Diagnosing cognitive impairment and dementia in primary health care -- a more active approach is needed.
to determine the documentation rate of dementia in primary health care, the clinical characteristics of patients with documented and undocumented dementia, and the diagnostic evaluations made in cognitive impairment. cross-sectional population-based study with a retrospective review of medical history. primary health care in the municipality of Lieto, Southwestern Finland. all the inhabitants aged 64 and over in Lieto. Participation rate 82%, numbers = 1260. assessment of dementia according to DSM-IV criteria, and severity according to Clinical Dementia Rating. Possible documentation of dementia and evaluations done were reviewed from primary health care medical records. 112 patients with dementia were found. The sensitivity of the general practitioners' judgment of dementia was 48.2% and the specificity 99.6%. The documentation rate of dementia was 73% in severe, 46% in moderate and 33% in mild dementia. A greater proportion of the patients with undocumented dementia were male (P = 0.003), lived at home (P = 0.003), coped better with the instrumental activities of daily living (P = 0.006), had more depression (P = 0.029) and milder dementia (P = 0.005) than patients with documented dementia. Thyroid stimulating hormone was measured in 51% of the patients with suspected memory impairment or dementia, B12 vitamin in 20%, and serum calcium in 18%. Twenty-eight per cent of the patients had been tested for cognitive function, 68% for depressive symptoms, and 88% for social abilities. Forty-two per cent of patients were referred to a specialist, 32% of patients who were over 75 years. less than half of the patients with dementia had their diagnosis documented in primary care medical records. Documentation increased in more advanced dementia. The diagnostic evaluations for reversible causes of dementia were insufficient in primary care, and they were done at a late phase of cognitive impairment.


Psychotropic drug use in a cohort of workers 4 years after an industrial disaster in France.
Two years after the 2001 Toulouse industrial disaster, a longitudinal study was set up to evaluate the impact of the disaster. The current substudy examines the medium-term impact (5 years) the incident had on the mental health of 3,004 participants. As part of the monitoring, data relating to the psychotropic drug use of 2,494 participants were collected from administrative databases 4 years after the disaster. Use of psychotropics was higher among women for anxiolytics (10.4% for men and 15.0% for women), hypnotics (10.5% and 17.0%), and antidepressants (7.6% and 11.2%). Exposure to the disaster, especially proximity to the exposure, was significantly associated with the use of antidepressants in men, OR = 3.22, 95% CI[1.57, 6.61]. This was also the case for other exposure factors (saw dead or injury, injured, home damage, death or injury loved one, psychological disorders, exposure toxic fumes): range of OR 1.75 to 2.52 in men, 1.48 to 1.62 in women. In conclusion, this study highlights the medium-term psychological impact of an industrial disaster on psychotropic drug use and the potential for using medical records data as a means for tracking postdisaster mental health.


Knowledge of Suicide Risk Factors, But Not Suicide Ideation Severity, Is Greater Among College Students Who Viewed 13 Reasons Why.
To test associations between viewing 13 Reasons Why, Season 1 and past week suicide ideation severity, behavior risk, stigma, and knowledge in college students. To explore whether personal exposure to suicide and depressive symptom severity moderated these associations. Eight-hundred and eighteen college students, 64% (n = 522) of whom watched 13 Reasons Why. Students completed surveys online. Multivariate negative binomial regressions were used to test associations between watching 13 Reasons Why and suicide-related variables, and interaction terms. Suicide ideation severity and suicide behavior risk were not significantly associated with viewing 13 Reasons Why; however, there was limited statistical power to detect associations. The association between watching 13 Reasons Why and greater suicide knowledge was stronger among those who did not have personal exposure to suicide. 13 Reasons Why may be a platform for psychoeducation on suicide, particularly among those who do not have personal exposure.


The legacy of fossil fuels.
Currently, over 80% of the energy used by mankind comes from fossil fuels. Harnessing coal, oil and gas, the energy resources contained in the store of our spaceship, Earth, has prompted a dramatic expansion in energy use and a substantial improvement in the quality of life of billions of individuals in some regions of the world. Powering our civilization with fossil fuels has been very convenient, but now we know that it entails severe consequences. We treat fossil fuels as a resource that anyone anywhere can extract and use in any fashion, and Earth's atmosphere, soil and oceans as a dump for their waste products, including more than 30 Gt/y of carbon dioxide. At present, environmental legacy rather than consistence of exploitable reserves, is the most dramatic problem posed by the relentless increase of fossil fuel global demand. Harmful effects on the environment and human health, usually not incorporated into the pricing of fossil fuels, include immediate and short-term impacts related to their discovery, extraction, transportation, distribution, and burning as well as climate change that are spread over time to future generations or over space to the entire planet. In this essay, several aspects of the fossil fuel legacy are discussed, such as alteration of the carbon cycle, carbon dioxide rise and its measurement, greenhouse effect, anthropogenic climate change, air pollution and human health, geoengineering proposals, land and water degradation, economic problems, indirect effects on the society, and the urgent need of regulatory efforts and related actions to promote a gradual transition out of the fossil fuel era. While manufacturing sustainable solar fuels appears to be a longer-time perspective, alternatives energy sources already exist that have the potential to replace fossil fuels as feedstocks for electricity production.


Arteriographic evaluation of small coronary arteries.
The purpose of this study was to determine the accuracy of imaging small coronary arteries with current radiographic equipment. Phantom assessments were performed using a phantom that comprises a large array of circular objects of varying diameter and contrast density. More objects could be identified in the moving cinearteriogram than in single cine frames. Using the largest object as the calibration standard, diameters less than 1 mm were markedly overestimated. A simple morphometric method showed that arteriographic visualization of small vessels was better by digital processing than by cine recording. However, there was no statistically significant difference in the average size of the smallest identifiable vessel by either method (0.5 versus 0.51 mm). After correcting for overestimation and the inaccurate imaging of the smallest detectable vessels, the practical arteriographic threshold is approximately 0.5 mm. Parametric imaging holds promise, but its significance for evaluating small vessel disease has yet to be determined.


High current ion beam transport using solenoids.
In the framework of the future project FAIR several upgrade programs and construction of new facilities are in progress such as the U(4+) upgrade for the existing high current injector and the new 70 MeV proton injector. For both injectors solenoids in the low energy beam transport section are foreseen to inject the beam into the following rf accelerator. The paper presents beam quality measurements of high current ion beams behind a solenoid using a slit-grid emittance measurement device, viewing targets, and a pepper pot measurement device at the high current test bench at GSI.


Sweet's syndrome triggered by pneumococcal vaccination.
Sweet's syndrome is the most frequent category among the neutrophilic dermatosis and is diagnosed by clearly defined criteria. Vaccines are included as potential triggers of this syndrome. Nevertheless, there are few reports unveiling such association. Herein, we describe the case of a patient who developed Sweet's syndrome after pneumococcal vaccination. To our knowledge, this is the second case of Sweet's syndrome triggered by pneumococcal vaccine reported, and the first one specifically with the 13-valent conjugate vaccine.


In vitro kinematics of the shoulder following rotator cuff injury.
Tears in the rotator cuff may result in altered mechanics of the glenohumeral joint. It is not unusual for some patients with cuff tears to exhibit near normal motion with the injured shoulder, while other patients with the same magnitude of injury are unable to achieve full elevation on the injured side. The effect of simulated tears of the rotator cuff on active glenohumeral joint kinematics was investigated by testing eight cadaveric specimens using an in vitro shoulder simulator. Active abduction of the humerus was produced by applying forces to simulate loading of the supraspinatus, subscapularis, infraspinatus/teres minor, and the anterior, middle, and posterior thirds of the deltoid. Three sequential 1cm lesions were created in the rotator cuff, the first two in the supraspinatus tendon and the third in the subscapularis tendon. The plane of abduction moved posteriorly and became more abnormal throughout abduction with increased tear size. No difference was observed in the internal/external rotation of the humerus or the position of the humeral head on the glenoid during elevation. In order to generate the motions achieved by the intact joint, patients with rotator cuff insufficiency likely employ other muscle groups. Retraining muscle groups surrounding the glenohumeral joint may decrease the need for surgical interventions.


Wetting of biological lipids on aqueous substrates.
We study the dynamics and final wetting state of skin lipids on water and brine by fluorescence microscopy and ellipsometry. When a lipid droplet is brought into contact with the water surface, a lipid wetting film spreads out rapidly by a Marangoni effect. Subsequently, this film undergoes a dewetting instability. However, the final equilibrium is not partial wetting. The film breaks up into droplets with a mesoscopic (approximately 50 A) film in between. These observations result from a subtle interplay between short- and long-range forces: surfactants naturally present in the lipids favor wetting, while the van der Waals forces oppose it. In addition, this reveals the likely organization of the hydrolipid film that covers and protects the skin.


Alterations in left ventricular geometry, wall stress, and ejection performance after correction of congenital aortic stenosis.
Children with congenital aortic stenosis have "excessive" left ventricular hypertrophy with reduced resting systolic wall stress that allows for supernormal ejection performance. If aortic stenosis is uncorrected, this pattern persists until adulthood. The effect of removing the aortic pressure gradient on left ventricular hypertrophy and wall stress in children with congenital aortic stenosis is unknown. To test the hypothesis that removal of the stimulus for hypertrophy by aortic valve replacement or repair would normalize left ventricular mass and wall stress, we measured left ventricular ejection performance, wall stress, and contractile function in seven patients at cardiac catheterization before and 36 +/- 7 months after surgical correction of congenital aortic stenosis. After aortic valve replacement or repair, the aortic valve gradient fell from 87 +/- 12 to 7 +/- 4 mm Hg, and peak left ventricular pressure fell from 187 +/- 14 to 128 +/- 8 mm Hg. Left ventricular ejection fraction decreased postoperatively from 86 +/- 4% to 74 +/- 4% (p less than 0.001), whereas velocity of circumferential fiber shortening decreased from 2.15 +/- 0.15 to 1.6 +/- 0.11 (p less than 0.002). Left ventricular mass remained unchanged preoperatively (121 +/- 14 g/m2) and postoperatively (121 +/- 16 g/m2), but wall thickness (h) decreased in relation to ventricular radius (r) (h/r = 0.55 +/- 0.05 preoperatively, 0.36 +/- 0.02 postoperatively; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Radionuclide angiographic assessment of left ventricular function during exercise in patients with a severely reduced ejection fraction.
To study the effect of exercise on left ventricular ejection fraction in patients with congestive cardiomyopathy and the relation of the response to the origin of the myocardial dysfunction, 30 patients with a severely reduced ejection fraction (30 percent or less) were evaluated with radionuclide angiography. Group I consisted of 16 patients with ischemic cardiomyopathy and a mean (+/- standard deviation) resting ejection fraction of 22.3 +/- 6.1 percent. Group II was composed of 14 patients with primary cardiomyopathy and a mean resting ejection fraction of 19.3 +/- 4.7 percent. The mean age, left ventricular end-diastolic pressure, cardiac index and resting left ventricular ejection fraction of Groups I and II were similar; however, the change in the ejection fraction during similar levels of exercise differed significantly. The mean exercise ejection fraction decreased to 16.7 +/- 6.8 percent in Group I, but increased to 24.6 +/- 6.4 percent in Group II (p less than 0.001). Thus, exercise usually results in a directionally opposite change in left ventricular ejection fraction depending on the origin of the congestive cardiomyopathy.


