Increased expression of c-fos in the medial preoptic area after mating in male rats: role of afferent inputs from the medial amygdala and midbrain central tegmental field.
Immunocytochemical methods were used to localize the protein product of the immediate-early gene, c-fos, in male rats after exposure to, or direct physical interaction with, oestrous females. Increasing amounts of physical contact with a female, with resultant olfactory-vomeronasal and/or genital-somatosensory inputs, caused corresponding increments in c-fos expression in the medial preoptic area, the caudal part of the bed nucleus of the stria terminalis, the medial amygdala, and the midbrain central tegmental field. Males bearing unilateral electrothermal lesions of the olfactory peduncle showed a significant reduction in c-fos expression in the ipsilateral medial amygdala, but not in other structures, provided their coital interaction with oestrous females was restricted to mount-thrust and occasional intromissive patterns due to repeated application of lidocaine anaesthetic to the penis. No such lateralization of c-fos expression occurred in other males with unilateral olfactory lesions which were allowed to intromit and ejaculate with a female. These results suggest that olfactory inputs, possibly of vomeronasal origin, contribute to the activation of c-fos in the medial amygdala. However, lesion-induced deficits in this type of afferent input to the nervous system appear to be readily compensated for by the genital somatosensory input derived from repeated intromissions. Unilateral excitotoxic lesions of the medial preoptic area, made by infusing quinolinic acid, failed to reduce c-fos expression in the ipsilateral or contralateral medial amygdala or central tegmental field following ejaculation. By contrast, combined, unilateral excitotoxic lesions of the medial amygdala and the central tegmental field significantly reduced c-fos expression in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area after mating; no such asymmetry in c-fos expression occurred when lesions were restricted to either the medial amygdala or central tegmental field. This suggests that afferent inputs from the central tegmental field (probably of genital-somatosensory origin) and from the medial amygdala (probably of olfactory-vomeronasal origin) interact to promote cellular activity, and the resultant induction of c-fos, in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area. The monitoring of neuronal c-fos expression provides an effective means of studying the role of sensory factors in governing the activity of integrated neural structures which control the expression of a complex social behaviour.


Localization of transferrin binding protein in relation to iron, ferritin, and transferrin receptors in the chicken cerebellum.
We have demonstrated that transferrin binding protein (TfBP), ferritin, and iron, are specifically localized in Bergmann glia, while the transferrin receptor is confined to Purkinje cells in the chicken cerebellum. The results of this study suggest that Bergmann glia have previously undescribed functions related to iron regulation such as sequestration of iron and the maintenance of iron homeostasis in the cerebellum.


Some molecular structural features of glycogen in the kidneys of diabetic rats.
Glycogen, a highly-branched glucose polymer, functions as a sugar reservoir in many organs and tissues. Liver glycogen comprises small β particles which can bind to form into large agglomerates (α particles) which readily degrade to β particles in diabetic livers. Muscle glycogen has only β particles, optimal for quick energy release. Healthy kidney contains negligible glycogen, but there is an abnormally high accumulation in diabetic kidneys. We here compare the molecular structure of glycogen in diabetic kidneys with that in liver and muscle, using a diabetic rat model. This involved exploring extraction techniques to minimize glycogen degradation. Using size exclusion chromatography and transmission electron microscopy, it was found that there were only β particles in diabetic kidneys. These are postulated to form during periods of abnormally high blood sugar, the driving force being the need to reduce blood sugar under such circumstances.


Immunopathogenesis of experimental melanin-protein induced uveitis.
The etiology of uveitis, a general term for inflammatory disorders of the uveal tract, has not been clarified. The purpose of this study is to investigate the immunopathogenesis during experimental uveitis induced by bovine melanin associated antigen (BMAA). Experimental melanin-induced uveitis (EMIU) was induced in male Lewis rats by injection of BMAA and delayed type hypersensitivity (DTH) testing was performed. Fluorescence-activated cell sorting (FACS) analysis was used to examine expression of cell adhesion molecules with antibodies to ICAM-1 and LFA-1. BMMA-induced uveitis resembled human AAU, with onset and peak at approximately 14 and 21 days after immunization, respectively. Signs of uveitis disappeared by 4 weeks postimmunization. Histologic study revealed major infiltration of the iris and ciliary body by numerous inflammatory cells and minor infiltration of the choroid. DTH testing showed that ears injected with antigen were more swollen than non-injected ears. FACS analysis demonstrated that ICAM-1 and LFA-1 expression increased during EMIU, with ICAM-1 expression higher than that of LFA-1. In conclusion, BMAA is uveitogenically active in Lewis rats. Immunopathogenesis appeared to be mediated by cell expressing ICAM-1 and LFA-1.


The two major subspecies of Fusobacterium necrophorum have distinct leukotoxin operon promoter regions.
Fusobacterium necrophorum, a gram-negative, non-spore-forming anaerobe, is a normal inhabitant of the alimentary tract of animals and humans. Two types of F. necrophorum, subspecies necrophorum (biotype A) and funduliforme (biotype B), have been recognized, which differ morphologically, biochemically and biologically. The organism is an opportunistic pathogen that causes numerous necrotic conditions (necrobacillosis) such as bovine hepatic abscesses and ruminant foot abscesses. Subspecies necrophorum strains are considered to be more virulent for cattle and have been shown to produce greater amounts of leukotoxin than subspecies funduliforme strains. The leukotoxin operon of F. necrophorum consists of three genes (lktBAC) of which the leukotoxin structural gene (lktA) is the second gene in the operon. In this study, the promoter regions of the leukotoxin operons from the two subspecies were identified and their nucleotide sequence compared. The promoter regions were found to differ in sequence, in length of the sequence between the upstream determinant (oppF) and the first gene of the leukotoxin operon (lktB), and in promoter strength as assayed in Escherichia coli host cells.


