulfide (H2S) is a key gasotransmitter in agriculture and has been reported to increase the growth of plants in the first two weeks and to mitigate the effects of environmental stressors. GYY-4137 is widely used in these studies because it slowly releases H2S, but there is disagreement as to whether it requires enzymes to release H2S. In this article we describe the release of H2S in water without enzymes and that it releases H2S faster in organic solvents than in water or when mixed in topsoil. Furthermore, we describe the long-term effect of dosing pea, radish, and lettuce plants with GYY-4137 for up to six weeks. The effect of GYY-4137 on plant growth for six weeks was either positive or negative depending on the loading of GYY-4137 and how it was applied to plants. The addition of GYY-4137 to lettuce plants via potting mix resulted in reduced growth and death of the plants. In contrast, application of GYY-4137 to the leaves of lettuce plants increased the harvest weight of the leaves by up to 86%. Our results demonstrate that GYY-4137 can have a positive, important effect on the growth of plants but that this effect is dependent on several factors.


[Perinatal morbidity and mortality secondary to systemic lupus erythematosus in a tertiary care institution].
Autoimmune diseases occur more often in procreation age women, being systemic lupus erythematosus (SLE) a multisystemic, chronic inflammatory illness, the prototype of them. Evaluate the behavior of perinatal morbidity/mortality in a group of pregnant patients, identifying maternal and secondary neonatal complications secondary to SLE. Between January 1992 and December 1997, seventy two cases of maternal SLE were seen at the Instituto Nacional de Perinatología in Mexico City. Maternal and neonatal files were reviewed retrospectively in search of maternal and neonatal complications secondary to SLE. Maternal SLE diagnosis was confirmed in all cases: Ideal reproductive age was seen in 84.7% and extreme ages in 15.3% of the maternal population. Effective prenatal control was carried out in 87% of the pregnancies and 16.6% required at least one hospitalization during gestation. The most frequent complications were infectious (37.5%), haematologic (13.9%) and renal (5.5%). No mortality was seen in the maternal population. Normal weight for gestational age was seen in 58.3% of the neonates and low weight for gestational age in 41.6%; prematurity was seen in the same percentage (41.6%). The most frequent complications in the neonatal population were haematologic (18.0), respiratory (12.5%), metabolic (8.3%) and heart block and cutaneous lesions (1.4%). Neonatal lupus was diagnosed in 8.3%, and survival was of 94.4%). Maternal and neonatal morbidity secondary to SLE was seen in less than 50% of the cases. Infectious complications, the most frequent in the maternal population, is probably secondary to medical treatment. Of the patients with neonatal lupus only 2.8% had heart block and cutaneous lesions. Maternal outcome and neonatal repercussion of maternal SLE do not differ in relation to other authors results. However it is necessary to evaluate the immunologic behavior and genetic predisposition because each population has a different of HLA antigens.


Association of hue discrimination loss and diabetic retinopathy.
The results of Farnsworth-Munsell 100-hue, visual acuity, and visual field testing were compared with the severity of retinopathy in a group of 90 diabetic patients. The patients showed significantly higher than expected Farnsworth-Munsell 100-hue scores, with a tritanlike axis, compared with published age norms for nondiabetic individuals. The magnitude of the acquired blue-yellow hue discrimination defect correlated significantly and to a similar extent with both the severity of overall diabetic retinopathy and the severity of macular edema and hard exudate formation. Visual acuity loss correlated somewhat more significantly with macular edema than with overall retinopathy, whereas the converse was true for visual fields. For all visual function tests, the correlations were more significant for fluorescein leakage in the macula than for capillary nonperfusion in the macula. Abnormal hue discrimination was found in 65% (32/49) of eyes with proliferative diabetic retinopathy, suggesting a potential role for this test in screening for proliferative diabetic retinopathy in primary care facilities. Also, because the ability of diabetic patients with color vision deficiency to perform color-dependent tests for urinary and blood glucose may be impaired, such patients should be made aware of this potential problem.


Correlation of the risk of breast cancer and disruption of the circadian rhythm (Review).
Breast cancer is the worldwide leading cause of cancer incidence among women. Night shift work exposure has been recently considered one of the significant breast cancer risk factors in industrialized countries. The mechanisms by which this work exposure may be responsible for cancer development is still discussed. In the last 15 years, many authors have paid attention to the relationship between night shift work and breast cancer risk. In the current study, eight case-control studies and four prospective epidemiological studies describing such relationship are discussed. A positive correlation between night shift work and breast cancer risk was described in 8 out of 12 studies. However, different reasons suggest that some of these studies have an Achilles heel according to the International Agency of Cancer (IARC) indications. Both the circadian system alteration and the melatonin output reduction, related to the exposure to light-at-night during night shift work, remain the most valid hypotheses on the causal relation of shift work and breast cancer. Overall, the results of the present study suggest that there is an association between night shift work and breast cancer development in western countries. However, further studies are needed to confirm such association and to understand which biomolecular mechanisms may be involved in the pathogenesis of cancer diagnosed in patients with night shift work exposure.


Auditory encoding abnormalities in children with autism spectrum disorder suggest delayed development of auditory cortex.
Findings of auditory abnormalities in children with autism spectrum disorder (ASD) include delayed superior temporal gyrus auditory responses, pre- and post-stimulus superior temporal gyrus (STG) auditory oscillatory abnormalities, and atypical hemispheric lateralization. These abnormalities are likely associated with abnormal brain maturation. To better understand changes in brain activity as a function of age, the present study investigated associations between age and STG auditory time-domain and time-frequency neural activity. While 306-channel magnetoencephalography (MEG) data were recorded, 500- and 1000-Hz tones of 300-ms duration were binaurally presented. Evaluable data were obtained from 63 typically developing children (TDC) (6 to 14 years old) and 52 children with ASD (6 to 14 years old). T1-weighted structural MRI was obtained, and a source model created using single dipoles anatomically constrained to each participant's left and right STG. Using this source model, left and right 50-ms (M50), 100-ms (M100), and 200-ms (M200) time-domain and time-frequency measures (total power (TP) and inter-trial coherence (ITC)) were obtained. Paired t tests showed a right STG M100 latency delay in ASD versus TDC (significant for right 500 Hz and marginally significant for right 1000 Hz). In the left and right STG, time-frequency analyses showed a greater pre- to post-stimulus increase in 4- to 16-Hz TP for both tones in ASD versus TDC after 150 ms. In the right STG, greater post-stimulus 4- to 16-Hz ITC for both tones was observed in TDC versus ASD after 200 ms. Analyses of age effects suggested M200 group differences that were due to a maturational delay in ASD, with left and right M200 decreasing with age in TDC but significantly less so in ASD. Additional evidence indicating delayed maturation of auditory cortex in ASD included atypical hemispheric functional asymmetries, including a right versus left M100 latency advantage in TDC but not ASD, and a stronger left than right M50 response in TDC but not ASD. Present findings indicated maturational abnormalities in the development of primary/secondary auditory areas in children with ASD. It is hypothesized that a longitudinal investigation of the maturation of auditory network activity will indicate delayed development of each component of the auditory processing system in ASD.


Comparison of visual SLAM and IMU in tracking head movement outdoors.
Tracking head movement in outdoor activities is more challenging than in controlled indoor lab environments. Large-magnitude head scanning is common under natural conditions. Compensatory gaze (head and eye) scanning while walking may be critical for people with visual field loss. We compared the accuracy of two outdoor head tracking methods: differential inertial measurement units (IMU) and simultaneous localization and mapping (SLAM). At a fixed location experiment, a gaze aiming test showed that SLAM outperforms IMU in terms of error (IMU: 9.6°, SLAM: 4.47°). In an urban street walking experiment conducted with five patients with hemifield loss, the IMU drift, quantified by root-mean-square deviation, was as high as 68.1°, while the drift of SLAM was only 5.3°. However, the SLAM method suffered from data loss due to tracking failure (~10% overall, and ~ 18% when crossing streets). Our results show that the SLAM and IMU methods have complementary properties. Because of no data gaps, the differential IMU method may be desirable as compared to SLAM in settings where the signal drift can be removed in post-processing and small gaze estimation errors can be tolerated.