Solid tumour chemotherapy using implantable collagen-poly (HEMA) hydrogel containing 5-fluorouracil.
Implantable collagen-poly(HEMA) hydrogels containing the anticancer drug 5-fluorouracil (5-FU) have been prepared and evaluated for their efficacy towards a solid tumour fibrosarcoma in Wistar rats. The tumour was developed by inoculation of a 10% tumour-cell suspension in the anterior aspect of the hind limb. Four groups were studied--untreated control, intratumoural injection of free 5-FU, subcutaneous implantation of placebo and implantation of 5-FU-bearing hydrogel pellets (10 mm diameter x 1 mm thick) containing the drug in close proximity to the tumour. The hydrogel showed an improved antitumour activity over free 5-FU as evidenced by the gross tumour weight assessments and by [3H]thymidine incorporation in-vitro. This was attributed to the controlled and slow release of 5-FU compared with free 5-FU over the same period of treatment. The implantation of hydrogel could thus be a potential alternative to free 5-FU therapy in the treatment of solid tumours such as fibrosarcoma.


Breast stereotactic core biopsy washings: abundant cell samples from clinically occult lesions for flow cytometric DNA analysis.
The object of this study was to determine by flow cytometry the cellular and DNA content of the washings of core biopsy samples and needles obtained during stereotactic core biopsies of clinically occult suspicious lesions. Fourteen-gauge core multipass biopsy inner-needle saline washings obtained after dislodgment of the tissue core samples (n = 30) and 14-ga mammotomy core biopsy specimen washings (n = 30) were analyzed by flow cytometry. Multipass core biopsy needle washings of 7 malignant and 23 benign lesions yielded a median of 10,584 cells per lesion (range 562-29,019 cells). Mammotomy core biopsy specimen washings of 10 malignant and 20 benign lesions yielded a median of 12,164 cells per lesion (range 1,295-115,150). Forty-four (73%) washings in each technique had more than 5000 cells. Flow cytometric DNA ploidy analysis was possible in 60 (100%) and the S phase percentage determination was possible in 59 (98%) of the washings. Aneuploidy was detected in 53% of malignant lesions and 2% of benign lesions. Core biopsy specimen or needle washings provide abundant fresh cellular material from clinically occult lesions for DNA analysis by flow cytometry.


Anxiety rating scales in Parkinson's disease: critique and recommendations.
Anxiety syndromes are common in patients with Parkinson's disease (PD) with up to 30% suffering from panic disorder, and up to 11% from generalized anxiety disorder (GAD). Anxiety is associated with increased subjective motor symptoms, more severe gait problems, dyskinesias, freezing, and on/off fluctuations. Anxiety has a negative impact on health related quality of life and is strongly associated with depressive syndromes. Since a variety of anxiety scales have been used in PD patients, the Movement Disorder Society commissioned a task force to assess the clinimetric properties of these scales in PD. A systematic review was conducted to identify anxiety scales that have either been validated or used in patients with PD. Six anxiety rating scales were identified. These were the Beck anxiety inventory, the hospital anxiety and depression scale, the Zung self-rating anxiety scale and anxiety status inventory, the Spielberger state trait anxiety inventory, and the Hamilton anxiety rating scale. In addition, Item 5 (anxiety) of the neuropsychiatric inventory was included in the review. No scales met the criteria to be "recommended," and all scales were classified as "suggested." Essential clinimetric information is missing for all scales. Because several scales exist and have been used in PD, the task force recommends further studies of these instruments. If these studies show that the clinimetric properties of existing scales are inadequate, development of a new scale to assess anxiety in PD should be considered.


Grand rounds: first metatarsophalangeal joint replacement.
For approximately 30 years foot and ankle surgeons have been using a variety of techniques and devices to replace the first metatarsophalangeal joint. During this time there have been a multitude of implant designs and modifications, most attempting to anatomically and functionally replace the natural joint surfaces. The advantages and disadvantages of these many designs and various biomaterials has long been debated in scientific meetings and publications. Surgical technique, implant design, materials, and patient selection remain areas of heated debate and ongoing research. With this in mind, we asked leading foot and ankle surgeons to give their opinions on indications and utilization for joint replacement of the first metatarsophalangeal joint.


Iris microhemangiomas.
Iris microhemangiomas (IM) are benign proliferations of small, twisted blood vessels along the pupillary margin. They are usually bilateral and appear to be developmental in nature. IMs most commonly occur in patients with myotonic dystrophy and adult-onset diabetes mellitus, but have also been associated with respiratory disease, congential heart disease, and central retinal vein occlusion. Additionally, they may be found in individuals without obvious ocular or systemic abnormality. The etiology remains obscure. In this report, illustrative cases are followed by a brief discussion outlining typical clinical manifestations, etiological considerations, and possible implications.


The medically compromised patient.
Diabetes mellitus is found in up to 5 per cent of the population. There is an excess of blood sugar due to a deficiency or diminished effectiveness of insulin. It is a complex disease which, if not controlled, has many major complications including an increased incidence of heart attacks, strokes and vascular changes in many other organs. The management of young onset diabetic patients is directed towards: controlling the carbohydrate intake, testing the blood sugar by the patient and regular insulin injections. Great care must be taken in treating diabetics in the dental surgery. Except for children, any diabetic can be treated for simple dental procedures by ensuring freedom from pain, by eliminating stress and by ensuring that the patient does not miss a meal. Children, unstable diabetic patients and those with infections or requiring multiple extractions should be treated in hospital under the care of an endocrinologist. In hypertension it is only after a number of years that complications begin to appear. The main ones are those of stroke, retinal haemorrhages, renal failure and heart disease. Dentists should be encouraged to take the blood pressure of all adults who present for treatment. Patients with increased blood pressure yet controlled by drugs may be treated as normal patients. Those that are not well controlled should be referred to their physician. Dental appointments must be free of pain and stress should be avoided. A screening method is presented which assists in the evaluation of medically compromised patients.


Signal-to-noise ratio analysis in laser absorption spectrometers using optical multipass cells.
In high resolution absorption spectrometers with conventional light sources, the signal-to-noise ratio (SNR) is usually limited by the thermal noise level of the detector-preamplifier combination, which is independent of the light source power. However, the noise in many laser absorption spectrometers is dominated by the excess or shot noise which is dependent on the transmitted laser power, and which in turn is dependent on the number of reflections in a multipass cell. The optimum absorption path length for a high frequency modulated (FM) and a conventional wavelength modulated (WM) diode laser absorption spectrometer is investigated in this paper. The major result is that, due to the power attenuation by the multipass cell, the best SNR of a shot noise limited FM spectrometer is achieved at substantially shorter absorption paths, when compared with the excess noise limited WM spectrometer. This finding implies that the implementation of the FM technique in absorption spectrometers with multipasscells can improve the SNR only by 1 order of magnitude. Although desirable, this is substantially less than the improvement of 2 orders of magnitude expected in quantum limited conditions with a single pass cell.


Missed Chopart dislocation. The importance of being aware of midtarsal injuries.
Chopart (midtarsal) joint dislocations are relatively rare but potentially serious injuries. Their low prevalence and the possible absence of evident radiological findings cannot justify misdiagnosis because an adequate and correct treatment is required to achieve a proper clinical outcome.A midtarsal joint dislocation in a 19-year-old woman is described, in which diagnosis was performed at 8 weeks of evolution. An open reduction was performed by a double approach (medial and lateral) and a Kirschner wire joint stabilization. A tone-year of follow-up, loss of reduction was not observed and the patient was pain-free, although she referred to functional limitation when running.Besides describing the treatment of this particular injury, this study is aimed at increasing the level of clinical suspicion in order to avoid misdiagnosis such as occurred in our case.


Dermatoglyphic and cytogenetic studies in parents of children with trisomy 21.
Dermatoglyphic studies were carried out of 131 mothers and 95 fathers of children with Down syndrome and 200 controls (100 males and 100 females) using the Hopkins single score method. Twelve percent of the mothers and 2% of the fathers showed dermatoglyphic abnormalities including a distal axial triradius (t"), hypothenar ulnar loops, radial loops on digits IV and V and abnormal palmar creases, resulting in a positive Hopkins score or a score in the "overlapping range" (greater than -3). The origin of the extra chromosome could be determined in 23 of a total group of 40 families. In 22 of the former, the mother was the donor of the extra chromosome; in one it was the father, In these 23 families, a Hopkins score in the overlapping range was found in three mothers who were all under the age of 35 years at the birth of the affected child. Since cytogenetic studies cannot easily differentiate between meiotic nondisjunction and mosaicism as a basis for 21 trisomy in the progeny, it is possible that mothers with positive overlapping Hopkins scores represent undetected mosaics for a trisomic cell line. The dual approach utilizing dermatoglyphic and cytogenetic studies may aid in identifying persons with an enhanced risk for having children with Down syndrome.


An international study of psychological problems in primary care. Preliminary report from the World Health Organization Collaborative Project on 'Psychological Problems in General Health Care'.
This article describes a large longitudinal multicenter collaborative study that investigated the form, frequency, course, and outcome of psychological problems that were seen in primary health care settings in 15 different sites around the world. The research employed a two-stage sampling design in which the 12-item General Health Questionnaire was administered to 26,422 persons aged 18 to 65 years who were consulting health care services. Of these persons, 5604 were selected for detailed examinations using standardized instruments and were followed up at 3 months and 1 year to provide information on course and outcome. All assessment instruments have been translated into 13 different languages. The project has produced a database that allows for the exploration of the nature of psychological disorders experienced by patients in general medical care and their association with physical illness, illness behavior, and disability over time.