The vascular Ehlers-Danlos syndrome.
Vascular Ehlers-Danlos syndrome (EDS) is a life-threatening inherited disorder of connective tissue causing severe arterial and gastrointestinal fragility and rupture, as well as complications of surgical and radiologic interventions. The diagnosis should be considered in patients under the age of 45 years who present with arterial tearing or dissection, colonic perforation, or visceral rupture. As for many orphan diseases, delayed diagnosis can lead to inaccurate care. Therefore, vascular EDS is particularly important to surgeons, radiologists, and obstetricians because knowledge of the diagnosis may help in the management of visceral complications. There are currently no specific treatments for this genetic condition, and medical intervention is limited to symptomatic treatment, precautionary measures, genetic counseling, and prenatal diagnosis. A clinical trial is ongoing to study the effectiveness of beta blockers with vasodilating properties in vascular EDS. Complications require hospitalization, observation in an intensive care unit, and sometimes emergency surgical intervention. CT, echography, and MRI are the most useful imaging modalities. Arteriography is contraindicated. Whenever possible, a wait-and-see attitude with close surveillance is preferable to unwarranted surgery. Surgical treatment carries a high mortality, whereas the mortality rate associated with endovascular treatment is unknown. To improve the likelihood of good surgical outcome, the surgeon must be informed of the patient's condition. The intent of surgery is to control hemorrhage if an artery, with or without aneurysm, has ruptured and to reconstruct the arterial vasculature. For vascular repair, simple procedures should be preferred, because more complex techniques can result in further injury and hemorrhage. Postoperative surveillance must be prolonged with close medical follow-up and serial CT scans. Pregnant women with vascular EDS should be considered high-risk cases and be provided special care.


Localization of alpha-fetoprotein during the formation of the neural tube and somites in chick embryo.
Very little is known about the biological role of alpha-fetoprotein (AFP) in normal development. This study was undertaken to look for AFP-positive tissues involved in active morphogenetic and histogenetic events. Using a polyclonal antibody specific for AFP and the immunoperoxidase technique, we have studied the AFP localization during the formation of the neural tube and somites in chick embryo. Immunostaining of early whole embryos, cephalic fold stage, shows a strong immunoreaction for AFP in the cephalic and neural folds. In a more advanced stage of the development (6-somite stage), the AFP expression has followed the caudal direction of the neural fold forming process. Immunostaining of 6- and 9-somite embryo sections shows an increase of AFP expression from the most undifferentiated (the neural fold), to the most differentiated (the neural tube). AFP does not label the non-segmented paraxial mesoderm, from which the somite is derived. Instead, when the paraxial mesoderm is segmented and has formed a somite, AFP positive cells are detected in the somite. The morphological differentiation of somite is joined to one biochemical differentiation, since the myotome and sclerotome cells are AFP positive while the dermatome cells are AFP negative. The sclerotome cells become AFP negative when they surround the notochord to form the vertebral body. The results presented here strongly suggest a close association of AFP with cell proliferation and differentiation.


Operational Data Model Conversion to ResearchKit.
The increasing use of electronic health information systems brings up an unresolved issue: the lack of interoperability between these systems. The Clinical Data Interchange Standards Consortium's Operational Data Model (ODM) is an xml based standard for the exchange of clinical data and metadata. The University of Münster has been using ODM to store medical forms in a web based metadata registry called Portal of Medical Data Models, which includes a complete set of tools to transform ODM forms into other formats. One kind of medical form is the Patient Reported Outcome, a trending type due to its easy integration with mobile data capture systems. ResearchKit is a development framework that allows the easy creation of these for iOS devices; unfortunately its current interoperability is limited. This research proposes a mapping between ODM and ResearchKit and presents the successful implementation of a converter for ODM into JSON based ResearchKit readable files.


Body image changes during early adulthood.
Results from recent studies on body image have revealed differences between college-age individuals and older samples. In this study, adults 17 to 40 years old were evaluated for their body dissatisfaction on the Figure Rating Scale. Females had higher levels of body dissatisfaction than males and these differences did not diminish with age. However, consistent with physical changes in adulthood, current and ideal ratings became more discrepant with age. Interestingly, for women, affective and cognitive dimensions of body dissatisfaction became more consistent. Research on early adulthood personality development is used to help explain these results.


[Agraphia of Gerstmann syndrome--attempt at characterization].
A review is given of well documented cases of Gerstmann's syndrome covering one century from 1888 to 1991 complemented by two own observations, Convergencies as well as divergencies are pointed out. It is concluded, that although aphasia may be an accompanying condition, aphasic agraphia as described in linguistic terms is not a sufficient explanation of agraphia in Gerstmann's syndrome which implies spatial-graphic particularities like disturbances of symmetry, reduplications of strokes, defective line orientation, choice of a different letter type and occurrence of nonsense characters not contained in the alphabet. Literal paragraphs may appear as well, while semantic errors are virtually lacking. These features are known to occur in apractic or constructive agraphia whose localisation is usually in the left angular/subangular region coincident with a disconnection from homotopic right hemisphere areas by damage of commissural fibres. Lesions of these non-dominant areas may lead to spatial agraphia.


Management of Cocaine-Induced Myocardial Infarction: 4-Year Experience at an Urban Medical Center.
In 2008, the American Heart Association and the American College of Cardiology released guidelines for the management of cocaine-induced myocardial infarction (CIMI). We hypothesized that CIMI patients are likely to receive less invasive and more conservative management than patients with MI without history of cocaine use. We conducted a retrospective analysis on patients younger than 65 years presenting with acute MI between April 1, 2008 and December 31, 2012. Patients were classified as cocaine-negative MI or CIMI based on either urine toxicology results or self-reported cocaine use. Categorical and continuous variables were compared using χ(2) or t test as appropriate. The primary outcome was cardiac catheterization or stress testing. The secondary outcome was a 30-day readmission rate for major adverse cardiovascular events. Multiple logistic regression models calculated odds ratios (ORs) for the primary outcomes adjusting for patient demographics and comorbidities. Of 378 MI patients, 4.2 % had CIMI. CIMI patients were younger (50 vs 54 years; P < 0.01) predominantly African American (56% vs 16%, P < 0.01), and mostly active smokers (88% vs 58%, P = 0.02). They were more likely to receive stress testing (adjusted OR 3.61, 95% confidence interval 1.04-12.53) and less likely to undergo cardiac catheterization (adjusted OR 0.12, 95% confidence interval 0.03-0.45). The 30-day readmission rate for major adverse cardiovascular events was higher in CIMI compared with cocaine-negative MI patients (38% vs 13%; P = 0.03). The use of cocaine in patients presenting with acute MI appears to impact management decisions of providers. Patient-centered postdischarge arrangements need better coordination for this patient group to optimize their follow-up care.


Topical tretinoin in the treatment of vulvar lichen sclerosus: an advisable option?
To assess the effectiveness and safety of a 24-week application of tretinoin 0.025% cream, with an alternate-day regimen, in achieving control of VLS signs and symptoms. 17 patients affected with VLS were included. The main efficacy parameters were the response rate, as defined by protocol parameters, the rate of patients achieving an improvement from baseline of ≥75% in the subjective and objective scores, and the mean reduction in subjective and objective scores throughout the treatment. The safety of the treatment was also assessed. By the end of the 24-week treatment, 12 patients (70.6%) experienced a response; 35.3% and 17.6% of patients achieved an improvement of at least 75% in subjective and objective scores, respectively. Mean scores of itching, leukoderma (pallor) and hyperkeratosis decreased significantly in the study patients, and none presented itching-related excoriations. Erythema increased compared with baseline. Six patients (35.29%) experienced some side effects related to tretinoin, mainly mild erythema and burning. None of the subjects discontinued the treatment because of side effects. Tretinoin 0.025% cream applied for 24 weeks may represent a useful alternative option to corticosteroids in the treatment of active VLS, acting particularly on hyperkeratosis and pallor.