Role of adenosine in behavioral state modulation: a microdialysis study in the freely moving cat.
There is considerable evidence to suggest that the activity of forebrain and mesopontine cholinergic neurons is intimately involved in electroencephalographic arousal. Furthermore, our previous in vitro investigation suggested that both cholinergic systems are under a powerful tonic inhibitory control by endogenous adenosine. We thus examined the in vivo effect, on electrographically defined behavioral states, of microdialysis perfusion of adenosine into the cholinergic zones of the substantia innominata of the basal forebrain and the laterodorsal tegmental nucleus of freely moving cats. Localized perfusion of adenosine into either the basal forebrain or the laterodorsal tegmental nucleus caused a marked alteration in sleep-wake architecture. Adenosine (300 microM) perfused into either the basal forebrain or laterodorsal tegmental nucleus produced a dramatic decrease in waking, to about 50% of the basal level. Perfusion into the basal forebrain resulted in a significant increase in rapid eye movement sleep, while slow wave sleep was unchanged. In contrast, adenosine perfusion into the laterodorsal tegmental nucleus produced an increase of both slow wave sleep and rapid eye movement sleep, the magnitude of which were proportional to the decrease in waking. Electroencephalographic power spectral analysis showed that adenosine perfusion into the basal forebrain increased the relative power in the delta frequency band, whereas higher frequency bands (theta, alpha, beta and gamma) showed a decrease. These data strongly support the hypothesis that adenosine might play a key role as an endogenous modulator of wakefulness and sleep. The decrease in wakefulness may be directly related to the inhibition of cholinergic neurons of the basal forebrain and the laterodorsal tegmentum. The increase in rapid eye movement sleep is a novel but robust effect whose origin, at present, is uncertain. The observation that local perfusion of adenosine into either the basal forebrain or the laterodorsal tegmental nucleus dramatically decreases wakefulness suggests that these areas might represent a major site of action of the xanthine stimulants (adenosine antagonists) found in coffee and tea.


Interleukin-2 and the IL-2 receptor: new insights into structure and function.
Interleukin-2 (IL-2) was originally identified in 1976 as a growth factor for T lymphocytes. Since that time it has become an important mediator of immune function through its effects on the growth, development, and activity of T and B lymphocytes, natural killer cells, and lymphokine-activated killer cells. Only cells that bear a specific receptor for IL-2 respond to its immunoregulatory effects. Of all the lymphokine-receptor systems in immunology, perhaps most is known about the structure, function, and binding properties of IL-2 and its cognate receptor. There are two distinct, membrane-associated IL-2 binding components in the high-affinity IL-2 receptor: an alpha subunit and a beta subunit, which associate in a non-covalent manner. Each of these polypeptides can occur on the cell surface in the absence of the other and bind IL-2, although with only low or intermediate affinity relative to the high-affinity receptor complex. The primary structure of each chain has now been deduced from full-length cDNA. The rapid rate of association between IL-2 and the IL-2R alpha subunit is important in the formation of high-affinity binding sites, and the inducibility of the alpha gene contributes to the highly regulated and transient display of high-affinity IL-2R. The IL-2R beta chain controls the slow dissociation rate of IL-2 from the high-affinity receptor. Also, IL-2R beta appears centrally involved in internalization of IL-2 and signal transduction, functions mediated presumably through its long intracytoplasmic domain. However, the actual mechanism of signal transduction in the IL-2/IL-2R system remains undefined. IL-2R beta is a member of a novel family of cytokine-receptor proteins that includes receptors for IL-4, IL-6, and erythropoietin.


Regional gray matter volume is associated with empathizing and systemizing in young adults.
Empathizing is defined as the drive to identify the mental states of others for predicting their behavior and responding with an appropriate emotion. Systemizing is defined as the drive to analyze a system in terms of the rules that govern the system in order to predict its behavior. Using voxel-based morphometry and questionnaires in a large sample of normal, right-handed young adults, we investigated the regional gray matter volume (rGMV) correlates of empathizing and systemizing and additionally those of the D score, which is the difference between systemizing and empathizing, to reveal the comprehensive picture of those correlates. Negative rGMV correlates of empathizing and positive rGMV correlates of the D score (formed by the negative correlation between rGMV and empathizing), were found primarily in nodes in the default mode network, mirror neuron system, dorsal anterior cingulate cortex, and the lateral part of the prefrontal cortex together with other areas. Positive rGMV correlates of systemizing and of the D score (formed by the positive correlation between rGMV and systemizing) were found primarily in nodes in the external attention system, middle cingulate cortex, and other regions. Negative rGMV correlates of systemizing were found in an area close to the left posterior insula and putamen. These findings reconcile some previously inconsistent findings, provide other new findings and suggest that these areas contribute to empathizing-systemizing. Furthermore, the negative/positive rGMV correlates of empathizing and positive/negative rGMV correlates of systemizing overlapped substantially. This may be in line with the notion that empathizing and systemizing compete neurally in the brain.


Hemoglobin, exercise training, and health status in patients with chronic heart failure (from the HF-ACTION randomized controlled trial).
Anemia is common in patients with chronic heart failure (HF), with a prevalence ranging from 10% to 56%, and may be a risk factor for poor outcomes. Anemia in HF remains poorly understood, with significant gaps in its impact on health-related quality of life (HRQoL), with most studies in HF being retrospective or from registries. The purpose of this study was to explore the relation of hemoglobin (Hgb) with HRQoL and training-induced changes in HRQoL in a cohort of patients in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). Using data from HF-ACTION, a randomized controlled trial of exercise training in patients with HF and low left ventricular ejection fractions, HRQoL was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 3 and 12 months, and annually up to 4 years. Treatment group effects on HRQoL were estimated using linear mixed models according to the intention-to-treat principle. It was hypothesized that baseline Hgb would be correlated with baseline KCCQ scales and that Hgb would moderate the beneficial effect of exercise training on HRQoL. Hgb level was not significantly correlated with baseline HRQoL. Baseline Hgb did not moderate the beneficial effect of exercise training on KCCQ overall or subscales relative to usual care. In conclusion, in the HF-ACTION cohort, there was no correlation with baseline Hgb and baseline HRQoL as measured by the KCCQ. In addition, the beneficial effects of HRQoL from exercise training were not modulated by baseline Hgb.


Hypotensive effect of bunitrolol at low plasma concentrations in conscious, unrestrained spontaneously hypertensive rats.
Effects of bunitrolol on mean arterial pressure (MAP) and heart rate (HR) were studied in conscious, unrestrained spontaneously hypertensive (SHR) rats at rest and during handling stress. Propranolol was employed as a reference drug. Plasma drug concentrations were determined to related with the cardiovascular effects of the drugs. Bunitrolol produced a tachycardia for the first 2 hr and a significant reduction in resting MAP at 3 and 4 hr after the oral dose (5 mg/kg) when plasma bunitrolol concentration was less than 10 ng/ml, indicating the difference between cardiac and vascular beta adrenoceptors in sensitivity to intrinsic sympathomimetic action or direct vasodilator action. Propranolol (5 mg/kg) produced no discernible effects on resting MAP and HR. Stress-induced tachycardia was significantly inhibited by both drugs throughout the experiment, while significant inhibition of hypertensive response was observed only at 4 hr after the treatment. Both bunitrolol and propranolol were rapidly absorbed from the gastrointestinal tract. Plasma half-life of these drugs were almost the same values of around 2 hr. These results indicate that dose size, plasma concentrations, and procedures and the timing of blood pressure measurement are the important factors to be considered when the antihypertensive effect of beta-blockers is studied in SHR rats.