Effect of pulp and paper mill effluent (BKME) on physiological parameters of roach (Rutilus rutilus) infected by the digenean Rhipidocotyle fennica.
Physiological parameters were measured after experimental infection of roach (Rutilus rutilus L.) with Rhipidocotyle fennica Gibson, Valtonen et Taskinen, 1992 (Digenea) cercariae. The fish were caught from two lakes: a eutrophic bleached kraft mill effluent (BKME)-contaminated lake and an oligotrophic unpolluted lake. The intensity of infection was followed up to 10 days post infection (p.i.) and physiological parameters indicating non-specific stress responses and the condition of fish were examined simultaneously. The mean abundance, the number of parasites per fish, of R. fennica was significantly higher in the fish from the contaminated water during the first two days p.i., probably reflecting the decreased resistance of these fish to infection. The decrease of leukocrit, as well as the increase of the activity of transaminases (GOT and GPT) in infected fish of both groups are suggestive of pathological processes caused by cercariae penetrating the fish. A significantly lower leukocrit value, as well as higher alkaline phosphatase activity and plasma chloride levels were noted in fish originating from the contaminated lake compared to those from the unpolluted lake. No significant differences were noted in haematocrit, plasma protein and calcium values between the fish from the uncontaminated and contaminated lakes, or between the infected and uninfected control fish.


[Surgical treatment of benign lesions and strictures of the bile ducts].
Benign strictures of the biliary ducts are treated surgically in 90% of cases. Usually they are caused by trauma to the choledochous duct during gallbladder operations. Younger patients are frequently affected and, particularly if the strictures go untreated, can suffer from secondary complications such as cholangitis or secondary biliary cirrhosis with the serious dangers of portal hypertension and even hepatic failure and death. Although immediate treatment by end-to-end anastomosis has sometimes been described, this method is reasonable only for smooth cuts to the choledochous duct. Good long-term results have been achieved in 86% of cases with Roux-en-Y hepaticojejunostomy. In general, the best way to avoid complications is the all-important surgical maxim of correct indication for the primary operation. The best course is to limit the decision for surgery to symptomatic gallstones.


Correlation between prenatal ultrasound and postmortem findings in 1029 fetuses following termination of pregnancy.
A prenatal ultrasound examination and a postmortem examination provide the basis for correct diagnosis in fetuses terminated due to congenital anomalies. The aim of this study was to correlate fetal anomalies detected by ultrasound examination with those identified at autopsy following termination of pregnancy (TOP) over a 30-year period, and to evaluate the correlation between findings at different gestational ages and assess these trends over time. The study group consisted of 1029 TOPs performed over a 30-year period, from 1985 to 2014. The gestational age ranged between 11 and 33 weeks. Prenatal ultrasound examinations were performed at the National Center for Fetal Medicine, St Olavs Hospital, Trondheim, Norway. Autopsies were performed at the Department of Pathology and Medical Genetics at the same hospital or a collaborating hospital. There was full agreement between ultrasound and autopsy findings in 88.1% (907/1029) of TOPs, and the main diagnosis was correct in 97.9% (1007/1029). When comparing the 15-year period of 2000-2014 with that of 1985-1999, the difference in the rates of full agreement and agreement in the main diagnosis was statistically significant. In 1.3% (13/1029) of cases, ultrasound findings were not confirmed at autopsy. There were no false-positive diagnoses leading to TOP. Throughout the 30-year period, there was an increase in early TOPs, whereas late TOPs declined. Our study demonstrates that there is a clear correlation between ultrasound and autopsy findings, which is continuously improving. Despite this high correlation, there is reason to continue the practice of validation to ensure the safety of the diagnostic process leading to TOP. The trend towards an earlier termination emphasizes the necessity of such a practice. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.


New autopsy findings in different brain regions of a preterm neonate with kernicterus: neurovascular alterations and up-regulation of efflux transporters.
Kernicterus is an irreversible brain damage caused by bilirubin deposition in selective brain regions. Sick and preterm infants with hyperbilirubinemia are particularly susceptible to the condition. We studied autopsied brain tissue from a premature female infant with kernicterus with a bilirubin:albumin molar ratio of 1.0, hypoxia, acidosis, and seizures. The patient, previously described as having cerebellar axon/myelin loss and angiogenic sprouting, was assessed for histopathological features in brain regions less investigated, such as hippocampus and corpus striatum. Results were compared with age-matched controls. Increased blood vessel density with poorly defined lumen structures was observed in the mesencephalon, pons, and medulla oblongata, and, more predominantly, in the corpus striatum and hippocampus. These two regions exhibited increased expression of vascular endothelial growth factor, paralleled by vascular endothelial growth factor receptor-2, and albumin extravasation into the brain parenchyma. No similar findings were observed in the nonjaundiced babies with hypoxia that served as controls (one preterm with sepsis and a term infant with pneumonia). We found increased cellular expression of multidrug resistance-associated protein 1 and P-glycoprotein in the hippocampus, known as defensive mechanisms against bilirubin-induced cytotoxicity. Increased density of blood vessels and microvascular permeability, together with parenchymal albumin, may have contributed to increasing the brain content and retention of bilirubin, a condition implicated in kernicterus disease. This novel finding in a premature baby with kernicterus and associated risk factors deserves to be investigated in similar patients to better understand the less-well described effects of bilirubin-induced neurological sequelae in preterm infants.


N-methyl-D-glucamine improves the laser-induced fluorescence capillary electrophoresis performance in the total plasma thiols measurement.
We describe an ultrarapid capillary electrophoresis with laser-induced fluorescence (CE-LIF) method for total plasma thiols measurement. Reduced thiols by 10% tri-n-butylphosphine (TBP) were derivatized in 10 min at room temperature with 5-iodoacetamidofluorescein (5-IAF) as fluorescent reagent. We show that CE-LIF allows a baseline separation of total plasma cysteinylglycine, homocysteine, cysteine, and glutathione in less than 5 min when N-methyl-D-glucamine in run buffer was added. CE was compared with high-performance liquid chromatography (HPLC) with fluorescence detection. The Bland-Altman test and Passing-Bablok regression demonstrates that the results obtained by CE-LIF and by HPLC are highly comparable. The simplified procedure of sample preparation, the short incubation and fast separation times, the high specificity, sensitivity and reproducibility, and the lower cost of analysis suggest that our proposed method can be considered valuable for the automation analysis in a routine laboratory.


Attenuation of 19-9 antigen secretion in human colorectal carcinoma cell cultures by transfection with cDNA encoding novel ADP-ribosylation factor-like proteins.
We have used cDNAs coding for novel ADP-ribosylation factor-like molecules (ARL184 and ARL184Delta) to alter 19-9 antigen glycoprotein secretion in cultured human colorectal carcinoma cells SW1116 by transfection and cloning. This ARL contains a lipophilic N-terminal with an isoleucyl and 3 leucyl residues, 4 functioning consensus sequence GTP binding sites, and 184 total aminoacyl residues. An ARL cDNA was also constructed deleting the codon for the N-terminal glycyl moiety. The resulting cell clones were shown by Northern blots to overexpress ARL mRNA. Electron microscopy-immunocytochemistry also indicated the overexpression of ARL granules subcellularly. Secretion of the tumor-associated 19-9 antigen into apical medium was decreased 3- to 5-fold and the secretion of TCA/PTA precipitable 3H-labeled glycoprotein was decreased by 34% in clone SW1116(ARL184)Delta. Western blot analyses of cell homogenates and media were in agreement with the secretion assays and showed a diminution of 170-200 kDa, 19-9, antigenicity in transfected cells and their media. Apical secretion of 19-9 antigen was diminished 14-fold in cells, SW1116 (ARL184)alpha, transfected with the complete ARL cDNA sequence, suggesting that the glycyl moiety may be required for maximal abatement. However, incorporation of label from [3H]myristate into 22-kDa bands of NP-40 extracts and ARL-antigenic molecules of parent cells was 3-fold greater than that in samples from the two transfectants; thus the transfected cells may not myristylate the overexpressed ARL efficiently. Notwithstanding the N-terminal glycyl moiety undergoing some other modification, we conclude that overexpression of this ARL is sufficient to generate a 19-9-deficient phenotype. These ARLs may eventually disrupt terminal oligosaccharide glycosylation, resulting in an apparent diminished exocytosis of 19-9 glycoprotein carriers by transfected and cloned cells.


Revealing the anaerobic acclimation of microbial community in a membrane bioreactor for coking wastewater treatment by Illumina Miseq sequencing.
The dynamic change of microbial community during sludge acclimation from aerobic to anaerobic in a MBR for coking wastewater treatment was revealed by Illumina Miseq sequencing in this study. The diversity of both Bacteria and Archaea showed an increase-decrease trajectory during acclimation, and exhibited the highest at the domestication interim. Ignavibacteria changed from a tiny minority (less than 1%) to the dominant bacterial group (54.0%) along with acclimation. The relative abundance of Betaproteobacteria kept relatively steady, as in this class some species increased coupled with some other species decreased during acclimation. The dominant Archaea shifted from Halobacteria in initial aerobic sludge to Methanobacteria in the acclimated anaerobic sludge. The dominant bacterial and archaeal groups in different acclimation stages were indigenous microorganisms in the initial sludge, though some of them were very rare. This study supported that the species in "rare biosphere" might eventually become dominant in response to environmental change.


Workplace bullying and subsequent health problems.
Cross-sectional studies demonstrate that exposure to bullying in the workplace is positively correlated with self-reported health problems. However, these studies do not provide a basis to draw conclusions on the extent to which bullying leads to increased health problems or whether health problems increase the risk of being bullied. To provide better indications of a causal relationship, knowledge from prospective studies on the association between bullying in the workplace and health outcomes is therefore summarised. We conducted a systematic literature review of original articles from central literature databases on longitudinal associations between bullying in the workplace and health. Average associations between bullying and health outcomes are calculated using meta-analysis. A consistent finding across the studies is that exposure to bullying is significantly positively related to mental health problems (OR =1.68; 95% KI 1.35-2.09) and somatic symptoms (OR = 1.77; 95% KI 1.41-2.22) over time. Mental health problems are also associated with subsequent exposure to bullying (OR = 1.74; 95% KI 1.44-2.12). Bullying is positively related to mental health problems and somatic symptoms. The association between mental health problems and subsequent bullying indicates a self-reinforcing process between mental health and bullying. The methodological quality of the studies that were conducted is relatively sound. However, based on the existing knowledge base there are no grounds for conclusions regarding an unambiguous causal relationship between bullying and health.