[Bacteriological, pharmacokinetic and clinical studies of sulbactam/ampicillin in the pediatric field].
The usefulness of sulbactam/ampicillin (SBT/ABPC) in the treatment of pediatric infections was evaluated. 1. Twenty pediatric patients with infection were treated with SBT/ABPC and an intravenous dosage of 27.8-47.4 mg/kg, 3 to 4 times a day. Clinical efficacies in 18 patients excluding 2 patients of Mycoplasma pneumonia (9 cases of pneumonia, 6 urinary tract infection, 1 tonsillitis, 1 maxillary sinusitis and 1 osteomyelitis) were judged to be excellent in 13 patients and good in 5. There was no case of failure. 2. Bacteriological efficacies against 16 strains (1 Staphylococcus aureus, 3 Enterococcus faecalis, 4 Haemophilus influenzae, 2 Haemophilus parainfluenzae, 5 Escherichia coli and 1 Serratia sp.) isolated from 13 of the 18 patients were rated as "eradicated" for 13 strains, "decreased" for 1 and "unchanged" for 2 with an eradication rate of 81.3%. Of 13 strains eradicated, 3 were those with high beta-lactamase productivity. 3. Rash as a side effect developed in 1 patient and eosinophilia and elevated GOT and GPT were observed in 7 patients but none of them were serious. 4. Blood levels of the drug following an intravenous dose of 30 mg/kg were determined in 2 pediatric patients. Blood levels of SBT and ABPC at 30 minutes after intravenous administration were 19.0 and 29.2 micrograms/ml in one patient and 21.0 and 31.6 micrograms/ml in another, respectively, and those at 4 hours were 0.48 and 0.62 microgram/ml in one patient and 0.59 and 0.89 microgram/ml in another, respectively. The half-lives of SBT were 0.67 and 0.70 hour and those of ABPC were 0.64 and 0.69 hour in the 2 patients, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Microwave heating characteristic of multilayered structures in a single-mode cavity.
In this study, nonconductor (PZT), semiconductor (Si) and conductor (Pt/Ti) whose permittivity and permeability are distinctive are prepared into various multilayered structures for exploring the heating behavior of microwave (2.45 Hz) in a single-mode cavity. The heating efficiency of the semiconductor and conductor was much higher at the maximum of H field than that of E field. At the H maximum, the Si layer was useful to generate high temperature and the Pt/Ti accelerated the heating rate. At the E maximum, the Si layer was also in favor of obtaining high temperature, but the Pt/Ti layer partially suppressed the microwave heating. The effect of PZT on the heating processing was not obviously observed at the maximum of both H and E fields.


Improved verbal learning in the semantic variant of primary progressive aphasia when using semantic cues.
The semantic variant of primary progressive aphasia (PPA-S) is characterized by impairments in confrontation naming and single word comprehension. Although episodic memory may be relatively spared, there can be impairment in verbal learning tasks. We report a patient with PPA-S and impaired verbal learning who was tested to learn if when provided with semantic categories, her learning would improve. A 70-year-old right-handed woman with a 2-year history of progressive difficulties with word finding, naming, and memory was tested for language and memory deficits using the Hopkins Verbal Learning Test-Revised (HVLT-R). She was then retested with the HVLT-R after being provided with the three semantic categories to which these words belonged. Confrontation naming was impaired on the Boston Naming Test. Sentence repetition was normal. Comprehension testing with word picture matching and sentence comprehension was normal. On a test of semantic associations, Pyramids and Palm Trees, she was impaired. She was also impaired on tests of verbal learning (HVLT-R) (total: 13) but not recall. When a different version of the HVLT-R was given with the semantic categories of the words given beforehand, her scores improved (total: 26). This patient with PPA-S had an impairment of verbal learning, but not delayed recall. When given a semantic category cue beforehand, her verbal learning performance improved. This observation suggests that this patient did not spontaneously use semantic encoding. Using a semantic cueing strategy may help other patients with PPA-S improve their capacity for verbal learning.


Frequency and phase locking of noise-sustained oscillations in coupled excitable systems: array-enhanced resonances.
We study the interplay among noise, weak driving signal and coupling in excitable FitzHugh-Nagumo neurons. Due to coupling, noise-sustained oscillations become locked to the signal as functions of both signal frequency and noise intensity. Higher order m:n locking tongues and various array-enhanced resonance features are demonstrated. This resonance and locking behavior due to a time scale matching between noise-sustained oscillations and the signal is fundamentally different from stochastic resonance in usual noisy threshold elements.


Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation.
Exercising muscle hypoperfusion stimulates afferents (metaboreceptors) involved in the regulation of ventilation. Atrial fibrillation (AF), particularly when combined with diseases causing endothelial (ED) impairment, such as hypertension (HP) and diabetes mellitus (DM), depresses the ED activity and enhances exercise hyperventilation. The relationship between these two functions and the underlying mechanisms have not been explored previously. In lone AF or AF associated with HP or DM (12 subjects in each cohort), we investigated the brachial artery flow-mediated dilatation (ED function) and ventilation during the recovery phase of handgrip (metaboreflex) exercise for subjects receiving placebo or oral vitamin C (double-blind crossover), both before and after cardioversion (CV) to sinus rhythm. Baseline ED impairment was increasingly more severe and the ergoreflex activity more pronounced in AF + HP and AF + DM compared with lone AF. Vitamin C and CV significantly improved both flow-mediated dilatation and metaboreflex activity in lone AF and AF + HP, and vitamin C did not produce any additive effect when administered after CV. In AF + DM, neither vitamin C nor CV was effective. This study provides the following information: AF generates oxidative injury, which is less when the arrhythmia is lone AF and greater when the arrhythmia is associated with HP. In DM, the oxidative injury generated by AF is refractory to a rather weak antioxidant, like vitamin C, or the baseline damage is such as to prevent any additive influence of AF. In AF, a cause-effect link exists between ED dysfunction and metaboreflex activity. Ventilatory advantages of CV seem to be inversely related with the extension of the underlying ED oxidative impairment.