Intake of vitamin C and E in pregnancy and risk of pre-eclampsia: prospective study among 57 346 women.
It has been suggested that vitamin C, alone or in combination with vitamin E, may protect against pre-eclampsia, whereas the safety of high-dose vitamin E supplements has been questioned. We investigated dietary intakes of vitamins C and E to see if they correlated with the incidence of pre-eclampsia. Prospective cohort study. The Danish National Birth Cohort; a population-based pregnancy cohort; analyses were based on 57 346 pregnancies. Vitamin intake was estimated from a food frequency questionnaire completed in gestational week 25, recording intake from diet and supplements during the previous four weeks. Pre-eclampsia diagnoses were obtained from the Danish National Patient Registry; we worked with two entities, 'pre-eclampsia (all types)' and 'severe pre-eclampsia/eclampsia/HELLP'. We adjusted for confounding factors by logistic regression. A small increase in the incidence of severe disease was also seen in the group of women (64, n = 49 373) with a high intake of vitamin E from supplements and dietary sources. The incidence of 'pre-eclampsia (all types)' did not correlate with dietary vitamin C and E intake. There was a decreasing trend (P = 0.01) in the incidence of 'severe pre-eclampsia/eclampsia/HELLP' with increasing dietary vitamin C intake; with an intake of 130-170 mg/day as reference, odds ratios ranged from 1.21 (95% confidence interval 0.83 to 1.75) for an intake below 70 mg/day to 0.70 (0.40 to 1.23) for an intake exceeding 275 mg/day (total n = 57 346). For vitamin E intake aggregated from diet and supplements (n = 49 373), with an intake of 10.5-13.5 mg/day as reference, the 'severe pre-eclampsia/eclampsia/HELLP' odds ratio was 1.46 (1.02 to 2.09) for an intake exceeding 18 mg/day. Low dietary intake of vitamin C was associated with a trend towards an increased incidence of either severe pre-eclampsia, eclampsia or HELLP. A small increase in the incidence of severe disease was also seen in the group of women with a high intake of vitamin E from supplements and dietary sources.


Protein-induced low molecular weight hydrogelator self-assembly through a self-sustaining process.
Controlling how, when and where a self-assembly process occurs is essential for the design of the next generation of smart materials. Along this route, enzyme-assisted self-assembly is a powerful tool developed during the last decade. Here we introduce another strategy allowing for spatiotemporal control over peptide self-assemblies. We use a Fmoc-peptide precursor in dynamic equilibrium with its low molecular weight hydrogelator (LMWH) through a reversible disulfide bond. In the absence of proteins, no self-assembly of the hydrogelator is observed. In the presence of proteins, their interactions with the precursor initiate a self-assembly process of the hydrogelator around them. This self-assembly displaces the equilibrium between precursor and LMWH according to Le Chatelier's principle, producing new hydrogelators available to pursue the self-assembly growth. One thus establishes a self-sustaining cycle fuelled by the self-assembly itself until full consumption of the LMWH. For proteins in solutions this process can lead to a supramolecular hydrogel whereas for proteins deposited on a surface, the gel growth is initiated exclusively from the surface.


Towards improved quality of GPCR models by usage of multiple templates and profile-profile comparison.
G-protein coupled receptors (GPCRs) are targets of nearly one third of the drugs at the current pharmaceutical market. Despite their importance in many cellular processes the crystal structures are available for less than 20 unique GPCRs of the Rhodopsin-like class. Fortunately, even though involved in different signaling cascades, this large group of membrane proteins has preserved a uniform structure comprising seven transmembrane helices that allows quite reliable comparative modeling. Nevertheless, low sequence similarity between the GPCR family members is still a serious obstacle not only in template selection but also in providing theoretical models of acceptable quality. An additional level of difficulty is the prediction of kinks and bulges in transmembrane helices. Usage of multiple templates and generation of alignments based on sequence profiles may increase the rate of success in difficult cases of comparative modeling in which the sequence similarity between GPCRs is exceptionally low. Here, we present GPCRM, a novel method for fast and accurate generation of GPCR models using averaging of multiple template structures and profile-profile comparison. In particular, GPCRM is the first GPCR structure predictor incorporating two distinct loop modeling techniques: Modeller and Rosetta together with the filtering of models based on the Z-coordinate. We tested our approach on all unique GPCR structures determined to date and report its performance in comparison with other computational methods targeting the Rhodopsin-like class. We also provide a database of precomputed GPCR models of the human receptors from that class. GPCRM SERVER AND DATABASE: http://gpcrm.biomodellab.eu.


Bacterial Community Selection of Russula griseocarnosa Mycosphere Soil.
Russula griseocarnosa is a wild, ectomycorrhizal, edible, and medicinal fungus with high economic value in southern China. R. griseocarnosa fruiting bodies cannot be artificially cultivated. To better understand the effects of abiotic and biotic factors on R. griseocarnosa growth, the physicochemical properties of R. griseocarnosa and its associated bacterial communities were investigated in two soil types (mycosphere and bulk soil) from Fujian, Guangdong, and Guangxi Provinces. The results revealed that the diversity, community structure, and functional characteristics of the dominant mycosphere bacteria in all geographical locations were similar. Soil pH and available nitrogen (AN) are the major factors influencing the mycosphere-soil bacterial communities' structure. The diversity of soil bacteria is decreased in R. griseocarnosa mycosphere when compared with the bulk soil. Burkholderia-Paraburkholderia, Mycobacterium, Roseiarcus, Sorangium, Acidobacterium, and Singulisphaera may also be mycorrhiza helper bacteria (MHB) of R. griseocarnosa. The functional traits related to the two-component system, bacterial secretion system, tyrosine metabolism, biosynthesis of unsaturated fatty acids, and metabolism of cofactors and vitamins were more abundant in R. griseocarnosa mycosphere soil. The mycosphere soil bacteria of R. griseocarnosa play a key role in R. griseocarnosa growth. Application of management strategies, such as N fertilizer and microbial fertilizer containing MHB, may promote the conservation, propagation promotion, and sustainable utilization of R. griseocarnosa.


Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis.
Aim: We performed a systematic review and network meta-analysis evaluating the safety and efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among dialysis chronic kidney disease patients. Methods: Safety was evaluated with any adverse events (AEs), serious adverse events (SAEs), and 12 common events. Efficacy was mainly analyzed with hemoglobin response. All reported results were summarized using mean difference and risk ratio (RR) with 95% confidence interval (CI). Publication bias was assessed through funnel plots. Results: Twenty trials (19 studies) with 14,947 participants were included, comparing six HIF-PHIs with erythropoiesis-stimulating agents (ESAs). No significant differences were indicated in overall AEs and SAEs between each HIF-PHI and ESA. The occurrence of gastrointestinal disorder was higher in enarodustat and roxadustat than in ESAs (RR: 6.92, 95% CI: 1.52-31.40, p = 0.01; RR: 1.30, 95% CI: 1.04-1.61, p = 0.02). The occurrence of hypertension was lower in vadadustat than in ESAs (RR: 0.81, 95% CI: 0.69-0.96, p = 0.01). The occurrence of vascular-access complications was higher in roxadustat (RR: 1.15, 95% CI: 1.04-1.27, p<0.01) and lower in daprodustat (RR: 0.78, 95% CI: 0.66-0.92, p<0.01) than in ESAs. In the risk of the other nine events, including cardiovascular events, no significant differences were observed between HIF-PHIs and ESAs. For hemoglobin response, network meta-analysis showed that compared with ESAs, significant increases were shown in roxadustat (RR: 1.04, 95% CI: 1.01-1.07, p<0.01) and desidustat (RR: 1.22, 95% CI: 1.01-1.48, p = 0.04), whereas noticeable reductions were indicated in vadadustat (RR: 0.88, 95% CI: 0.82-0.94, p<0.01) and molidustat (RR: 0.83, 95% CI: 0.70-0.98, p = 0.02). There was no significant difference between daprodustat and ESAs (RR: 0.97, 95% CI: 0.89-1.06, p = 0.47). Conclusion: Although HIF-PHIs did not show significant differences from ESAs in terms of overall AEs and SAEs, statistical differences in gastrointestinal disorder, hypertension, and vascular-access complications were observed between HIF-PHIs, which deserved to be noted in clinical decision making. Systematic review registration: This study is registered with PROSPERO (registration number CRD42022312252).