Hormonal and vascular fluid responses to maximal exercise in trained and untrained males.
The trained condition is associated with alterations in fluid regulation. In attempt to elucidate mechanisms responsible for these differences, resting, postexercise (maximal treadmill exercise of 8-13 min duration), and recovery measurements were made in seven trained (mean peak O2 consumption was 60.5 +/- 1.6 ml.kg-1.min-1) and seven untrained (mean peak O2 consumption was 40.7 +/- 1.7 ml.kg-1.min-1) male subjects. Samples were obtained by venipuncture with subjects seated. No significant differences in resting plasma osmolality (Osm), sodium, potassium, antidiuretic hormone (ADH), aldosterone, renin activity, or atrial natriuretic factor were found between groups. Maximal exercise produced significant increases in all of the above variables. Values immediately postexercise were similar between groups except for plasma Osm and sodium, which were significantly higher in the untrained group. Despite a reduction in plasma volume of equal magnitude in both groups, trained subjects demonstrated an increase in vascular proteins and mean corpuscular volume during exercise. This increase in plasma protein may be an important initiating factor responsible for the elevated plasma volume after 1-h recovery from exercise in the trained group. Lastly, similar ADH responses despite lower Osm in trained subjects may indicate that training increases the sensitivity of ADH to osmotic stimulation.


Structure and Function of TET Enzymes.
Mammalian DNA methylation mainly occurs at the carbon-C5 position of cytosine (5mC). TET enzymes were discovered to successively oxidize 5mC to 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). TET enzymes and oxidized 5mC derivatives play important roles in various biological and pathological processes, including regulation of DNA demethylation, gene transcription, embryonic development, and oncogenesis. In this chapter, we will discuss the discovery of TET-mediated 5mC oxidation and the structure, function, and regulation of TET enzymes.


Towards the development of clinical measures for spinal cord injury based on the International Classification of Functioning, Disability and Health with Rasch analyses.
To determine whether the International Classification of Functioning, Disability and Health (ICF) categories relevant to spinal cord injury (SCI) can be integrated in clinical measures and to obtain insights to guide their future operationalization. Specific aims are to find out whether the ICF categories relevant to SCI fit a Rasch model taking into consideration the dimensionality found in previous investigations, local item dependencies, or differential item functioning. All second-level ICF categories collected in the Development of ICF Core Sets for SCI project in specialized centers within 15 countries from 2006 through 2008. Secondary data analysis. Adults (N=1048) with SCI from the early postacute and long-term living context. Not applicable. Two unidimensional Rasch analyses: one for the ICF categories from body functions and body structures components and another for the ICF categories from the activities and participation component. Results support good reliability and targeting of the ICF categories in both dimensions. In each dimension, few ICF categories were subject to misfit. Local item dependency was observed between ICF categories of the same chapters. Group effects for age and sex were observed only to a small extent. The validity of ICF categories to develop measures of functioning in SCI for clinical practice and research is to some extent supported. Model adjustments were suggested to further improve their operationalization and psychometrics.


Novel automated microbial screening of platelet concentrates.
The recovery of bacteria and the speed of detection of microbial growth in platelet concentrates (PC) were studied, comparing a novel automated blood culture system (BacT/Alert) with two traditional methods. Full-scale experiments were performed with a total of 33 units of PC (average content 320 x 10(9) platelets per unit) obtained from pooled buffy coats. Six strains known as possible PC contaminants were tested: S. epidermidis, S. aureus, P. aeruginosa, B. cereus, E. aerogenes, and S. sanguis. Using an inoculum of 50-98 bacteria/ml, bacterial contamination was detected in all of 11 PCs on 132 sampling occasions. With a small inoculum (0.3-9 bacteria/ml), the bacterial contamination was detected in all PCs in which abundant growth appeared, but failed to be detected in some instances where the bacterial content was very small. All of 11 uninoculated PC controls were negative. With the automated method the time for detection of a culture-positive PC was 6-16 h, clearly shorter than with the two manual-visual systems. The new system provides a rapid, reliable, and labour-saving method for screening of bacterial contamination in PCs. This would increase safety particularly if the present 5-day shelf life were extended.


Amplified expression of dominant-negative transforming growth factor-beta type II receptor inhibits collagen type I production via reduced Smad-3 activity.
As a pleiotropic protein, transforming growth factor (TGF)-beta induces its effects by binding to its Ser/Thr kinase receptor type II and then recruiting and activating receptor type I, which is phosphorylated and activates Smads that transduce the signal to the nucleus. In this work, the authors blocked TGF-beta1 signal transduction pathway via delivery of a dominant-negative receptor-II (DeltaCyTbRII)-cDNA lacking Ser/Thr kinase intracytoplasmic domain activity. Thus, Cos-1 and hepatic stellate cells were cotransfected with pCMV5-DeltaCyTbRII and pAdTrack-green fluorescent protein using lipofectamine. Fluorescence microscopy demonstrated an average 10% transfection efficiency. Radiolabeled 125I-TGF-beta was bound mostly by cell membrane-expressed truncated receptor-II rather than wild-type receptor type II. Electrophoretic mobility shift assays were performed using consensus Smad-2 and -3 sequences rendering a three-fold decrease in DNA-binding activity, reflecting a down-activation in Smad complexes in pCMV5-DeltaCyTbRII-transfected cells, but not in mock-transfected cells. The identity of these transcriptional factors was confirmed using irrelevant double-stranded oligonucleotides and specific antibodies to compete for DNA binding. Also, collagen I mRNA expression showed a five-fold decrease, which was reflected at the protein level as a diminished collagen type I production in pCMV5-DeltaCyTbRII-transfected Cos-1 cells as measured by [3H]proline incorporation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Thus, this could be a useful strategy to downregulate or prevent exacerbated synthesis and deposition of extracellular matrix in a given fibrotic process.


Effect of Activated Charcoal on Rivaroxaban Complex Absorption.
To quantify the impact of activated charcoal (AC) on rivaroxaban exposure in healthy volunteers. This was an open-label study with an incomplete cross-over design of single-dose rivaroxaban (40 mg) administered alone or with AC in 12 healthy volunteers. The study comprised three treatment periods in randomised sequence, one with rivaroxaban administered alone and two with AC given at 2, 5 or 8 h post-dose. Rivaroxaban plasma concentration was measured in blood samples drawn at 16 time points. The pharmacokinetic model of rivaroxaban alone or with AC administration was built using a non-linear mixed-effect modelling approach. The pharmacokinetic model was based on a one-compartment model with an absorption rate described by the sum of three inverse Gaussian densities to reproduce multiphasic and prolonged absorption. The inclusion in the model of each AC administration schedule significantly improved objective function value. AC reduced the area under the rivaroxaban concentration-time curve by 43% when administered 2 h post-dose, by 31% when administered 5 h post-dose and by 29% when administered 8 h post-dose. Based on the estimated pharmacokinetic model, simulations suggested that AC might have an impact even after 8 h post-dose. AC administration significantly reduces exposure to rivaroxaban even if AC is administered 8 h after rivaroxaban. These results suggest that AC could be used in rivaroxaban overdose and accidental ingestion to antagonise absorption. CLINICALTRIAL. NCT02657512.


Comparative phenotypic analysis and genome sequence of Clostridium beijerinckii SA-1, an offspring of NCIMB 8052.
Production of butanol by solventogenic clostridia is controlled through metabolic regulation of the carbon flow and limited by its toxic effects. To overcome cell sensitivity to solvents, stress-directed evolution methodology was used three decades ago on Clostridium beijerinckii NCIMB 8052 that spawned the SA-1 strain. Here, we evaluated SA-1 solventogenic capabilities when growing on a previously validated medium containing, as carbon- and energy-limiting substrates, sucrose and the products of its hydrolysis d-glucose and d-fructose and only d-fructose. Comparative small-scale batch fermentations with controlled pH (pH 6.5) showed that SA-1 is a solvent hyper-producing strain capable of generating up to 16.1 g l(-1) of butanol and 26.3 g l(-1) of total solvents, 62.3 % and 63 % more than NCIMB 8052, respectively. This corresponds to butanol and solvent yields of 0.3 and 0.49 g g(-1), respectively (63 % and 65 % increase compared with NCIMB 8052). SA-1 showed a deficiency in d-fructose transport as suggested by its 7 h generation time compared with 1 h for NCIMB 8052. To potentially correlate physiological behaviour with genetic mutations, the whole genome of SA-1 was sequenced using the Illumina GA IIx platform. PCR and Sanger sequencing were performed to analyse the putative variations. As a result, four errors were confirmed and validated in the reference genome of NCIMB 8052 and a total of 10 genetic polymorphisms in SA-1. The genetic polymorphisms included eight single nucleotide variants, one small deletion and one large insertion that it is an additional copy of the insertion sequence ISCb1. Two of the genetic polymorphisms, the serine threonine phosphatase cbs_4400 and the solute binding protein cbs_0769, may possibly explain some of the observed physiological behaviour, such as rerouting of the metabolic carbon flow, deregulation of the d-fructose phosphotransferase transport system and delayed sporulation.