Quantitative structure-activity relationships in a series of endogenous and synthetic steroids exhibiting induction of CYP3A activity and hepatomegaly associated with increased DNA synthesis.
The results of a quantitative structure-activity relationship (QSAR) study on a total of 14 steroids exhibiting induction of a CYP3A-associated activity and increase in liver weight/DNA synthesis is reported. It is found that different, but related, structural descriptors correlate with increase in ethylmorphine N-demethylase activity (r=0.92) and with the increase in liver weight (r=0.78) and DNA synthesis (r=0.78). Although there is a strong correlation between increase in liver weight and DNA content (r=0.999), neither of these correlated with ethylmorphine N-demethylase activity. These findings are discussed in the light of CYP3A induction, substrate specificity and inhibition; a proposed model of human CYP3A4 based on sequence homology with CYP102, a bacterial P450 of known crystal structure, demonstrates the possible mode of interaction between substrates and inhibitors within the putative active site.


Normal Newborn Heart Rate in the First Five Minutes of Life Assessed by Dry-Electrode Electrocardiography.
There is limited evidence regarding the heart rate (HR) during the first minutes of life. Nonetheless, resuscitative actions within the first minute are partly guided by different HR levels. The advent of an electrocardiographic (ECG) HR sensor with early HR detection has provided the opportunity to study changes immediately following delivery. The objectives were to determine immediately following delivery: (i) the time to achievement of reliable ECG signals using dry electrodes, (ii) changes in HR, and (iii) the influence of the onset of breathing and cord clamping on the HR. Healthy term neonates were randomly included between July and October 2013. The HR was recorded by the ECG sensor, placed over the abdomen immediately after birth. Fifty-five newborns were included. The median time from birth to placement of the HR sensor was 3 s (quartiles: 2 and 5), and the median time to the start of breathing was 6 s (quartiles: 2 and 15). The HR was around 120 beats/min (bpm) in the first seconds of life. As determined via breakpoint analysis, the HR increased by 1 beat in the first 40 s to 149 ± 33 bpm, followed by a moderate increase until 130 s and stabilization thereafter. After the onset of breathing, the HR decreased for 10 s and then increased. Minimal HR changes were observed after cord clamping. A dry-electrode ECG sensor detected reliable ECG signals almost immediately after birth. The normal HR increased significantly in spontaneously breathing infants during the first minute, influenced by the onset of breathing. Delayed cord clamping had a minimal impact on the HR, likely reflecting an earlier onset of breathing.


In Vitro Assays to Evaluate the Migration, Invasion, and Proliferation of Immortalized Human First-trimester Trophoblast Cell Lines.
Cell movement is a critical property of trophoblasts during placental development and early pregnancy. The significance of proper trophoblast migration and invasion is demonstrated by pregnancy disorders such as pre-eclampsia and intrauterine growth restriction, which are associated with inadequate trophoblast invasion of the maternal vasculature. Unfortunately, our understanding of the mechanisms by which the placenta develops from migrating trophoblasts is limited. In vitro analysis of cell migration via the scratch assay is a useful tool in identifying factors that regulate trophoblast migratory capacity. However, this assay alone does not define the cellular changes that can result in altered cell migration. This protocol describes three different in vitro assays that are used collectively to evaluate trophoblast cell movement: the scratch assay, the invasion assay, and the proliferation assay. The protocols described here may also be modified for use in other cell lines to quantify cell movement in response to stimuli. These methods allow investigators to identify individual factors that contribute to the cell movement and provide a thorough examination of potential mechanisms underlying apparent changes in cell migration.


Ionic liquid-promoted regiospecific Friedlander annulation: novel synthesis of quinolines and fused polycyclic quinolines.
Several room-temperature ionic liquids (ILs) based on 1-butylimidazolium salts with varying anions were synthesized and evaluated for the preparation of biologically active substituted quinolines and fused polycyclic quinolines using the Friedlander heteroannulation reaction. On screening, 1-butylimidazolium tetrafluoroborate [Hbim]BF4 was found to be the best ionic liquid for the heteroannulation reaction, and the reasons to this effect are well explained. The reactions proceed very well under relatively mild conditions without any added catalyst. The IL acts as a promoter for this regiospecific synthesis and can be recycled. By this green approach, various quinolines were prepared in excellent yields and purity and well-characterized.


Food quality and safety: traceability and labeling.
This article discusses food systems in general, their development over the past 120 years, and realities and problems faced by a world population of over 6 billion people. Various food and feed problems are mentioned, and the concept of "traceability" is discussed in the context of the broader and more useful approach of using "good practices" at all levels of the food chain.


Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function.
1. The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function. 2. After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0 +/- 3.0, 11.1 +/- 3.0, 8.7 +/- 3.7 and 6.7 +/- 2.1 l h-1 (means +/- s.d.) in patients with creatinine clearances (CLcr) of > 100, 41-100, 21-40, and 8-20 ml min-1, respectively. .3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CLcr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CLcr < 40 ml min-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups. 4. This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.


Essentiality of copper in humans.
The biochemical basis for the essentiality of copper, the adequacy of the dietary copper supply, factors that condition deficiency, and the special conditions of copper nutriture in early infancy are reviewed. New biochemical and crystallographic evidence define copper as being necessary for structural and catalytic properties of cuproenzymes. Mechanisms responsible for the control of cuproprotein gene expression are not known in mammals; however, studies using yeast as a eukaryote model support the existence of a copper-dependent gene regulatory element. Diets in Western countries provide copper below or in the low range of the estimated safe and adequate daily dietary intake. Copper deficiency is usually the consequence of decreased copper stores at birth, inadequate dietary copper intake, poor absorption, elevated requirements induced by rapid growth, or increased copper losses. The most frequent clinical manifestations of copper deficiency are anemia, neutropenia, and bone abnormalities. Recommendations for dietary copper intake and total copper exposure, including that from potable water, should consider that copper is an essential nutrient with potential toxicity if the load exceeds tolerance. A range of safe intakes should be defined for the general population, including a lower safe intake and an upper safe intake, to prevent deficiency as well as toxicity for most of the population.