A Generative Modeling Approach to Calibrated Predictions: A Use Case on Menstrual Cycle Length Prediction.
We explore how to quantify uncertainty when designing predictive models for healthcare to provide well-calibrated results. Uncertainty quantification and calibration are critical in medicine, as one must not only accommodate the variability of the underlying physiology, but adjust to the uncertain data collection and reporting process. This occurs not only on the context of electronic health records (i.e., the clinical documentation process), but on mobile health as well (i.e., user specific self-tracking patterns must be accounted for). In this work, we show that accurate uncertainty estimation is directly relevant to an important health application: the prediction of menstrual cycle length, based on self-tracked information. We take advantage of a flexible generative model that accommodates under-dispersed distributions via two degrees of freedom to fit the mean and variance of the observed cycle lengths. From a machine learning perspective, our work showcases how flexible generative models can not only provide state-of-the art predictive accuracy, but enable well-calibrated predictions. From a healthcare perspective, we demonstrate that with flexible generative models, not only can we accommodate the idiosyncrasies of mobile health data, but we can also adjust the predictive uncertainty to per-user cycle length patterns. We evaluate the proposed model in real-world cycle length data collected by one of the most popular menstrual trackers worldwide, and demonstrate how the proposed generative model provides accurate and well-calibrated cycle length predictions. Providing meaningful, less uncertain cycle length predictions is beneficial for menstrual health researchers, mobile health users and developers, as it may help design more usable mobile health solutions.


Prognostic implications of bronchogenic carcinoma proven by bronchoscopic biopsy.
A total of 104 cases of bronchoscopically biopsy proven bronchogenic carcinoma are reviewed. Twenty-seven of 39 patients with operable lesions underwent pulmonary resection. There are seven patients with squamous cell tumors who are long-term, cancer-free survivors. The operative mortality was low at 2.3 per cent. A positive bronchoscopic biopsy should not be considered a contraindication for exploration, and an aggressive approach for squamous cell lesions seems justified.


Olfactomedin 4 inhibits cathepsin C-mediated protease activities, thereby modulating neutrophil killing of Staphylococcus aureus and Escherichia coli in mice.
Neutrophils kill bacteria generally through oxidative and nonoxidative mechanisms. Whereas much research has focused on the enzymes essential for neutrophil killing, little is known about the regulatory molecules responsible for such killing. In this study, we investigated the role of olfactomedin 4 (OLFM4), an olfactomedin-related glycoprotein, in neutrophil bactericidal capability and host innate immunity. Neutrophils from OLFM4⁻/⁻ mice have increased intracellular killing of Staphylococcus aureus and Escherichia coli in vitro. The OLFM4⁻/⁻ mice have enhanced in vivo bacterial clearance and are more resistant to sepsis when challenged with S. aureus or E. coli by i.p. injection. OLFM4 was found to interact with cathepsin C, a cysteine protease that plays an important role in bacterial killing and immune regulation. We demonstrated that OLFM4 inhibited cathepsin C activity in vitro and in vivo. The cathepsin C activity in neutrophils from OLFM4⁻/⁻ mice was significantly higher than that in neutrophils from wild-type littermate mice. The activities of three serine proteases (neutrophil elastase, cathepsin G, and proteinase 3), which require cathepsin C activity for processing and maturity, were also significantly higher in OLFM4⁻/⁻ neutrophils. The bacterial killing and clearance capabilities observed in OLFM4⁻/⁻ mice that were enhanced relative to wild-type mice were significantly compromised by the additional loss of cathepsin C in mice with OLFM4 and cathepsin C double deficiency. These results indicate that OLFM4 is an important negative regulator of neutrophil bactericidal activity by restricting cathepsin C activity and its downstream granule-associated serine proteases.


Community reinforcement and family training: an effective option to engage treatment-resistant substance-abusing individuals in treatment.
Many individuals with substance use disorders are opposed to seeking formal treatment, often leading to disruptive relationships with concerned significant others (CSOs). This is disturbing, as untreated individuals are often associated with a variety of other addiction-related problems. Community Reinforcement and Family Training (CRAFT) provides an option to the more traditional treatment and intervention approaches. The objective of this systematic review was to compare CRAFT with the Alcoholics Anonymous/Narcotics Anonymous (Al-Anon/Nar-Anon) model and the Johnson Institute intervention in terms of its ability to engage patients in treatment and improve the functioning of CSOs. The electronic databases PubMed, PsycINFO, EMBASE, CINAHL and the Cochrane Library were consulted. Four high-quality randomized controlled trials were identified, with a total sample of 264 CSOs. Data were synthesized to quantify the effect with 95% confidence intervals, using the random effects model. CRAFT produced three times more patient engagement than Al-Anon/Nar-Anon [relative risk (RR) 3.25, 95% confidence interval (CI) 2.11-5.02, P < 0.0001; numbers needed to treat (NNT) = 2] and twice the engagement of the Johnson Institute intervention (RR 2.15, 95% CI 1.28-3.62, P = 0.004; NNT = 3). Overall, CRAFT encouraged approximately two-thirds of treatment-resistant patients to attend treatment, typically after [corrected] four to six CRAFT sessions. CSOs showed marked psychosocial and physical improvements whether they were assigned to CRAFT, Al-Anon/Nar-Anon or the Johnson Institute intervention within the 6-month treatment window. CRAFT has been found to be superior in engaging treatment-resistant substance-abusing individuals compared with the traditional programmes.


Correlation between a self-administered walk test and a standardised Six Minute Walk Test in adults.
This study was undertaken to assess the correlation between a self-administered, adapted Six Minute Walk Test (the Home-Heart-Walk) and the standard Six Minute Walk Test based on the American Thoracic Society guideline. A correlational study was conducted at a university campus in Sydney, Australia. Thirteen healthy volunteers underwent the Home-Heart-Walk and the standard Six Minute Walk Test on a single occasion. The distance that participants walked during the two tests was assessed using Pearson's correlation. The correlation between the Home-Heart-Walk and the Six Minute Walk Test distance was 0.81. The Home-Heart-Walk distance was highly correlated to the standard Six Minute Walk Test distance in this study. This relationship provides confidence for further research in populations to facilitate monitoring and evaluation.