In situ two-dimensional high-resolution profiling of sulfide in sediment interstitial waters.
A recently developed technique of diffusive gradients in thin films (D6T)-computer-imaging densitometry (CID) was improved to study in situ two-dimensional distributions of sulfide in sediment interstitial waters adjacent to the DGT device. The in situ profiler accumulates sulfide from the sediment interstitial water through a diffusive gel onto a AgI binding gel to form black Ag2S. The amount of sulfide bound in the binding gel is then determined from the gray scale density of the dried binding gel. New gel-making procedures were employed to produce stable, evenly dispersed AgI binding gels and to minimize the darkening of the AgI gel upon exposure to light The improved DGT-CID technique was used to profile the distribution of sulfide in sediment interstitial waters at Delta Marsh, a highly productive Prairie wetland on the south shore of Lake Manitoba, at a vertical and lateral resolution of < or = 0.4 mm. The in situ high-resolution microprofiles revealed unprecedented two-dimensional heterogeneity in sulfide concentrations in the sediment interstitial waters adjacent to the DGT device. The mosaic distribution of oxic and sulfidic microenvironments suggested not only the complexity and heterogeneity of the biogeochemistry of sulfur species and sulfide-binding metals (e.g., Cd, Cu, Pb, Hg, Zn) in sediments but also the capability of aquatic organisms for coping with the sulfidic environment


The three mechanisms of intracellular chloride accumulation in vascular smooth muscle of human umbilical and placental arteries.
Recordings of membrane potential (Em) and intracellular [Cl-] ([Cl-]i) were made from the smooth muscle of human umbilical and placental arteries, using double-barrelled, ion-sensitive microelectrodes. In both arteries, [Cl-]i was above equilibrium with Em. In the umbilical artery, [Cl-]i was 33.8+/-0.9 mM (+/-SD, n=19) and Em -54.9+/-1.3 mV and in the placental artery respectively 35.1+/-0.7 mM (n=17) and -50.6+/-0.9 mV. In both arteries, [Cl-]i was reduced and Em hyperpolarised significantly by successive additions of 100 microM 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulphonic acid (DIDS), 10 microM bumetanide and 1 mM acetazolamide, thus revealing the presence of Cl-/HCO3- exchange, (Na+K+Cl) cotransport and "pump III". In the presence of all three inhibitors, [Cl-]i was in equilibrium with Em. As in earlier studies on rat arterial smooth and cardiac muscle, pump III was unaffected by DIDS, bumetanide, metolazone and the removal of Na+, partly inhibited by chlorothiazide and fully inhibited by ethacrynic acid. The results are discussed in terms of the possibility that of chloride accumulating systems may regulate vasomotor tone in the foetoplacental unit.


Pattern of adhesion molecule expression on vascular endothelium in Helicobacter pylori-associated antral gastritis.
The inflammatory response in Helicobacter pylori-associated gastritis (HAG) is characterized by an intense infiltrate of granulocytes and lymphocytes. The emigration of white blood cells into sites of inflammation is mediated by receptors on endothelial cells and on blood leukocytes. The aim of this study was to characterize endothelial adhesion molecule expression in HAG leading to leukocyte infiltration. Endothelially expressed adhesion molecules were studied in situ by immunohistochemical analysis of antral mucosal biopsy specimens from 20 control patients, 10 of whom had chemical gastritis, 10 normal mucosa, and 44 HAG. Adjacent biopsies were used to evaluate messenger RNA (mRNA) transcripts for the respective adhesion molecule and its inducing cytokines. Constitutive expression of P-selectin was found in all groups. Intercellular adhesion molecule 1 (ICAM-1) was up-regulated in patients with HAG and chemical gastritis in contrast to normal controls. Vascular adhesion molecule 1 (VCAM-1) was only found within lymphoid aggregates present in HAG. Neither mRNA transcripts nor the protein product of E-selectin were detected in normal or inflamed mucosa, although mRNA of the E-selectin-inducing cytokines, tumor necrosis factor alpha and interleukin 1beta, were found. Data suggest a major role of ICAM-1 and VCAM-1 in leukocyte-endothelial interaction in HAG without E-selectin up-regulation showing a unique pattern within the gastrointestinal tract, in contrast to observations made in inflammatory bowel disease.


Scaling behavior for the onset of convection in a colloidal suspension.
We investigate the early stages of mass convection in a colloidal suspension at high solutal Rayleigh number Ras. From the time evolution of shadowgraph images and by assuming a diffusive growth of the boundary layers we obtain an indirect measurement of the concentration boundary layer thickness delta* at the onset of convection. We show that the dimensionless boundary layer thickness delta=delta*/d scales as Ra-ps, where Ras=Rasdelta is a modified solutal Rayleigh number for convection which accounts for the actual density unbalance and d is the thickness of the sample layer. This scaling behavior is analogous to that reported at steady state for turbulent convection in simple fluids. We find p=0.35, a value compatible with the exponent 1/3, reported for turbulent heat convection in simple fluids at steady state.


Test--retest variability of Randot stereoacuity measures gathered in an unselected sample of UK primary school children.
To determine the test-retest reliability of the Randot stereoacuity test when used as part of vision screening in schools. Randot stereoacuity (graded-circles) and logMAR visual acuity measures were gathered in an unselected sample of 139 children (aged 4-12, mean 8.1±2.1 years) in two schools. Randot testing was repeated on two occasions (average interval between successive tests 8 days, range: 1-21 days). Three Randot scores were obtained in 97.8% of children. Randot stereoacuity improved by an average of one plate (ie, one test level) on repeat testing but was little changed when tested on the third occasion. Within-subject variability was up to three test levels on repeat testing. When stereoacuity was categorised as 'fine', 'intermediate' or 'coarse', the greatest variability was found among younger children who exhibited 'intermediate' or 'coarse'/nil stereopsis on initial testing. Whereas 90.8% of children with 'fine' stereopsis (≤50 arc-seconds) on the first test exhibited 'fine' stereopsis on both subsequent tests, only ∼16% of children with 'intermediate' (>50 but ≤140 arc-seconds) or 'coarse'/nil (≥200 arc-seconds) stereoacuity on initial testing exhibited stable test results on repeat testing. Children exhibiting abnormal stereoacuity on initial testing are very likely to exhibit a normal result when retested. The value of a single, abnormal Randot graded-circles stereoacuity measure from school screening is therefore questionable.


A model of spatial localization and its application to strabismus.
Visually guided, spatially oriented behavior involves an ongoing integration of signals regarding the loci of the retinal images and the position and orientation of the eye. In the strabismic this requires an altered spatial metric resulting from a functional readaptation to avoid confusion and diplopia. A comparator mechanism for evaluating these two signals is presented. A case report using "disruptive" therapeutic procedures that deliberately alter the strabismic's visual-postural control system is presented. A treatment plan for altering the anomalous binocular link, a characteristic of the well adapted strabismic, is described and related to the comparator mechanism.


Identification of in vitro growth conditions for c-Kit-negative hematopoietic stem cells.
Our laboratory recently identified a quiescent class of pluripotent hematopoietic stem cells (PHSCs) that are lineage negative (Linneg), lack c-Kit, and are able to give rise to c-Kit-positive (c-Kitpos) PHSCs in vivo. This population fails to proliferate in vitro but has delayed reconstituting activity in vivo. In this study, we purified these cells to enrich for the PHSCs and we identified in vitro conditions capable of supporting their maturation. The c-Kit-negative (c-Kitneg) cells exhibited differential expression of Sca-1, CD34, CD43, CD45, and Thy 1.2. We purified the cells based on Sca-1, as it is expressed on active PHSCs. We detected pre-colony-forming unit spleen (pre-CFU-s) activity in both the Sca-1neg and Sca-1pos populations, indicating the presence of primitive PHSCs in both populations. However, our in vitro studies suggest that the Sca-1pos population is enriched for PHSCs. The in vitro systems that support the growth of these dormant cells include a modified long-term marrow culture and various stromal cell lines. In modified long-term bone marrow cultures, c-Kitneg cells gave rise to c-Kitpos PHSCs, with long-term reconstitution activity in vivo. Thus we have established an in vitro system to examine PHSC maturation that will allow us to study the mediators of the c-Kitneg to c-Kitpos transition.


[Spanish version of the Multidimensional health locus of control scale innursing students].
To determine the preliminary psychometric properties of the Spanish form of the Multidimensional Health Locus of Control Scale (MHLC), which consists of three subscales: (1) Internalitu, (2) Powerful other externality, and (3) Chance externality. It also aims to study the relationship that the internal/external health control beliefs has with self-esteem, self-efficacy and perceived competence in a sample of nursing undergraduates. An observational and cross-sectional study including 109 nursing students who completed an anonymous questionnaire containing the demographic variables and the Spanish versions of the MHLC, the Rosenberg Self-Esteem Scale, the General Self-Efficacy Scale, and the Perceived personal competence Scale. A Cronbach's alpha coefficient of 0.713 for Internality, 0.665 for Chance and 0.728 for Powerful other were obtained. The test-retest correlation for the 18 items of the MHLC was 0.866. Internality subscale was positively and significantly correlated with self-efficacy and competence. By contrast, chance externality has negative and significant correlations with self-esteem and competence. There are no significant gender differences in any of the subscales. Younger subjects show greater tendency to external attribution. Factor analysis confirms the three-factor hypothesis. The results suggest that the Spanish form of the MHLC has adequate construct validity and acceptable metric properties. Also, they evidence the relationship between the attribution of health-related internal control with the perceived well-being and confidence in their own skills and abilities.


Glutathione S-transferase A1 polymorphisms and acute graft-vs.-host disease in HLA-matched sibling allogeneic hematopoietic stem cell transplantation.
Busulfan and the metabolites of cyclophosphamide are conjugated with glutathione and catabolized by enzymes of the cytosolic glutathione S-transferases family. There are clearly linked single nucleotide polymorphisms in the promoter region of the glutathione S-transferase A1 gene (i.e., GSTA1*A, -567T, -69C and -52G; GSTA1*B, -567G, -69T and -52A). We assessed whether the clinical outcomes, including acute graft-vs.-host disease, of 61 patients with hematological malignancies, following HLA-matched sibling allogeneic stem cell transplantation using busulfan/cyclophosphamide conditioning are altered by glutathione S-transferase A1 genotypes. Globally, grade II-IV acute graft-vs.-host disease developed in 13 patients (21%). Grade II-IV acute graft-vs.-host disease developed in 15.2% of 46 patients with GSTA1*A/*A diplotype and in 40.0% of 15 patients with GSTA1*A/*B or GSTA1*B/*B diplotype (p = 0.04). Moreover, this relationship between GSTA1*A/*A diplotypes and lower incidence of acute graft-vs.-host disease was independent of the age, gender, stem cell source, and disease status. The incidences of acute skin graft-vs.-host disease were 7% (3/46) in patients with GSTA1*A/*A and 27% (4/15) in patients without GSTA1*A/*A (p = 0.009, univariate; p = 0.01, multivariate). Acute hepatic graft-vs.-host disease developed in 6 (13%) of 46 patients with the GSTA1*A/*A diplotype and in 4 (27%) of 15 patients without this diplotype (p = 0.09, univariate; p = 0.12, multivariate). Ten patients (16%) developed hepatic veno-occlusive disease. No significant difference was found in the incidence of hepatic veno-occlusive disease between patients with and without the GSTA1*A/*A diplotype (19.6% vs. 6.7%; p = 0.24). We conclude that the GSTA1*A/*A diplotype is an independent protective factor against acute graft-vs.-host disease, especially for skin graft-vs.-host disease, and probably for hepatic graft-vs.-host disease, in patients using busulfan/cyclophosphamide conditioning. The identification of glutathione S-transferase A1 genotypes prior to allogeneic stem cell transplantation could allow conditioning regimens and graft-vs.-host disease prophylaxis to be modified to improve outcome.