The antennal sensilla of adult mayflies: Rhithrogena semicolorata as a case study.
The present paper reports on an ultrastructural investigation of the sensilla on the antennal flagellum of the imago (SEM and TEM) and subimago (SEM) of the mayfly Rhithrogena semicolorata. Sensilla coeloconica of two different sizes, named big and small pegs, are distinguishable in both stages. The big pegs are lobe-shaped with a porous cuticle. The small pegs are more or less conical with a smooth cuticle. TEM seriate sections revealed that the big pegs are innervated by three neurons, which enter the peg. The dendrite sheath opens at the entrance to the peg and leaves the dendrites in contact with the outside through pores and pore tubules. This structure is in agreement with that reported for single-walled olfactory receptors. The small pegs may be innervated by two or four neurons. In both cases, two unbranched dendrites enter the peg and are in close association with the peg wall. These show features typical of hygroreceptors. In the small pegs innervated by four neurons, the other two neurons stop short of entering the peg, and one of them branches. This last could constitute the thermoreceptive unit. The function of the fourth neuron is unknown.The presence of olfactory sensilla in adult mayflies, such as Paleoptera, is relevant to the study of evolutionary trends in insect odour perception. Hygro-thermoreceptors are important in such fragile aquatic insects, which need a moist environment for moulting and reproduction.


Different vascular risk factor profiles among cortical infarcts, small deep infarcts, and primary intracerebral haemorrhage point to different types of underlying vasculopathy. A study from the L'Aquila Stroke Registry.
The type of small-vessel disease in small deep (lacunar) infarcts (SDIs) remains contentious as opposed to that in primary intracerebral haemorrhage (PICH), which is lipohyalinosis in most cases. Therefore, we compared risk factor profiles as indicators of underlying vessel pathology, between patients with SDI and patients with PICH, and those with a non-cardio-embolic infarct involving the cortex (CORTI). Multivariate regression analysis showed the diabetes mellitus [odds ratio (OR) 0.56; 95% confidence interval (CI) 0.34-0.90] and hypercholesterolaemia (OR 0.63; 95% CI 0.40-0.99) were more strongly associated with CORTI than with SDI. Carotid stenosis was associated with SDI in comparison with PICH (OR 7.5; 95% CI 1.02-54.94). Compared with PICH, CORTI was more strongly associated with diabetes mellitus (OR 3.27; 95% CI 1.38-7.76), carotid stenosis (OR 24.42; 95% CI 4.99-119.45), and hypercholesterolaemia (OR 3.12; 95% CI 1.47-6.65), whereas hypertension was associated with PICH (OR 0.37; 95% CI 0.18-0.79). These data support the hypothesis that small-vessel atheromatosis rather than small-vessel lipohyalinosis underlies lacunar infarcts in most cases.


Serum thrombopoietin level is not regulated by transcription but by the total counts of both megakaryocytes and platelets during thrombocytopenia and thrombocytosis.
Thrombopoietin (Tpo) regulates platelet production, but the mechanisms regulating the serum Tpo level and platelet count in circulation have been a subject of debate. Tpo was reported to be expressed mainly in liver and kidney, but we found that Tpo is expressed in all tissues examined: abundantly in liver, kidney, muscle, colon, brain and intestine, and moderately in bone marrow, spleen, lung, stomach, heart, thymus, ovary, and endothelial and leukemic cell lines. The levels of Tpo transcripts in major Tpo producing organs, liver and kidney, and in the platelet production sites bone marrow and spleen, were constant during acute thrombocytopenia induced by anti-platelet monoclonal antibody administration in mice, and during thrombocytosis induced by Tpo injection. Furthermore, we noticed that platelet count is not exactly inversely proportional to serum Tpo level. During acute thrombocytopenia, serum Tpo level transiently increased a few hours after antibody injection, and returned to the basal level just when matured megakaryocytes accumulated in bone marrow and spleen but the platelet count was still low. Matured megakaryocytes in bone marrow and spleen increased when the serum Tpo level decreased, and decreased when platelet count rebounded. Taken together with other observations, we propose here a modified version of Kuter and Rosenberg's theory, that is, Tpo is constitutively expressed in a variety of organs throughout the body, even in acute thrombocytopenia and thrombocytosis, and that the serum Tpo level is not regulated by Tpo gene expression nor only by platelet counts in circulation, but by the total counts of both megakaryocytes in bone marrow and spleen and of platelets in circulation.


Effect of plasmid DNA encoding the porcine granulocyte-macrophage colony-stimulating factor on antigen-presenting cells in pigs.
We previously demonstrated that intradermal (ID) delivery of plasmid DNA encoding the porcine granulocyte-macrophage colony-stimulating factor (GM-CSF) 7 days before DNA vaccination enhances both cellular and humoral responses in pigs. In the present work, we studied the effect of the GM-CSF gene on antigen-presenting cells (APC) in pigs. We demonstrated that ID delivery of this gene significantly increased the number of epidermal CD1(+) cells (Langerhans' cells, skin dendritic cells) at the injection site at day 7. This was accompanied by an enhanced percentage of APC at the immune induction site following DNA vaccination, whereas a positive effect on APC maturation could not be demonstrated. Taken together, our data suggest that both DC recruitment to the immunization site and expansion of APC in the draining LN following DNA vaccination might contribute to the immune enhancing effect of plasmid encoded GM-CSF in pigs.


Importance of psychotic features to long-term course in major depressive disorder.
Most efforts to describe the prognostic significance of psychotic features in depression have been limited to single assessments 1 year or less after the initial evaluation. However, the various biological and treatment response differences between patients with psychotic and nonpsychotic depression suggest that prognostic differences may be very long-term. The 787 patients described here entered the study as they sought treatment at one of five academic medical centers; they had either RDC major depressive disorder or schizo-affective depression (other than the mainly schizophrenic subtype) and completed at least 6 months of follow-up. Of these, 144 (18.3%) had psychotic depression as defined here. Patients provided follow-up interviews at 6-month intervals for 5 years and annually thereafter; 98 of those with psychotic depression and 434 of those with non-psychotic depression were followed for 10 years. Those who began follow-up with psychotic depression had fewer weeks with minimal symptoms in each of the 10 years of follow-up and reported more psychosocial impairment at both 5 and 10 years. Both the index episode and the first recurrence of psychotic depression lasted longer than nonpsychotic episodes, but nonpsychotic episodes among previously psychotic individuals were relatively brief. Intervals between episodes were significantly shorter for patients who had ever been psychotic. Together with evidence that psychotic features are highly recurrent, these data show 1) that psychotic features denote a lifetime illness of greater severity and 2) that within individuals, psychotic features may emerge in only the more severe episodes.