BPX-01 Minocycline Topical Gel Shows Promise for the Treatment of Moderate-to-severe Inflammatory Acne Vulgaris.
Background and objectives: Acne vulgaris is a highly prevalent and multifactorial skin disorder that can adversely impact health-related quality of life. Factors that contribute to the pathogenesis of acne include pilosebaceous proliferation of proinflammatory Propionibacterium acnes (P. acnes) bacteria, presence of circulating androgens, excess sebum production, abnormal follicular keratinization, and multiple inflammatory cascades. Oral tetracyclines-especially doxycycline and minocycline-are frequently prescribed for the treatment of moderate-to-severe acne, given their anti-inflammatory properties and their effect on P. acnes reduction. Notwithstanding their established efficacy in the management of acne vulgaris, there is a desire to limit systemic exposure to antibiotics given growing concerns regarding bacterial resistance as well as the potential for serious side effects. This report describes outcomes of two randomized, vehicle-controlled trials (Phases IIa and IIb) of BPX-01, a topical minocycline gel, in the treatment of moderate-to-severe acne. Methods: In Study 1 (NCT02709096), at a single center, 33 subjects with highly fluorescing facial skin were randomized 2:1 to BPX-01 1% or vehicle control once-daily treatment for four weeks. Changes in P. acnes quantitative bacteriological cultures were assessed, as well as cutaneous tolerance to the study drug by both subjects and the investigator. In Study 2 (NCT02815332), subjects with moderate-to-severe inflammatory nonnodular acne (n=226) at 15 centers were randomized 1:1:1 to treatment with BPX-01 1%, BPX-01 2%, or vehicle control once-daily for 12 weeks. The primary endpoint was reduction in the number of inflammatory lesions; other endpoints included the number of noninflammatory lesions, Investigator's Global Assessment (IGA) of severity, and subjective ratings (investigator and subject) of acne. In both studies, cutaneous tolerability and safety were assessed, and plasma minocycline levels were tracked with a highly sensitive assay. Results: In Study 1, BPX-01 treatment reduced P. acnes colonization by 90.9 percent, which exceeded the reduction in the vehicle control group (65.53%; p=0.020). In Study 2, treatment with BPX-01 2% reduced the number of inflammatory lesions by 58.5 percent, exceeding the reduction in the vehicle control group (43.8%; p=0.0256). Trends toward an improvement preferential to BPX-01 2% were observed in the other endpoints. Across both studies, BPX-01 treatment was well-tolerated, with no photosensitivity, postinflammatory hyperpigmentation, or skin discoloration reported. A single subject (out of 259 study participants ) was identified to have detectable levels of plasma minocycline at low levels (42ng/mL) after 12 weeks of treatment but had no signs or symptoms associated with systemic administration of minocycline. Conclusion: BPX-01 appears to exhibit an effectiveness profile for reduction of inflammatory (nonnodular) acne lesions similar to that of oral minocycline formulations. However, because BPX-01 is topical and exhibits negligible systemic exposure, the likelihood of adverse events associated with oral minocycline use is much lower. These results demonstrate effectiveness of BPX-01 topical minocycline gel in reducing P. acnes colonization, suggesting that the BPX-01 2% formulation is a promising treatment for moderate-to-severe nonnodular, inflammatory acne vulgaris in both reduction of inflammatory lesions and also overall improvement in facial acne according to IGA.


TIMP3: a physiological regulator of adult myogenesis.
Myogenic differentiation in adult muscle is normally suppressed and can be activated by myogenic cues in a subset of activated satellite cells. The switch mechanism that turns myogenesis on and off is not defined. In the present study, we demonstrate that tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of TNFalpha-converting enzyme (TACE), acts as an on-off switch for myogenic differentiation by regulating autocrine TNFalpha release. We observed that constitutively expressed TIMP3 is transiently downregulated in the satellite cells of regenerating mouse hindlimb muscles and differentiating C2C12 myoblasts. In C2C12 myoblasts, perturbing TIMP3 downregulation by overexpressing TIMP3 blocks TNFalpha release, p38 MAPK activation, myogenic gene expression and myotube formation. TNFalpha supplementation at a physiological concentration rescues myoblast differentiation. Similarly, in the regenerating soleus, overexpression of TIMP3 impairs release of TNFalpha and myogenic gene expression, and delays the formation of new fibers. In addition, downregulation of TIMP3 is mediated by the myogenesis-promoting microRNA miR-206. Thus, TIMP3 is a physiological regulator of myogenic differentiation.


Focused comprehensive, quantitative, functionally based echocardiographic evaluation in the critical care unit is feasible and impacts care.
To determine whether comprehensive quantitative echocardiogram could be used as a resuscitation tool in critically ill surgical patients and to assess its effect on patient care. Prospective observational. The Trauma and Surgical Intensive Care Units of the University of Maryland Medical Center. Critically ill trauma and surgical patients. The Focused Rapid Echocardiographic Evaluation (FREE), an abbreviated version of a comprehensive transthoracic echocardiogram, which is under an approved protocol, was performed. Over a 30-month period, 791 FREEs were performed on 659 patients. The mean patient age was 60 (±17) years. Ninety-one percent were intubated and 80% were postoperative. Ejection fraction was reported for 95%, and cardiac index was reported for 89% of FREE studies. Right heart function was assessed for 94%. Measures of volume status--internal left ventricular diameter, inferior vena cava diameter, diameter change, and stroke volume variation--were reported for 88%, 79%, 75%, and 89% of patients, respectively. The FREE was judged to be useful by the consulting primary care team for 95% of patients, and altered the plan of care for 57%. The most common change was administration of a fluid bolus (43%), followed by change from an original prestudy plan to one of monitoring (24%), diuresis (23%), addition/titration of an inotropic agent (19%), and/or addition/titration of a vasoconstrictor (8%). The FREE is feasible and alters care in the intensive care unit by providing clinical data not otherwise available at the bedside. Further studies are warranted to assess the impact of comprehensive echocardiogram-directed resuscitation on patient outcomes.


Vitamin D and Age-Related Macular Degeneration.
In recent years, the relationship between vitamin D and health has received growing attention from the scientific and medical communities. Vitamin D deficiencies have been repeatedly associated with various acute and chronic diseases, including age-related macular degeneration (AMD). Its active metabolite, 1α,25-dihydoxy vitamin D, acts as a modulator of cell proliferation, differentiation and apoptosis, and cumulative data from experimental and observational studies suggest that relatively a lower vitamin D status could be a potential risk factor for the development of early and/or late AMD. Herein, we made a narrative review of the mechanisms linking a potential role of vitamin D with the current concepts of AMD pathophysiology.


In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp.
Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ line activating point mutations of the rearranged during transfection (RET) proto-oncogene. RET encodes a receptor with tyrosine kinase activity that targets several intracellular signaling cascades, such as RAS-RAF-ERK1/2, PIK3-AKT, and STAT transcription factors. The objective of this study was to assess the function of three germ line RET variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three kindreds of isolated AS-MTC. For this purpose, we employed vectors expressing each of the RET variants and measured the number of NIH3T3 transformation foci and soft agar colonies, the degree of activation of known RET intracellular signaling targets (ERK1/2, STAT1, STAT3, and TCF4), and the extent of ERK1/2 inhibition on sorafenib treatment. We found that RET variants Arg886Trp and Glu511Lys have shown increased in vitro transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not significantly increased the number of foci and agar colonies relative to wild-type RET (RET-WT). The variants Glu511Lys and Arg886Trp showed 10- and 12.5-fold ERK1/2 activation respectively, that was significantly higher than that observed for RET-WT (fivefold). Increased levels of STAT1 and TCF4 activation were only observed for RET Arg886Trp (2.5- and 3-fold versus 1.2- and 2-fold in RET-WT respectively). The three RET variants analyzed here were sensitive to treatment with sorafenib. In conclusion, our results allow to classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens.


Resistance of Plasmodium falciparum to chemotherapy with 4-aminoquinolines in the Ok Tedi area of Papua New Guinea.
In the North Fly region of the Western Province of Papua New Guinea 491 cases of Plasmodium falciparum infection were monitored in vivo for sensitivity to chloroquine and amodiaquine over a 2-year period; 41% resistance was detected. The RI type accounted for 74% of the resistant strains detected; 43% of these recrudesced on day 28 or shortly thereafter. 22% of resistant strains were RII type and 4% R III. The infections were categorized as imported or locally acquired. Imported infections accounted for 58% of the cases monitored and showed a resistance rate of 49%. Resistance was detected in 24% of the cases indigenous to the North Fly region (13% in the Kiunga-Ningerum area and 38% in the Ok Tedi-Star Mountains area). Linguistic groups immediate to the Ok Tedi mining operation, the Wopkaimin and Kamfaiwolmin, showed an increase in resistance from 28% in 1986 to 55% the following year. This increase was associated with renewed construction activity within the mine's development area. Two falciparum malaria outbreaks were experienced during this study, the second being attributed to introduced strains. The study showed the impact of age and variation of malaria endemicity in suppressing resistance. The study also demonstrated a possible cross-resistance problem between imported cases of P. falciparum treated with amodiaquine and chloroquine, with resistance rates of 58% and 60%, respectively, demonstrated in children under 10 years of age. The 61% amodiaquine resistance rate in locally acquired infection in children was attributed to drug pressure, since chloroquine resistance in the same group was reported at 19%. RIII-type resistance in children was only detected in those treated with amodiaquine. The efficacy of amodiaquine in clearing only 41% of the P. falciparum infections in children was a major concern. All 201 resistant P. falciparum infections detected over the 24-month monitoring period responded to treatment with quinine and Fansidar.


Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases.
The Fas/APO-1-receptor associated cysteine protease Mch5 (MACH/FLICE) is believed to be the enzyme responsible for activating a protease cascade after Fas-receptor ligation, leading to cell death. The Fas-apoptotic pathway is potently inhibited by the cowpox serpin CrmA, suggesting that Mch5 could be the target of this serpin. Bacterial expression of proMch5 generated a mature enzyme composed of two subunits, which are derived from the pre-cursor proenzyme by processing at Asp-227, Asp-233, Asp-391, and Asp-401. We demonstrate that recombinant Mch5 is able to process/activate all known ICE/Ced-3-like cysteine proteases and is potently inhibited by CrmA. This contrasts with the observation that Mch4, the second FADD-related cysteine protease that is also able to process/activate all known ICE/Ced-3-like cysteine proteases, is poorly inhibited by CrmA. These data suggest that Mch5 is the most upstream protease that receives the activation signal from the Fas-receptor to initiate the apoptotic protease cascade that leads to activation of ICE-like proteases (TX, ICE, and ICE-relIII), Ced-3-like proteases (CPP32, Mch2, Mch3, Mch4, and Mch6), and the ICH-1 protease. On the other hand, Mch4 could be a second upstream protease that is responsible for activation of the same protease cascade in CrmA-insensitive apoptotic pathways.


Offline consolidation in implicit sequence learning.
The goal of this study was to investigate offline memory consolidation with regard to general motor skill learning and implicit sequence-specific learning. We trained young adults on a serial reaction time task with a retention interval of either 24 h (Experiment 1) or 1 week (Experiment 2) between two sessions. We manipulated sequence complexity (deterministic vs probabilistic) and motor responses (unimanual or vs bimanual). We found no evidence of offline memory consolidation for sequence-specific learning with either interval (in the sense of no deterioration over the interval but no further improvement either). However, we did find evidence of offline enhancement of general motor skill learning with both intervals, independent of kind of sequence or kind of response. These results suggest that general motor skill learning, but not sequence-specific learning, appears to be enhanced during offline intervals in implicit sequence learning.


Murine models of Pneumocystis infection recapitulate human primary immune disorders.
Despite the discovery of key pattern recognition receptors and CD4+ T cell subsets in laboratory mice, there is ongoing discussion of the value of murine models to reflect human disease. Pneumocystis is an AIDS-defining illness, in which risk of infection is inversely correlated with peripheral CD4+ T cell counts. Due to medical advances in the control of HIV, the current epidemiology of Pneumocystis infection is predominantly due to primary human immunodeficiencies and immunosuppressive therapies. To this end, we found that every human genetic immunodeficiency associated with Pneumocystis infection that has been tested in mice recapitulated susceptibility. For example, humans with a loss-of-function IL21R mutation are severely immunocompromised. We found that IL-21R, in addition to CD4+ T cell intrinsic STAT3 signaling, were required for generating protective antifungal class-switched antibody responses, as well as effector T cell-mediated protection. Furthermore, CD4+ T cell intrinsic IL-21R/STAT3 signaling was required for CD4+ T cell effector responses, including IL-22 production. Recombinant IL-22 administration to Il21r-/- mice induced the expression of a fungicidal peptide, cathelicidin antimicrobial peptide, which showed in vitro fungicidal activity. In conclusion, SPF laboratory mice faithfully replicate many aspects of human primary immunodeficiency and provide useful tools to understand the generation and nature of effector CD4+ T cell immunity.


Alcohol-related breast cancer in postmenopausal women - effect of CYP19A1, PPARG and PPARGC1A polymorphisms on female sex-hormone levels and interaction with alcohol consumption and NSAID usage in a nested case-control study and a randomised controlled trial.
Alcohol consumption is associated with increased risk of breast cancer (BC), and the underlying mechanism is thought to be sex-hormone driven. In vitro and observational studies suggest a mechanism involving peroxisome proliferator-activated receptor gamma (PPARγ) in a complex with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and interaction with aromatase (encoded by CYP19A1). Use of non-steroidal anti-inflammatory drugs (NSAID) may also affect circulating sex-hormone levels by modifying PPARγ activity. In the present study we assessed whether genetic variation in CYP19A1 is associated with risk of BC in a case-control study group nested within the Danish "Diet, Cancer and Health" cohort (ncases = 687 and ncontrols = 687) and searched for gene-gene interaction between CYP19A1 and PPARGC1A, and CYP19A1 and PPARG, and gene-alcohol and gene-NSAID interactions. Association between the CYP19A1 polymorphisms and hormone levels was also examined among 339 non-HRT users. Incidence rate ratios were calculated based on Cox' proportional hazards model. Furthermore, we performed a pilot randomised controlled trial to determine the effect of the PPARG Pro(12)Ala polymorphism and the PPARγ stimulator Ibuprofen on sex-hormone levels following alcohol intake in postmenopausal women (n = 25) using linear regression. Genetic variations in CYP19A1 were associated with hormone levels (estrone: P rs11070844 = 0.009, estrone sulphate: P rs11070844 = 0.01, P rs749292 = 0.004, P rs1062033 = 0.007 and P rs10519297 = 0.03, and sex hormone-binding globulin (SHBG): P rs3751591 = 0.03) and interacted with alcohol intake in relation to hormone levels (estrone sulphate: P interaction/rs2008691 = 0.02 and P interaction/rs1062033= 0.03, and SHBG: P interaction/rs11070844 = 0.03). CYP19A1/rs3751591 was both associated with SHBG levels (P = 0.03) and with risk of BC (Incidence Rate Ratio = 2.12; 95 % Confidence Interval: 1.02-4.43) such that homozygous variant allele carriers had increased levels of serum SHBG and were at increased risk of BC. Acute intake of alcohol decreased blood estrone (P = <0.0001), estrone sulphate (P = <0.0001), and SHBG (P = 0.009) levels, whereas Ibuprofen intake and PPARG Pro(12)Ala genotype had no effect on hormone levels. Our results suggest that genetically determined variation in CYP19A1 is associated with differences in sex hormone levels. However, the genetically determined differences in sex hormone levels were not convincingly associated with BC risk. The results therefore indicate that the genetically determined variation in CYP19A1 contributes little to BC risk and to alcohol-mediated BC risk. NCT02463383, June 3, 2015.


The bereavement gap: grief, human dignity and legal personhood in the debate over Zoe's law.
A Bill before the New South Wales Parliament attempted to re-frame harm to late-term fetuses as grievous bodily harm to the fetus itself rather than (under the existing law) grievous bodily harm to the mother. To achieve this, the Bill extended legal personhood to the fetus for a limited number of offences. The Bill was brought on behalf of Brodie Donegan, who lost her daughter Zoe at 32 weeks' gestation when Donegan was hit by a drug-affected driver. This article asks what the perspective of a grieving mother can bring to the debate, in terms of helping the criminal law accurately come to grips with the complexity of pregnancy and the specific harm of fetal loss. It assesses the likely impacts of a change to fetal personhood and suggests an alternative legislative approach which is less likely to result in an erosion of bodily autonomy for pregnant women.