The diagnostic value of inhibin in infertility evaluation.
The fertility patient is entitled to a rapid and accurate diagnosis, a realistic assessment of the prospects for achieving pregnancy, and the timely initiation of an appropriate and effective therapy. The evaluation of ovarian reserve prior to initiation of ovarian stimulation is an important aspect of the infertility work-up of a woman requiring assisted reproductive techniques (ARTs). The ability of the ovary to respond to gonadotropin stimulation by the recruitment of a cohort of follicles is central to the success of treatment such as in vitro fertilization and intracytoplasmic sperm injection. Ovarian dysfunction, often age related, is an increasingly common cause of subfertility, and hyper- and hypogonadotropic dysovulation as well as the commoner polycystic ovarian syndrome (PCOS) are frequently encountered in fertility clinic. In cases of male-factor infertility, an ability to identify an accurate serum marker of Sertoli cell function has enhanced the diagnostic process, as previous endocrine markers such as follicle-stimulating hormone and testosterone were poor correlates of spermatogenic potential. The identification, purification, and cloning of the members of the inhibin-activin superfamily and the subsequent development of sensitive and highly specific two-site enzyme-linked immunoassays for these polypeptide hormones have provided tentative answers to many of the outstanding questions concerning the regulation of the hypothalamo-pituitary-gonadal axis. Assessment of serum levels of inhibin B appears to offer useful prognostic information about ovulatory function and predictive information about response to treatment. During very early pregnancy, especially in the presence of complications associated with ART such as multiple gestation and ovarian hyperstimulation syndrome, measurement of maternal levels of inhibin A and pro-alphaC offers a noninvasive test that can aid the counseling and management of patients.


Feedforward somatosensory inhibition is normal in cervical dystonia.
Insufficient cortical inhibition is a key pathophysiological finding in dystonia. Subliminal sensory stimuli were reported to transiently inhibit somatosensory processing. Here we investigated whether such subliminal feedforward inhibition is reduced in patients with cervical dystonia. Sixteen cervical dystonia patients and 16 matched healthy controls performed a somatosensory detection task. We measured the drop in sensitivity to detect a threshold-level digital nerve shock when it was preceded by a subliminal conditioning shock, compared to when it was not. Subliminal conditioning shocks reduced sensitivity to threshold stimuli to a similar extent in both patients and controls, suggesting that somatosensory subliminal feedforward inhibition is normal in cervical dystonia. Somatosensory feedforward inhibition was normal in this group of cervical dystonia patients. Our results qualify previous concepts of a general dystonic deficit in sensorimotor inhibitory processing.


Expression of cyclo-oxygenase 2 in rat brain following kainate treatment.
The transcriptional expression of the mitogen-inducible cyclo-oxygenase (COX-2) was investigated by in situ hybridization of kainate-treated rat brains. Kainate treatment rapidly induced COX-2 mRNA in neurons throughout the forebrain which was blocked by pretreatment with MK-801 or NBQX. Transient expression of COX-2 mRNA lasting about 8 h occurred in areas that were resistant to neuronal necrosis, while COX-2 mRNA expression persisted for 24-72 h in regions that were vulnerable. These results show that seizures result in increased COX-2 expression and support the hypothesis that COX-2 could be an important factor in the pathogenesis of delayed neuronal necrosis due to kainate excitotoxicity.


[Acute oliguric renal failure in hypoxic neonates born at full term].
Acute renal failure (ARF) is a frequent clinical condition in neonatal intensive care units (NICU). The leading cause of neonatal ARF is perinatal asphyxia (PS). The aim of this study was to examine the relationship between the degree of PS and the severity of ARF in term neonates. A prospective survey of 31 term neonates with Ps and but without congenital malformations or sepsis was performed in NICU of the regional Hospital of Gynaecology and Obstetrics in Belgrade (average number of deliveries about 6000 per year). ARF was diagnosed in the first 7 days of life when plasma creatinine was above 133 mumol/L for at least 48 hours while maternal renal function was normal. The degree of PS was determined according to Apgar score (AS) at 1 min. The severe PS was defined as AS < 3 and moderate PS as AS 4-6. Twenty neonates (64%) had oliguric ARF with urine output of 0.37 +/- 0.16 ml/kg/h while the others had nonoliguric ARF with urine output of 2.4 +/- 0.7 ml/kg/h. Most of neonates with oliguric ARF (65%) had severe perinatal asphyxia while in those with nonoliguric ARF moderate perinatal asphyxia predominated (73%). During hypoxic-ischaemic events many organs are injured, and the most vulnerable ones are kidneys and central nervous system. Our results showed a strong connection between perinatal asphyxia and A, which was in accordance with the results of other studies. Neonates with severe perinatal asphyxia had serious impairment of renal function, which was confirmed with strong correlation between Apgar score and plasma creatinine. In neonates with oliguric ARF, but not in those with nonliguric ARF, the highly positive linear correlations were found between AS and urinary output (r = 0.77; p < 0.01), plasma creatinine (r = 0.78; p < 0.01), fractional excretion of sodium (r = 0.76; p < 0.01), and index of renal failure (r = 0.80; p < 0.01). Only in oliguric neonates with severe perinatal asphyxia (31%) the outcome was fatal. We conclude that in tgerm neonates with severe perinatal asphyxia oliguric ARF was the predominant type of ARF. There is a good prediction of the severity of oliguric ARF according to the degree of perinatal asphyxia determined by Apgar score at 1 min.


Preoperative intra-arterial chemotherapy in patients with osteosarcoma: case report of seven patients below the age of 18 years.
In the period between 1987 and 1989, seven patients under 18 years of age with osteosarcoma of a lower limb were treated by preoperative intra-arterial chemotherapy. The age of the patients ranged from 12 to 17 years, the median age being 14.5 years. The polyethylene catheter was placed surgically into the lower epigastric artery. Two combinations of cytostatics were administered: adriamycin-bleomycin-cisplatin and high-dose methotrexate-vincristine-cisplatin. All patients, after two or three courses, underwent surgical resection of limb tumor. Tumor destruction ranged from 20 to 100%. Four patients with necrosis from 80-100% remained free of disease from 18 to 30 months: two, having necrosis of 40% and 95% respectively, died. The youngest patient whose necrosis was as low as 20%, after completion of the systemic chemotherapy, developed local recurrence and pulmonary metastases.


Suspect value of non-CSF viral cultures in the diagnosis of enteroviral CNS infection in young infants.
Laboratory criteria used for presumptive diagnosis of enteroviral meningitis were evaluated as predictors of cerebrospinal fluid (CSF) infection. Records were retrospectively analysed of infants under four months of age admitted to hospital between 1977 and 1987 with viral CSF cultures: those with enteroviruses isolated from CSF (group 1) were compared with those with enteroviruses isolated only from non-CSF sites (group 2). Predictive value computations demonstrated that no single or combined non-CSF culture accurately predicted isolation of enteroviruses from the CSF. These results suggest that CSF viral culture is imperative in establishing the diagnosis of enteroviral meningitis in young infants.


Relationship between tumour necrosis factor-related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor in human multiple myeloma patients.
Tumour necrosis factor-alfa (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL), which belongs to the TNF family of proteins, plays a role in the regulation of vascular responses, but its effect on the formation of new blood vessels (angiogenesis) is unclear. We analysed TRAIL concentrations in parallel with pro-angiogenic cytokines in serum and their expression in trephine biopsy (TB) in 56 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of TRAIL and TNF-α, as well as of VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. Furthermore, we observed a significant decrease in all studied pro-angiogenic cytokines and significant increase of TRAIL concentration after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with progression during the induction treatment. It was also established that TRAIL correlated statistically and negatively with pro-angiogenic cytokines such as VEGF with its receptor and expression of VEGF and syndecan-1 in TB. In summary, our data indicate that in MM patients, both clinical course and treatment responsiveness are associated with dynamic yet corresponding changes of levels of TRAIL parallel pro-angiogenic mediators such as VEGF with its receptor and expression of VEGF and syndecan-1 in TB.


Changes in conformational dynamics of mRNA upon AtGRP7 binding studied by fluorescence correlation spectroscopy.
The clock-regulated RNA recognition motif (RRM)-containing protein AtGRP7 (Arabidopsis thaliana glycine-rich RNA-binding protein) influences the amplitude of its transcript oscillation at the post-transcriptional level. This autoregulation relies on AtGRP7 binding to its own pre-mRNA. The sequence and structural requirements for this interaction are unknown at present. In this work, we used photoinduced electron transfer fluorescence correlation spectroscopy (PET-FCS) as a novel technique to study the role of target RNA secondary structure and conformational dynamics during the recognition and binding process. Conformational dynamics of single-stranded (ss) oligonucleotides were studied in aqueous solution with single-molecule sensitivity and high temporal resolution by monitoring fluorescence quenching of the oxazine fluorophore MR121 by guanosine residues. Comparative analysis of translational diffusion constants revealed that both ssRNA and ssDNA bind to AtGRP7 with similar dissociation constants on the order of 10(-7) M and that a minimal binding sequence 5'-UUC UGG-3' is needed for recognition by AtGRP7. PET-FCS experiments demonstrated that conformational flexibility of short, single-stranded, MR121-labeled oligonucleotides is reduced upon AtGRP7 binding. In contrast to many other RRM proteins, AtGRP7 binds to ssRNA preferentially if the RNA is fully stretched and not embedded within a stable secondary structure. The results suggest that AtGRP7 binding leads to a conformational rearrangement in the mRNA, arresting the flexible target sequence in an extended structure of reduced flexibility that may have consequences for further post-transcriptional processing of the mRNA.