Smoking differently modifies suicide risk of affective disorders, substance use disorders, and social factors.
Although an association between smoking and suicide has repeatedly been shown, information about a modifying influence of smoking on other risk factors for suicide is lacking. Axis I and Axis II disorders, sociodemographic factors, and tobacco use were assessed by a semi-structured interview including the Structured Clinical Interview for DSM-IV Axis I (SCID-I) and Personality Disorders (SCID-II) in 163 suicides (mean age 49.6+/-19.3 years; 64.4% men;) by psychological autopsy method and by personal interview in 396 living population-based control persons (mean age 51.6+/-17.0 years; 55.8% men). Smoking status (current smokers, lifetime non-smokers, and former smokers) differently modifies the effects of psychiatric disorders and sociodemographic variables on suicide risk. Former and current smoking modified suicide risk associated with affective disorders, but only current smoking increased suicide risk for substance use disorders. Ex-smokers with affective disorders, particularly with major depression, had less increased suicide risk than current smokers and non-smokers with affective disorders. Estimated suicide risks for personality disorders and 'no professional training' were strongly increased by smoking. Due to the small size of some of the subgroups, confidence intervals are wide. Therefore, precise risk estimation is not possible. Clinicians should interpret smoking as an indicator of increased risk of suicide for individuals with substance use disorders, personality disorders, and adverse social factors. Further studies are needed to investigate the effects of smoking cessation on suicide risk of patients with psychiatric disorders such as major depression and substance use disorders.


Synthesis and characterization of radial oligothiophenes: a new class of thiophene-based conjugated homologues.
[structure: see text] A series of thiophene-based homologues with an aromatic core surrounded by terthiophene "arms" with acetylene linkages has been synthesized by using Sonogashira coupling methods. The homologues were investigated spectroscopically in solution and in the solid state. They display extended pi-conjugation through the aromatic core that affects the strong emission and redox properties.


Biodegradable polymer membrane used as septal splint.
The treatment of a crooked nose is one of the most challenging rhinoplastic procedures. Correction of the abnormally curved or fractured septum has been reported using mostly scoring techniques, septoplasty and submucous resection techniques; cartilaginous spreader grafts can also be sutured to the distorted septum. Extracorporal septal straightening and repositioning/refixation is another useful but difficult technique. A common problem of septal cartilaginous grafting techniques is to harvest enough straight cartilage to correct the deformity. (Other donor sites such as rib cartilage are used, but harvesting additional cartilage is a time-consuming procedure and carries the risk of donor site morbidity.) Recent studies have been published using alloplastic internal splinting of the deformed septum. The use of poly p-dioxanone foils and porous polyethylene has been suggested before. In this study, a novel grafting material, a PolyMax membrane that has potential advantages over both materials, is presented. This is a porous biodegradable polymer made out of 70:30 poly(L-lactide-co-D,L-lactide) that remains stable for at least 7 months. Poly p-dioxanone loses its stability after only 2 months, whereas porous polyethylene is a permeable material that is controversial due to possible complications in cases of membrane exposure and infection. In this preliminary report the PolyMax membrane was used successfully in 3 patients.


Hereditary Pheochromocytoma.
Pheochromocytomas (PHEO) and paragangliomas (PGL) are rare neuroendocrine tumors with an estimated occurrence of 2 to 5 patients per million per year and an incidence of about 1 per 100 000 in the general population. These tumors may arise sporadically or be associated to various syndromes, namely multiple endocrine neoplasia type 2, neurofibromatosis type 1, Von Hippel-Lindau syndrome, and hereditary paraganglioma-pheochromocytoma syndromes. This article aims to review the current epidemiology, pathogenesis, clinical presentation, and genetic aspects of syndromes associated with hereditary PHEO/PGL. The literature research, conducted at PubMed database, included review articles, published from February 2009 to February 2014, written in English or Portuguese, using as query: "Hereditary AND Pheochromocytoma." These tumors can be part of a myriad hereditary conditions that are not yet fully understood. Nevertheless, important systemic symptoms and even fatal outcomes can occur. Knowledge of these hereditary conditions can ensure a more efficient detection, treatment, and even prevention of these neuroectodermal tumors, thus new tests and studies should be conducted.


Current management of pregnancy-associated breast cancer.
Pregnancy-associated breast cancer is the most common malignancy during pregnancy with an expected rise in incidence. The belief in the need for termination of pregnancy and that chemotherapy is contra-indicated during pregnancy is challenged by recent evidence. Patients can consider breast-conserving surgery and sentinel lymph node biopsy with acceptably low fetal risk from radiation exposure. A range of chemotherapeutics is possible in the second trimester in terms of drug class and frequency. Hormonal therapy and monoclonal antibody therapy are contra-indicated during pregnancy and lactation. Fetal outcome after in-utero exposure to chemotherapy appears similar to that in a non-pregnant population. Future pregnancy, in most situations, does not appear to be contra-indicated but a multidisciplinary and patient-centred approach is recommended. Fertility preservation techniques are also being developed with reported success and consequent pregnancies.


Baseline circulating tumor cell counts significantly enhance a prognostic score for patients participating in phase I oncology trials.
High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials. This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System. Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (P = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (P < 0.0001): good prognosis [score 0-1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2-3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks). CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials.


[Clinical and prognostic value of evaluation of atrial vulnerability in an electrophysiological endocavitary and transesophageal study].
Atrial fibrillation or flutter is frequently inducible during endocavitary or transesophageal electrophysiologic study. However, its clinic and prognostic significance has not yet been clarified. We studied 443 patients: 276 underwent endocavitary electrophysiologic study, 228 underwent transesophageal electrophysiologic study and 61 underwent both methods. In 343 of them a satisfactory echocardiogram was obtained. Patients were divided in three groups: gr. I, 93 patients with documented episodes of paroxysmal atrial fibrillation or flutter; gr. II, 257 patients with or without heart disease without clinical atrial fibrillation or flutter; gr. III, 93 symptomatic or asymptomatic Wolff-Parkinson-White patients without clinical atrial fibrillation or flutter. Gr. I included patients without overt heart disease (20), with WPW (11), mitral valve prolapse (4), and miscellaneous (58). Gr. II included patients without overt heart disease (49), with concealed Kent bundles (7), Mahaim (1) or James fibers (1) mitral valve prolapse (6), sick sinus syndrome (40), miscellaneous (91), or syncope of an unknown origin (62). Atrial vulnerability was evaluated both by endocavitary and transesophageal electrophysiologic study using two different protocols; the first protocol was moderately aggressive (prot. A), while the second was aggressive (prot. B). Endocavitary electrophysiologic study. Prot. A: single and double extrastimuli at the three heart rates (sinus, 100 and 150/m'), 10/m' incremental atrial pacing from 160 to 250/m; prot. B: prot. A + incremental atrial pacing from 260/m' up to 2:1 St-A block. Transesophageal electrophysiologic study. Prot. A: 10" atrial burst at 100-600/m' prot. B: prot. A + 6-9" increasing rate bursts from 200 to 800/m'. End point of all protocols: initiation of greater than 1' atrial fibrillation or atrial flutter. Endocavitary electrophysiologic study. A greater than 1' atrial fibrillation or atrial flutter was induced with the two protocols respectively in 67% (52/78) and 85% (51/60) of gr. I, in 17% (26/150) and 36% (38/105) of gr. II and in 35% (17/48) and 44% (21/48) of gr. III (gr. I vs gr. II p less than 0.001 for prot. A and p less than 0.01 for prot. B; gr. II vs gr. III p less than 0.001 for prot. A and NS for prot. B). Induced atrial fibrillation or atrial flutter using the two protocols had a greater than 5' duration respectively in 83 and 78% of gr. I, 62 and 42% of gr. II and in 41 and 38% of gr. III.(ABSTRACT TRUNCATED AT 400 WORDS)