Identifying sunscreen deserts in Cuyahoga County.
Low sunscreen use in patients of color (POC) is multifactorial and could be partially attributable to lack of access or the lack of knowledge about its use beyond skin cancer prevention. Dyschromia is among the top diagnoses for POC and sunscreen is first-line management. POC and lower socioeconomic status often face health disparities and are susceptible to having difficulty accessing food, health care, and medication. We look to see if they extend to sunscreen access by evaluating physical retailers. This study investigated sunscreen access by identifying potential sunscreen deserts and characterizing sunscreen availability and affordability in Cuyahoga County, Ohio. Sunscreen deserts were defined as census tracts that were both low-income and low-access, adapted from the definition of food deserts. Google Maps search of "sunscreen" and "sunscreen store" in Cuyahoga County identified sunscreen retailers to geocode addresses. Total number and average cost of sunscreens were collected for each retailer and compared by community type. Fisher exact test, analysis of variance, and logistic regression were used for analysis. One hundred forty-six retailers were included in analysis of four hundred twenty-one census tracts in the county. Sixty-seven tracts met the definition of sunscreen desert. Majority White tracts were less likely to be deserts and had more sunscreen formulations, than Majority Black tracts (p < 0.001). The majority of sunscreen deserts were in predominantly black communities, which had fewer stores and sunscreen formulations available. These findings indicate a lack of sunscreen available to a demographic of patients that could benefit from increased access, as it would help manage hyperpigmentation.


Short Communication: Plasma Lymphocyte Activation Gene 3 and Subclinical Coronary Artery Disease in the Multicenter AIDS Cohort Study.
Chronic inflammation, including among people with HIV (PWH), elevates immune cell expression of lymphocyte activation gene 3 (LAG3); however, low plasma LAG3 predicts cardiovascular disease (CVD) events in the general population. The associations among LAG3 plasma levels, subclinical atherosclerosis, inflammation, and HIV infection have not been well described. We measured plasma LAG3 in 704 men with and without HIV from the multicenter AIDS cohort study, who underwent coronary computed tomography angiography. HIV serostatus was not independently associated with LAG3 after adjustment for sociodemographic and CVD risk factors. Current smoking status and African American race were associated with lower LAG3, and age and sTNFαRI concentration were associated with greater LAG3. LAG3 was not associated with coronary artery stenosis. Thus, no difference was found in plasma LAG3 concentration by HIV serostatus, and no association between LAG3 and subclinical coronary atherosclerosis in men with and without HIV was observed.


Case report: an alternative treatment of deep traumatic overbite.
Multidisciplinary treatment of a case of deep traumatic overbite is presented. Complications of therapy and alternative treatment options are discussed. Methods used to provide a satisfactory aesthetic and functional outcome are described.


Effects of Bedroom Environmental Conditions on the Severity of Obstructive Sleep Apnea.
Epidemiological associations have demonstrated the effects of long-term air pollution to obstructive sleep apnea (OSA) through a physiological mechanism linking particulate matter exposure to OSA. This study aimed to determine the relationship between bedroom environmental conditions, OSA severity, and sleep quality. Sixty-three participants were enrolled for an overnight polysomnography; OSA was diagnosed between May to August 2016. Personal characteristics and sleep quality were obtained by a face-to-face interview. Bedroom environments, including data on particulate matter with an aerodynamic diameter less than 10 μm (PM10), temperature, and relative humidity, were collected by personal air sampling and a HOBO tempt/RH data logger. Sixty-eight percent of the participants experienced poor sleep. An elevation in 1-year mean PM10 concentration was significantly associated with an increase in apnea-hypopnea index (beta = 1.04, P = .021) and respiratory disturbance index (beta = 1.07, P = .013). An increase of bedroom temperature during sleep was significantly associated with poorer sleep quality (adjusted odds ratio 1.46, 95% confidence interval 1.01-2.10, P = .044). Associations between PM10 concentration and respiratory disturbance index were observed in the dry season (beta = 0.59, P = .040) but not in the wet season (beta = 0.39, P = .215). PM10 was not associated with subjective sleep quality. Elevation of PM10 concentration is significantly associated with increased OSA severity. Our findings suggest that reduction in exposure to particulate matter and suitable bedroom environments may lessen the severity of OSA and promote good sleep.


Activation of AMP-activated protein kinase prevents TGF-β1-induced epithelial-mesenchymal transition and myofibroblast activation.
Transforming growth factor (TGF)-β contributes to tubulointerstitial fibrosis. We investigated the mechanism by which TGF-β exerts its profibrotic effects and specifically the role of AMP-activated protein kinase (AMPK) in kidney tubular epithelial cells and interstitial fibroblasts. In proximal tubular epithelial cells, TGF-β1 treatment causes a decrease in AMPK phosphorylation and activation together with increased fibronectin and α-smooth muscle actin expression and decreased in E-cadherin. TGF-β1 causes similar changes in interstitial fibroblasts. Activation of AMPK with 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside, metformin, or overexpression of constitutively active AMPK markedly attenuated TGF-β1 functions. Conversely, inhibition of AMPK with adenine 9-β-d-arabinofuranoside or siRNA-mediated knockdown of AMPK (official name PRKAA1) mimicked the effect of TGF-β1 and enhanced basal and TGF-β1-induced phenotypic changes. Importantly, we found that tuberin contributed to the protective effects of AMPK and that TGF-β1 promoted cell injury by blocking AMPK-mediated tuberin phosphorylation and activation. In the kidney cortex of TGF-β transgenic mice, the significant decrease in AMPK phosphorylation and tuberin phosphorylation on its AMPK-dependent activating site was associated with an increase in mesenchymal markers and a decrease in E-cadherin. Collectively, the data indicate that TGF-β exerts its profibrotic action in vitro and in vivo via inactivation of AMPK. AMPK and tuberin activation prevent tubulointerstitial injury induced by TGF-β. Activators of AMPK provide potential therapeutic strategy to prevent kidney fibrosis and progressive kidney disease.


Association between hypertension and the alpha-adducin, beta1-adrenoreceptor, and G-protein beta3 subunit genes in the Japanese population; the Suita study.
This study focused on 3 genetic polymorphisms that have previously been implicated in hypertension: the alpha-adducin (ADD1/Gly460Trp), beta1-adrenoreceptor (ADRB1/Arg389Gly), and G-protein beta3 subunit (GNB3/C825T) gene polymorphisms. We determined genetic variants using the TaqMan system in a large cohort representing the general population in Japan (867 males, 1,013 females). Logistic analysis indicated that the ADD1/ G460W polymorphism was associated with hypertension in female subjects. The odds ratio of the WW genotype for hypertension was 1.53 (95%Cl, 1.12-2.08) over the WG+GG genotype (p=0.0070, p corrected (p(c)) =0.0420 corrected by the Bonferroni method). The ADRB1/R389G polymorphism tended to be associated with hypertensive status in male subjects (p=0.0117, p(c)=0.0702). The odds ratio of the GG genotype for hypertension was 0.38 (95%CI, 0.167-0.780) over the RR+RG genotype. The GNB3/C825T polymorphism was not associated with hypertensive status in either male or female subjects. The present results do not agree with those in previous reports. Almost all common variants may have only a modest effect on common diseases, and a single study even employing 1,880 subjects may lack the statistical power to detect a real association. Accordingly, it will be necessary to verify the association between these three genes and hypertension using a larger number of subjects from the Suita cohort or another population.


[Safe transportation of children: what is our responsibility as pediatricians?].
During 2009, 564 children died in Argentina from 0 to 14 in traffic accidents. The mortality rate for road accidents is 56/100,000 inhabitants and is 858% when compared to Sweden, the country with the lowest rate. Fifty percent were children transported in cars, 30% in heavy duty vehicles, 16.3% died when the vehicle overturned and 4.5% died in two wheeled vehicles. Serious injuries and death are more frequent in babies less than a year old. Seventy one per cent of children under 1 year old and 54% of those between 1 and 6 years old would avoid death in an accident if transported in adequate safety seats. This requires a joint effort between obstetricians and pediatricians to inform the family about the right type of safety seat. The State and other institutions should accompany this campaign to reduce the number of fatal accidents and their consequences.