Fellow Eye Comparisons for 7-Year Outcomes in Ranibizumab-Treated AMD Subjects from ANCHOR, MARINA, and HORIZON (SEVEN-UP Study).
To compare study and fellow eyes in subjects with age-related macular degeneration (AMD) for 7-year outcomes arising from contrasting treatment histories and disease statuses. Multicenter cohort study, predetermined secondary analysis. A total of 65 participants from the ranibizumab-treatment arms of the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR), Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD (MARINA), and Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON) trials, recruited for an update evaluation from 14 study sites. Seven-year visual outcomes and retinal imaging data were compared with the ANCHOR, MARINA, and HORIZON databases. Under the ANCHOR and MARINA protocols, study eyes had received monthly ranibizumab injections for the initial 2 years, during which fellow eyes were prohibited from anti-vascular endothelial growth factor (VEGF) treatments. Percentage of subjects with study eye vision better than fellow eye, vision change from baseline to year 7, and mean area of macular atrophy (MA) were predetermined secondary end points. Fellow eyes with exudative AMD had received a mean 7.3 total injections of anti-VEGF agents in the mean 3.4 years off-study. For the 35% of subjects with exudative AMD in both eyes at baseline, within-patient comparisons at year 7 showed better vision in the study eye in 82%, with better mean final vision in study eyes (54.7 vs. 27.3 letters in fellow eyes, P < 0.001). Also in this subgroup, study eyes, which had received 2 years of high-frequency ranibizumab, had less severe MA than the respective fellow eye at year 7 in 88% of patients (mean area ± standard deviation 2.8±2.2 mm(2) vs. 5.8±2.5 mm(2) in the fellow eyes, P = 0.0013). Final fellow eye vision outcome was significantly correlated with MA severity (coefficient -6.95, P < 0.001), and patients' inter-eye vision difference corresponded to the degree of MA asymmetry. Exudative fellow eyes remained at risk for further vision decline in later years under management with low-frequency anti-VEGF therapy. In patients with bilateral exudative AMD at baseline, final vision at year 7 was significantly better in study eyes than in fellow eyes, and MA was less severe. Macular atrophy area correlated with final visual outcomes, determined inter-eye vision differences, and was not attributable to high-frequency ranibizumab therapy.


An outbreak of leptospirosis on a single farm in east Otago.
To present an outbreak of leptospirosis on a dairy farm which had an unvaccinated herd. Nine people working or living on the farm were tested for the presence of leptospira antibody by the microscopic agglutination test. Nineteen cows randomly selected, were also tested. Three human cases and one suspected case were detected over a one month period (December 1992-January 1993). Seventy-nine percent of the dairy herd tested had serological evidence of infection with L hardjo. Leptospirosis continues to be a major occupational problem in New Zealand. The importance of herd vaccination and the use of protective clothing during milking is emphasised.


Impact of restrictive lung disorder on cardiovascular mortality in a general population: The Yamagata (Takahata) study.
Obstructive lung disorder (OLD) is known to be associated with cardiovascular disease. However, the impact of restrictive lung disorder (RLD) on cardiovascular mortality has not been fully investigated in the apparently healthy general population. To clarify whether RLD is associated with cardiovascular mortality in the general population. This community-based cohort study included 3247 subjects who participated in an annual health check in Takahata. We performed spirometry in registered subjects and found that 194 (6%) had RLD, 262 (8%) had OLD, and 73 (2%) had RLD and OLD (Mixed). During a 10-year follow-up, there were 210 deaths, including 57 cardiovascular deaths. Cardiovascular mortality of subjects with RLD was significantly higher than that of subjects with normal lung function. Although the subjects with RLD were younger, comprised fewer smokers, and were more likely to be female than those with OLD, cardiovascular mortality of subjects with RLD was comparable to that of subjects with OLD. Subjects with RLD had a higher prevalence of atrial fibrillation (AF) than those with OLD, and the prevalence of AF was increased with advanced severity of RLD. Multivariate Cox proportional hazard analysis revealed that RLD was an independent predictor of cardiovascular death (hazard ratio 2.61, 95% confidence interval, 1.22-5.21) after adjustment for confounders, but OLD was not. The net reclassification improvement and integrated discrimination improvement were significantly increased by the addition of RLD to conventional cardiovascular risk factors. The presence of RLD was associated with cardiovascular mortality in the general population.


Stable incidence of HIV diagnoses among Danish MSM despite increased engagement in unsafe sex.
Since introduction of highly active antiretroviral therapy (HAART), the prevalence of Danish HIV-positive men who have sex with men (MSM) has increased substantially. In contrast, the incidence of MSM diagnosed with HIV has not increased, and this paradox has been the focus of intensive debate. Study period was 1995-2010. Data were obtained from 2 Danish nation-wide registries of HIV and syphilis, and 5 consecutive surveys on sexual behavior in Danish MSM. We calculated incidences of HIV and syphilis in MSM, prevalence of HIV-positive MSM with detectable viral load (>400 HIV RNA copies/mL), and changes in frequency of unprotected anal intercourse. We introduce The Cohort Community Reproductive Rate (CCRR) to describe the number of newly diagnosed MSM per HIV-positive MSM per year and used Poisson regression to model CCRR. From 1995 to 2010, the prevalence of Danish MSM diagnosed with HIV increased from 1035 to 1813 (75%), whereas the number of HIV-positive MSM with detectable viral load (>400 HIV RNA copies/mL) decreased by 75% from 1035 to 262. The incidence of syphilis and unprotected anal intercourse rose dramatically in the same period, whereas CCRR decreased from 0.099 (95% confidence interval: 0.092 to 0.108) to 0.071 (95% confidence interval: 0.065 to 0.079). Our results strongly indicate that HAART has decreased the risk of transmission of HIV despite increased practice of unsafe sex and thereby substantiate that HAART should be offered to MSM to reduce risk of transmission of the disease.


[Chemical Constituents from Mallotus paniculatus (II)].
To study the chemical constituents of Mallotus paniculaus radix. The compounds were isolated with column chromatography. The chemical structures were identified by spectral and spectroscopic technology. Seven compounds were isolated from the n-BuOH extract and identified as scopoletin(1), isoscopletin(2), erythordiol(3), apigenin(4), 4-methoxybenzoic acid(5), acetylaleuritolic acid(6) and β-daucosterol (7). compounds 2 - 6 are isolated from this plant for the first time.


[Photoperiod effect testicular physiology in the stone-marten (Martes foina Erx.)].
The male Stone-Marten (Martes foina) has a well-defined sexual cycle with two very different phases: a breeding season (May-June) and a quiescent period (November-December). We can cause the onset of the testicular activity, during the quiescent phase, by an experimental increase of daylight (18 L-6 D).


CE: Original Research: The Experiences of Pregnant Smokers and Their Providers.
: Background: The U.S. Department of Health and Human Services' initiative Healthy People 2020 targets tobacco use, including smoking during pregnancy, as a continuing major health concern in this country. Yet bringing the U.S. Public Health Service's 2008 clinical practice guideline, Treating Tobacco Use and Dependence, into routine prenatal care remains challenging. Our previous nurse-managed intervention study of rural pregnant women found no significant cessation effect and significant discordance between self-reported smoker status and urinary cotinine levels. The overall purpose of this follow-up study was to increase our understanding of the experiences of pregnant smokers and their providers. No qualitative studies could be found that simultaneously explored the experiences of both groups. This qualitative descriptive study used focus group methodology. Nine focus groups were held in two counties in upper New York State; six groups consisted of providers and three consisted of pregnant women. Four semistructured questions guided the group discussions, which were audiotaped and transcribed verbatim. Transcripts were read and coded independently by six investigators. Themes were identified using constant comparative analysis and were validated using the consensus process. The total sample consisted of 66 participants: 45 providers and 21 pregnant women. Most of the providers were white (93%) and female (93%). A majority worked as RNs (71%); the sample included perinatal and neonatal nursery nurses, midwives, and physicians. The pregnant women were exclusively white (reflecting the rural demographic); the average age was 24 years. All the pregnant women had smoked at the beginning of their pregnancies. Four common themes emerged in both the provider and the pregnant women groups: barriers to quitting, mixed messages, approaches and attitudes, and program modalities. These themes corroborate previous findings that cigarette smoking is used for stress relief, especially when pregnancy itself is a stressor, and that pregnant women may feel guilty but don't want to be nagged or preached to. These results have implications for how smoking cessation programs for pregnant women should be designed. Health care providers need to be cognizant of their approaches and attitudes when addressing the subject of smoking cessation. Specific educational suggestions include "putting a face" to the issue of tobacco use during pregnancy. More research is needed on how best to implement the 2008 clinical practice guideline in specific populations.


Dynamic management of squamous cell cancer of the anal canal.
For many years the accepted treatment for squamous cell cancer of the anal canal has been abdominoperineal resection of the rectum. Recently, high dose radiation therapy has been advocated by some, and we initiated a study using a combination of radiation, chemotherapy and surgery. This review includes 44 patients treated by us from December 1971 to July 1983. We discontinued routine operation after 1975 because chemoradiation therapy eliminated the primary lesion in most patients. In fact, the gross lesion disappeared in 40 patients, 13 of whom had radical operations done on routine basis. Four operations were done for residual disease after chemoradiation treatment and one for local recurrence. The corrected, projected five year survival rate was 79% with a follow-up of at least four years in all patients. Most failures occurred in patients with large primary tumors, all of whom had radical operations after the preoperative therapy. This experience suggests that patients with primary lesions over 5 cm in maximum diameter should have an additional course of chemoradiation and/or abdominoperineal resection on a routine basis.


Group process and social climate of GROW, a community mental health organisation.
GROW, a community based mutual-help organisation, aims to provide the means for those who have been mentally ill to rehabilitate themselves and grow personally. We measured psychiatric symptoms, group processes, social environment and perceived social support in a sample of GROW group members. We found that GROW does provide the opportunity for and encourages some personal changes and does provide social support. We could not draw any conclusions about GROW's efficacy as a rehabilitative agent.


[Treatment of rheumatic polyarthritis with levamisole in 26 patients].
Twenty-six patients with rheumatic polyarthritis (serologically positive) were treated with levamisole at a daily dosage of 150 mg. Treatment was continuous for 3 months and 2 days weekly afterwards. Although improvement may appear from the 1st month onwards, it is more frequent between the 1st and 3rd month (13 good or very good results among the 16 patients still treated) and may even improve afterwards (11 good or very good results among the 11 patients still treated in the 6th month). However, the value of levamisole, which appears to be an active drug against rheumatic polyarthritis, is limited by the frequency of side-effects. In 17 cases the trial had to be discontinued for this reason. The most serious side-effects were of haematological nature (2 leukopenias, 1 thrombocytopenia), but in these patients agranulocytosis was not found.


Isopropyl amide derivatives of potent and selective muscarinic M2 receptor antagonists.
Low molecular weight amide derivatives were synthesized and evaluated as M(2) receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M(2) receptor antagonists with structural features different from our clinical candidate 1.