Metal ion complexes in the structural analysis of phospholipids by electrospray ionization tandem mass spectrometry.
The effects of metal cationization on collisionally activated dissociation (CAD) of phospholipids were investigated by electrospray ionization with quadrupole ion trap tandem mass spectrometry. The metal ions include Li(+), Na(+), K(+), Sr(2+), Ba(2+), and the first transition series. CAD of the transition metal ion-bound lipid complexes gave significant yields of product ions that identify the positions of the two fatty acyl substituents on the glycerophospholipid backbone. The cobalt(II) ion, which has a single naturally occurring isotope, was expected to be a better cationization reagent as it produces simpler mass spectra than other transition metal ions. CAD of the cobalt(II) ion complexes of glycerophosphoethanolamines, glycerophosphoglycerols and glycerophosphoserines yielded product ions that revealed information regarding both the lipid classes and the regiospecific positions of the two fatty acyl substituents.


Could enzyme replacement therapy promote immune tolerance in Gaucher disease type 1?
Among the lysosomal storage disorders, Gaucher disease (GD) features some of the most striking alterations in the immune system, including increased levels of cytokines and chemokines. Although studies have demonstrated the efficacy of enzyme replacement therapy (ERT) for GD, the ideal dosage remains controversial. In this study, we report differences in levels of cytokines (IL-6, TNF-a, and IFN-y) and chemokines (IL-8, IP-10, and MCP-1) in patients with GD type 1 treated with different ERT dosages and treatment durations. Patients were recruited from two ERT centers in Brazil and divided into two groups according to treatment facility. Comparison between groups showed that patients in group 1 had received ERT for longer (p=0.0078) and at higher doses (p=0.0002) than those in group 2. Patients in group 1 exhibited decreased levels of IL-6 (p=0.0006), TNF-α (p<0.0001), IFN-γ (p<0.0001), IL-8 (p=0.0083), IP-10 (p<0.0001), and MCP-1 (p<0.0001) when compared to patients in group 2. Otherwise, patients in both groups were clinically similar, with no differences in hemoglobin, platelet, or leukocyte counts. Our data suggest that in GD type 1 the dosage and duration of therapy may be associated with establishment of peripheral tolerance and, consequently, decreased serum levels of inflammatory cytokines and chemokines.


Enhanced levels of soluble CD40 ligand exacerbate platelet aggregation and thrombus formation through a CD40-dependent tumor necrosis factor receptor-associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway.
CD40 ligand is a thromboinflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40 ligand (sCD40L), which has been shown to influence platelet activation, although its exact functional impact on platelets and the underlying mechanisms remain undefined. We aimed to determine the impact and the signaling mechanisms of sCD40L on platelets. sCD40L strongly enhances platelet activation and aggregation. Human platelets treated with a mutated form of sCD40L that does not bind CD40, and CD40(-/-) mouse platelets failed to elicit such responses. Furthermore, sCD40L stimulation induces the association of the tumor necrosis factor receptor-associated factor-2 with platelet CD40. Notably, sCD40L primes platelets through activation of the small GTPase Rac1 and its downstream target p38 mitogen-activated protein kinase, which leads to platelet shape change and actin polymerization. Moreover, sCD40L exacerbates thrombus formation and leukocyte infiltration in wild-type mice but not in CD40(-/-) mice. sCD40L enhances agonist-induced platelet activation and aggregation through a CD40-dependent tumor necrosis factor receptor-associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway. Thus, sCD40L is an important platelet primer predisposing platelets to enhanced thrombus formation in response to vascular injury. This may explain the link between circulating levels of sCD40L and cardiovascular diseases.


Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy, and childhood acute leukemia: the ESTELLE study.
To investigate the role of parental smoking during pre-conception and pregnancy, maternal beverage consumption (alcohol, coffee and tea) during pregnancy and their possible interactions, in the etiology of childhood acute leukemia (CL). The ESTELLE study included 747 cases of CL [636 cases of acute lymphoblastic leukemia (ALL) and 100 cases of acute myeloblastic leukemia (AML)] diagnosed in France in 2010-2011 and 1,421 population controls frequency-matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to the mothers. The odds ratios (OR) and their 95 % confidence intervals were estimated using unconditional logistic regression models adjusted for potential confounders. AML, but not ALL, was non-significantly associated with alcohol drinking during pregnancy [OR = 1.3 (0.8-2.0)] with a significant positive dose-response trend (p-trend = 0.02). Pre-conception paternal smoking was significantly associated with ALL [OR = 1.2 (1.1-1.5)] and AML [OR = 1.5 (1.0-2.3)]. CL was not associated with maternal smoking [OR = 1.0 (0.8-1.2)], or maternal coffee [OR = 0.9 (0.8-1.1)] or tea drinking [OR = 0.9 (0.8-1.1)] during pregnancy. However, a high consumption of coffee (>2 cups/day) was significantly associated with ALL [OR = 1.3 (1.0-1.8)]. The findings constitute additional evidence that maternal alcohol drinking during pregnancy may be involved in AML, and that paternal smoking before pregnancy may be a risk factor for CL. The role of maternal coffee drinking in CL remains unclear and should be investigated further in consortium analyses and in large birth cohort studies with exposure assessment more contemporaneous with the exposure, before the occurrence of the disease.


Mechanism of inhibited growth of Bacillus pumilus by Propionibacterium freudenreichii subsp. shermanii.
Physiological studies were conducted in an attempt to elucidate the mechanism of inhibition of Bacillus pumilus by Propionibacterium freudenreichii subsp. shermanii. Inhibition of B. pumilus by P. shermanii occurred in media supplemented with 1% glucose, indicating that glucose utilization by the latter bacterium was not responsible for growth inhibition of the former bacterium. The medium pH in which P. shermanii inhibited the growth of B. pumilus was 4.3. Propionic acid was positively identified in the culture medium in which B. pumilus was inhibited by P. shermanii. The presence of propionic acid and a low medium pH may account for the inhibition of B. pumilus by P. shermanii. Sodium lactate concentrations of 0.8-1.0% were essential for the continuous growth of and propionic acid production by P. shermanii. Thus, use of P. shermanii to inhibit B. pumilus in foods would likely require a lactate source.