Circulating Exosomal MicroRNA-21 as a Biomarker in Each Tumor Stage of Colorectal Cancer.
We clarified the predictive and prognostic value of circulating plasma exosomal microRNA-21 (miR-21) in each TNM stage of colorectal cancer (CRC) patients. The microRNA (miRNA) profiles of the plasma exosomes, primary tumor tissues, and liver metastasis tissues from the same CRC patients were examined using a microarray. For validation analysis, the plasma exosome samples from 326 CRC patients were measured by TaqMan miRNA assays. In the miRNA microarray analyses, miR-21 showed the highest upregulation in exosomes, primary tumor tissues, and liver metastasis tissues. Significant correlations were demonstrated between exosomal miR-21 and tissue miR-21 levels. As for the relationship to the pathological condition, exosomal miR-21 showed a significant association with liver metastasis and TNM stage. The overall survival (OS) rates and disease-free survival (DFS) rates in high-exosomal-miR-21 patients were significantly worse than those in low-miR-21 patients. Exosomal miR-21 levels were an independent prognostic factor for OS and DFS in CRC patients with TNM stage II or III, and for OS in patients with TNM stage IV. Plasma exosomal miR-21 levels are a useful biomarker for the prediction of recurrence and poor prognosis in CRC patients with TNM stage II, III, or IV.


Segmentation of frame sequences obtained by a moving observer.
In many applications of computer vision, a frame sequence may be acquired using a moving camera. We propose ego-motion polar transformation for segmentation of such sequences. It is shown that segmentation and extraction of motion information become easier in the transformed domain. Our experience with a translating camera indicates that this technique can play a very important role in the analysis of moving observer dynamic scenes.


Interferon alpha-2a therapy in 18 hemangioblastomas.
Multiple hemangioblastomas (HBs) of the central nervous system (CNS) and retina are associated with von Hippel-Lindau disease (VHL) and also predispose individuals to renal cell carcinomas and visceral cysts. In VHL, microsurgery or radiosurgery cannot prevent new HBs from arising in the CNS or coagulation of retinal HBs. Multiple but thus far asymptomatic HBs pose a therapeutic problem. IFN-alpha-2a has antiangiogenic activity with an especially favorable effect on life-threatening hemangiomas of the liver in children. This is the first study to assess the efficacy of IFN-alpha-2a in treatment of asymptomatic HBs of the CNS and retina. Four patients (three with VHL) with a combined total of 15 HBs of the CNS, 3 HBs of the retina, and 14 renal and 2 pancreatic cysts were treated with s.c. IFN-alpha-2a for 12 months at 3 x 10(6) IU, 3 times/week. Baseline workup consisted of detailed neurological, ophthalmological, and radiological examinations. Follow-up studies at 3, 13, and 21 months were used to monitor the response. No de novo HBs were detected during the therapy, but one appeared 9 months after cessation of IFN-alpha-2a therapy. HBs of the CNS did not shrink markedly during the therapy. IFN-alpha-2a may decrease blood flow in HBs as suggested by shrinkage and diminished leakage of two retinal HBs. However, the therapy did not prevent visceral cysts from growing. The systemic response was also monitored by measurement of serum levels of vascular endothelial growth factor and erythropoietin, which remained essentially unchanged during the treatment. No serious side effects were recorded.


Evidence-based new service package vs. routine service package for smoking cessation to prevent high risk patients from cardiovascular diseases (CVD): study protocol for randomized controlled trial.
Smoking cessation is a high-priority intervention to prevent CVD events and deaths in developing countries. While several interventions to stop smoking have been proved successful, the question of how to increase their effectiveness and practicality in developing countries remains. In this study, a newly devised evidence-based smoking cessation service package will be compared with the existing service in a randomized controlled trial within the community setting of Thailand. This randomized control trial will recruit 440 current smokers at CVD risk because of being diabetic and/or hypertensive. Informed, consented participants will be randomly allocated into the new service-package arm and the routine service arm. The study will take place in the non-communicable disease clinics of the Maetha District Hospital, Lampang, northern Thailand. The new smoking-cessation service-package comprises (1) regular patient motivation and coaching from the same primary care nurse over a 3-month period; (2) monthly application of piCO + smokerlyzer to sustain motivation of smoker's quitting attempt and provide positive feedback over a 3-month period; (3) assistance by an assigned family member; (4) nicotine replacement chewing gum to relieve withdrawal symptoms. This new service will be compared with the traditional routine service comprising the 5A approach in a 1-year follow-up. Participants who consent to participate in the study but refuse to attempt quitting smoking will be allocated to the non-randomized arm, where they will be just followed up and monitored. Primary outcome of the study is smoking cessation rate at 1-year follow-up proven by breath analysis measuring carbomonoxide in parts per million in expired air. Secondary outcomes are smoking cessation rate at the 6-month follow-up, blood pressure and heart rate, CVD risk according to the Framingham general cardiovascular risk score, CVD events and deaths at the 12-month follow-up, and the cost-effectiveness of the health service packages. Intention-to-treat analysis will be followed. Factors influencing smoking cessation will be analyzed by the structure equation model. This multicomponent intervention, accessible at primary healthcare clinics, and focusing on the individual as well as the family and social environment, is unique and expected to work effectively. Current Controlled Trials ISRCTN89315117.


Fractal analysis of lateral movement in biomembranes.
Lateral movement of a molecule in a biomembrane containing small compartments (0.23-μm diameter) and large ones (0.75 μm) is analyzed using a fractal description of its walk. The early time dependence of the mean square displacement varies from linear due to the contribution of ballistic motion. In small compartments, walking molecules do not have sufficient time or space to develop an asymptotic relation and the diffusion coefficient deduced from the experimental records is lower than that measured without restrictions. The model makes it possible to deduce the molecule step parameters, namely the step length and time, from data concerning confined and unrestricted diffusion coefficients. This is also possible using experimental results for sub-diffusive transport. The transition from normal to anomalous diffusion does not affect the molecule step parameters. The experimental literature data on molecular trajectories recorded at a high time resolution appear to confirm the modeled value of the mean free path length of DOPE for Brownian and anomalous diffusion. Although the step length and time give the proper values of diffusion coefficient, the DOPE speed calculated as their quotient is several orders of magnitude lower than the thermal speed. This is interpreted as a result of intermolecular interactions, as confirmed by lateral diffusion of other molecules in different membranes. The molecule step parameters are then utilized to analyze the problem of multiple visits in small compartments. The modeling of the diffusion exponent results in a smooth transition to normal diffusion on entering a large compartment, as observed in experiments.


Late sodium current contributes to the reverse rate-dependent effect of IKr inhibition on ventricular repolarization.
The reverse rate dependence (RRD) of actions of I(Kr)-blocking drugs to increase the action potential duration (APD) and beat-to-beat variability of repolarization (BVR) of APD is proarrhythmic. We determined whether inhibition of endogenous, physiological late Na(+) current (late I(Na)) attenuates the RRD and proarrhythmic effect of I(Kr) inhibition. Duration of the monophasic APD (MAPD) was measured from female rabbit hearts paced at cycle lengths from 400 to 2000 milliseconds, and BVR was calculated. In the absence of a drug, duration of monophasic action potential at 90% completion of repolarization (MAPD(90)) and BVR increased as the cycle length was increased from 400 to 2000 milliseconds (n=36 and 26; P<0.01). Both E-4031 (20 nmol/L) and d-sotalol (10 μmol/L) increased MAPD(90) and BVR at all stimulation rates, and the increase was greater at slower than at faster pacing rates (n=19, 11, 12 and 7, respectively; P<0.01). Tetrodotoxin (1 μmol/L) and ranolazine significantly attenuated the RRD of MAPD(90,) reduced BVR (P<0.01), and abolished torsade de pointes in hearts treated with either 20 nmol/L E-4031 or 10 μmol/L d-sotalol. Endogenous late I(Na) in cardiomyocytes stimulated at cycle lengths from 500 to 4000 milliseconds was greater at slower than at faster stimulation rates, and rapidly decreased during the first several beats at faster but not at slower rates (n=8; P<0.01). In a computational model, simulated RRD of APD caused by E-4031 and d-sotalol was attenuated when late I(Na) was inhibited. Endogenous late I(Na) contributes to the RRD of I(Kr) inhibitor-induced increases in APD and BVR and to bradycardia-related ventricular arrhythmias.