Correlation of serum and urinary porphyrin levels in porphyria cutanea tarda.
A significant linear correlation was found between serum total porphyrin concentration and 24-hour total urinary porphyrin excretion in 18 patients with porphyria cutanea tarda sampled at diagnosis and during and after treatment on 73 occasions. This confirms that the serum porphyrin level parallels urinary porphyrin excretion and is an appropriate indicator of disease activity useful for monitoring patients in clinical practice.


Fatal air embolism during transurethral resection.
A case of fatal air embolism during transurethral resection is presented along with suggestions for treatment. The importance of prompt recognition of the condition is stressed.


Identification of ocular matrix metalloproteinases present within the aqueous humor and iridocorneal drainage angle tissue of normal and glaucomatous canine eyes.
The purpose of this study was to identify the most active matrix metalloproteinases (MMP) within the aqueous humor and iridocorneal angle tissue involved in the normal canine eye, and to compare these results to the MMP activity in dogs with glaucoma. Aqueous humor samples from 32 normal eyes and 26 glaucomatous eyes were obtained through aqueous centesis and analyzed for MMP activity. Iridocorneal angle tissue from 16 enucleated normal canine eyes and 5 enucleated glaucomatous eyes were dissected and homogenized into solution. Bradford total protein assays were determined for aqueous humor samples and iridocorneal angle tissue samples. Substrate gelatin zymography was performed using 0.2 microL volumes of an MMP-2/MMP-9 control, 2 microL volumes of aqueous humor samples, and 10 microg weights of total protein from iridocorneal angle tissue. The presence of MMP gel bands were identified visually and measured quantitatively by densitometry technique. A statistical analysis was performed on the data using Student's t-test, multiple logistic Wald's chi-squared regression, Pearson correlations, and repeated measures analysis. Within the aqueous humor of canine eyes, MMP-2 latent form was found to be the most relevant MMP. The quantity of latent MMP-2 within the aqueous humor of the glaucoma samples was significantly increased compared to the normal aqueous samples (P < 0.0001). Glaucoma occurrence was associated with elevated aqueous humor latent MMP-2 (P = 0.0002). Within the canine iridocorneal angle tissue, MMP-9 latent form and MMP-2 active form were found to be the most relevant MMPs. MMP-2 active form was found to be significantly increased in the glaucoma tissue samples when compared to the normal tissue samples (P = 0.0044). MMP-9 latent form was also found to be significantly increased in glaucomatous tissue when compared to the normal eyes (P = 0.0002). Tissue MMP-9 latent form was found to be associated with glaucoma status (P = 0.042). Glaucoma aqueous humor samples expressed a statistically increased latent MMP-2 when compared to normal eyes. Iridocorneal angle tissue from glaucomatous eyes expressed a statistically significant increase in active MMP-2 and latent MMP-9 when compared to normal eyes. These data demonstrate that there is an association between elevated levels of intraocular MMP-2 and MMP-9 and the presence of glaucoma.


Lamellar solid-liquid mesophase nucleated by Josephson vortices at the melting of the vortex lattice in Bi2Sr2CaCu2O(8+δ) superconductor.
The local effect of the Josephson vortices on the vortex lattice melting process in Bi2Sr2CaCu2O(8+δ) crystals in the presence of an in-plane field H(ab) is studied by differential magneto-optical imaging. The melting process is found to commence along the Josephson vortex stacks, forming a mesomorphic phase of periodic liquid and solid lamellas, the direction and spacing of which are controlled by H(ab). The reduction of the local melting field H(m) along the Josephson vortex stacks is more than an order of magnitude larger than the reduction of the average bulk H(m) by HH(ab).


Study of Mast Cells and Granules from Primo Nodes Using Scanning Ionic Conductance Microscopy.
Acupuncture points have a notable characteristic in that they have a higher density of mast cells (MCs) compared with nonacupoints in the skin, which is consistent with the augmentation of the immune function by acupuncture treatment. The primo vascular system, which was proposed as the anatomical structure of the acupuncture points and meridians, also has a high density of MCs. We isolated the primo nodes from the surfaces of internal abdominal organs, and the harvested primo nodes were stained with toluidine blue. The MCs were easily recognized by their stained color and their characteristic granules. The MCs were classified into four stages according to the degranulation of histamine granules in the MCs. Using conventional optical microscopes details of the degranulation state of MCs in each stage were not observable. However, we were able to investigate the distribution of the granules on the surfaces of the MCs in each stage, and to demonstrate the height profiles and three-dimensional structures of the MCs without disturbance of the cell membrane by using the scanning ion conductance microscopy.


Quenching of Charge Transfer in Nitrobenzene Induced by Vibrational Motion.
Although nitrobenzene is the smallest nitro-aromatic molecule, the nature of its electronic structure is still unclear. Most notably, the lowest-energy absorption band was assessed in numerous studies providing conflicting results regarding its charge-transfer character. In this study, we employ a combination of molecular dynamics and quantum chemical methods to disentangle the nature of the lowest-energy absorption band of nitrobenzene. Surprisingly, the charge-transfer transition from the benzene moiety to the nitro group is found to be quenched by a flow of charge into the opposite direction induced by vibrational motion. Beyond clarifying the charge-transfer character of nitrobenzene, we show that the widely used approach of analyzing the ground-state minimum-energy geometry provides completely wrong conclusions.


Predicting and preventing the future: actively managing multiple sclerosis.
Relapsing-remitting multiple sclerosis (MS) has a highly variable clinical course but a number of demographic, clinical and MRI features can guide the clinician in the assessment of disease activity and likely disability outcome. It is also clear that the inflammatory activity in the first five years of relapsing-remitting MS results in the neurodegenerative changes seen in secondary progressive MS 10-15 years later. While conventional first-line disease modifying therapy has an effect on relapses, about one third of patients have a suboptimal response to treatment. With the advent of highly active second-line therapies with their evident marked suppression of inflammation, the clinician now has the tools to manage the course of relapsing-remitting MS more effectively. The development of treatment optimisation recommendations based on the clinical response to first-line therapies can guide the neurologist in more active management of the early course of relapsing-remitting MS, with the aim of preventing both acute inflammatory axonal injury and the neurodegenerative process which leads to secondary progressive MS.


Discordance between anti-beta2-glycoprotein-I and anti-cardiolipin antibodies in patients with clinical criteria of antiphospholipid syndrome.
Clinical and immunological features of patients with clinical manifestations of the antiphospholipid syndrome (APS) with anti-beta2-glycoprotein-I antibodies (anti-beta2-GP-I) but without anticardiolipin antibodies (aCL) or any other autoimmune condition are not well documented. We sought to determine the clinical significance of positive anti-beta2-GP-I with negative aCL. From July 2002 through July 2003, 1,179 serum samples obtained in our hospital from the Community of Madrid were tested for anti-beta2-GP-I and aCL by enzyme-linked immunosorbent assay. Clinical records of patients with discordant anti-beta2-GP-I and aCL were retrospectively analysed. A total of 56 patients with discordant anti-beta2-GP-I and aCL were identified. By logistic regression analysis, after adjusting for age, sex and risk factors of thrombosis, the risk for developing APS criteria associated with anti-beta2-GP-I was significant [odds ratio 3.88; 95% confidence interval (CI): 1.05-14.27; p = 0.04). 15 out of 56 patients (26.8%) had positive anti-beta2-GP-I and negative aCL. 5 out of 15 anti-beta2-GP-I-positive patients had clinical APS without serological nor clinical evidence of any autoimmune disease. Determination of anti-beta2-GP-I should be considered in individual cases with clinical manifestations of primary APS and repeated negative results on conventional antiphospholipid antibody test.


Dermoscopy and digital dermoscopy analysis of palmoplantar 'equivocal' pigmented skin lesions in Caucasians.
The diagnosis of palmoplantar melanoma is often delayed and misdiagnosis is common, due to frequently unusual clinical presentation. We used a digital dermoscopy analyzer with a series of palmoplantar pigmented skin lesions (PP-PSL), and we compared sensitivity, specificity and diagnostic accuracy obtained with digital dermoscopy analysis (DDA) and classical dermoscopy. Digital dermoscopy images of 107 PP-PSL were retrospectively obtained from the database of images of 3 Italian centers. The lesions (25 melanomas and 82 nevi) were all removed because of the presence of clinical and/or dermoscopic suspicious features. All digital images were analyzed using appropriate algorithms, and the diagnostic accuracy of the model was calculated. For comparison, dermoscopic images were clinically evaluated by two dermatologists and the Cohen ĸ concordance with DDA was calculated. The stepwise logistic regression analysis selected only 5 parameters out of 49. The logistic model achieved a sensitivity of 96% and a specificity of 87.8%. The Cohen ĸ concordance, evaluated by the Landis and Koch scale, supplied a substantial agreement between dermoscopy and DDA. DDA might be a useful diagnostic instrument in the evaluation of preselected PP-PSL. However, these findings should be confirmed in a formal clinical trial.


Advantage of Being Multicomponent and Spatial: Multipartite Viruses Colonize Structured Populations with Lower Thresholds.
Multipartite viruses have a genome divided into different disconnected viral particles. A majority of multipartite viruses infect plants; very few target animals. To understand why, we use a simple, network-based susceptible-latent-infectious-recovered model. We show both analytically and numerically that, provided that the average degree of the contact network exceeds a critical value, even in the absence of an explicit microscopic advantage, multipartite viruses have a lower threshold to colonizing network-structured populations compared to a well-mixed population. We further corroborate this finding on two-dimensional lattice networks, which better represent the typical contact structures of plants.


Derivation of keratinocyte progenitor cells and skin formation from embryonic stem cells.
Despite numerous elegant transgenic mice experiments, the absence of an appropriate in vitro model system has hampered the study of the early events responsible for epidermal and dermal commitments. Embryonic stem (ES) cells are derived from the pluripotent cells of the early mouse embryo. They can be expanded infinitely in vitro while maintaining their potential to spontaneously differentiate into any cell type of the three germ layers, including epidermal cells. We recently reported that ES cells have the potential to recapitulate the reciprocal instructive ectodermal-mesodermal commitments, which are characteristic of embryonic skin formation. Derivation of epidermal cells from murine ES cells has been successfully established by exposing the cells to precisely controlled instructive influences normally found in the body, including extracellular matrix and the morphogen BMP-4. These differentiated ES cells are able to form, in culture, a multilayered epidermis coupled with an underlying dermal compartment similar to native skin. This bioengineered skin provides a powerful tool for studying the molecular mechanisms controlling skin development and epidermal stem cell properties.