Clinical pharmacokinetics of the anthrapyrazole CI-941: factors compromising the implementation of a pharmacokinetically guided dose escalation scheme.
The pharmacokinetics of the anthrapyrazole CI-941 has been investigated in conjunction with the Phase I evaluation of the drug with the intent of applying a pharmacokinetically guided dose escalation strategy. A starting dose of 5 mg/m2 was chosen, based on one-tenth the 10% lethal dose in mice. Due to the steep dose lethality relationship and nonlinear pharmacokinetics in mice, a target area under the CI-941 plasma concentration x time curve (AUC) of 110 microM x min (i.e., 40% of the mouse 10% lethal dose AUC) was chosen. This AUC was achieved in mice at 40 mg/m2. A total of 37 patients received 74 courses of CI-941 (5 to 55 mg/m2), with 26 patients consenting to pharmacokinetic monitoring. CI-941 was rapidly cleared from plasma, and a triexponential open model could be fitted to the data (t1/2 alpha = 7.6 +/- 2 min, t1/2 beta = 65 +/- 27 min, t1/2 zeta = 21 +/- 9 h). CI-941 was subjected to only limited urinary elimination, accounting for 5.2 +/- 2.8% of the administered dose. Wide interpatient variability in plasma CI-941 clearance at the starting dose and subsequent doses precluded the implementation of a pharmacokinetically guided dose escalation scheme, and the dose was escalated in 5-mg/m2 increments until the maximally tolerated dose was achieved. A number of investigations were performed to study potential reasons for variability in CI-941 clearance. However, CI-941 plasma protein binding (95 +/- 1%) and measures of pretreatment renal (51Cr-EDTA clearance), hepatic (plasma alanine transaminase and alkaline phosphatase levels), or cardiac function (left ventricular ejection fractions) did not relate strongly to CI-941 clearance. In patients treated at 40 mg/m2, the AUC values (156 to 415 microM x min) approximated or exceeded the target AUC. Fifty mg/m2 was the Phase II recommended dose. Further prospective studies are warranted to assess the utility of pharmacokinetically guided dose escalation strategies and to determine whether or not the variability encountered in clearance is unique to CI-941.


Detection of 13 mycotoxins in feed using modified QuEChERS with dispersive magnetic materials and UHPLC-MS/MS.
An analytical method for the simultaneous determination of 13 mycotoxins in feed by magnetic dispersive solid-phase extraction combined with ultra-high performance liquid chromatography and tandem mass spectrometry was developed. The samples were extracted with acetonitrile/water (80:20, v/v, containing 3% acetic acid), and separated by centrifugation after salting-out, and then treated with magnetic adsorbents to remove interferences. The separation of target mycotoxins was performed on an ACQUITY UPLC HSS T3 column using a mobile phase consisting of 1 mmol/L ammonium acetate with 0.1% formic acid and methanol by gradient elution. Good linearities for the 13 mycotoxins were achieved with correlation coefficients over 0.99, and the recoveries of mycotoxins were in the range of 89.3-112.6% at spiking at levels of 5, 20, and 100 μg/kg, with relative standard deviations of 0.9-10.4%. Based on the functional magnetic materials (MDN@Fe3 O4 , PSA@Fe3 O4 , ZrO2@ Fe3 O4 ) applied in dispersive solid-phase extraction, the pretreatment process is more convenient and it is beneficial to reduce the experimental cost by reusing the recycled magnetic materials. It is a simple, rapid, and environmentally friendly analytical method for the determination of mycotoxins in feed.


The diaphragm in health and disease.
The diaphragm consists of two separate muscles, the costal and crural parts, with different segmental innervation and different action on the rib cage. Diaphragmatic endurance is determined by the balance between energy supply and demand. Both an increase in demand and a decrease in supply of energy lead to diaphragmatic fatigue. Under conditions of reduced O2 transport to the body, the inspiratory muscles may command a disproportionate amount of the total body O2 consumption, particularly if the work of breathing is increased. Their energy demands may thus contribute significantly to the pathogenesis of cardiogenic shock and lactic acidosis. Inspiratory muscle fatigue can be diagnosed by observing and palpating: (1) abdominal paradox, a fall in abdominal pressure and an inward displacement of the abdomen during inspiration, and (2) respiratory alternans, a variation in abdominal pressure changes from breath to breath, reflected in variations in the inspiratory movements of rib cage and abdomen. Treatment consists in decreasing energy demands and increasing supplies. Artificial ventilation should be considered to accomplish the former. Methyl xanthines improve diaphragmatic contractility and specific diaphragmatic training programs improve diaphragmatic endurance.


Impact of Baltimore Healthy Eating Zones: an environmental intervention to improve diet among African American youth.
This study assessed the impact of a youth-targeted multilevel nutrition intervention in Baltimore City. The study used a clustered randomized design in which 7 recreation centers and 21 corner stores received interventions and 7 additional recreation centers served as comparison. The 8-month intervention aimed to increase availability and selection of healthful foods through nutrition promotion and education using point-of purchase materials such as posters and flyers in stores and interactive sessions such as taste test and cooking demonstrations. Two hundred forty-two youth-caregiver dyads residing in low-income areas of Baltimore City recruited from recreation centers were surveyed at baseline using detailed instruments that contained questions about food-related psychosocial indicators (behavioral intentions, self-efficacy, outcome expectancies, and knowledge), healthful food purchasing and preparation methods, and anthropometric measures (height and weight). The Baltimore Healthy Eating Zones intervention was associated with reductions in youth body mass index percentile (p = .04). In subgroup analyses among overweight and obese girls, body mass index for age percentile decreased significantly in girls assigned to the intervention group (p = .03) and in girls with high exposure to the intervention (p = .013), as opposed to those in comparison or lower exposure groups. Intervention youth significantly improved food-related outcome expectancies (p = .02) and knowledge (p < .001). The study results suggest that the Baltimore Healthy Eating Zones multilevel intervention had a modest impact in reducing overweight or obesity among already overweight low-income African American youth living in an environment where healthful foods are less available. Additional studies are needed to determine the relative impact of health communications and environmental interventions in this population, both alone and in combination.


Family practice as a specialty choice: effect of premedical and medical education.
Identification of beneficial and detrimental parameters influencing the choice of family practice as a career was the object of the study reported here. Curriculum components and elements during or before medical school were examined. A questionnaire listing 18 factors that influenced specialty choice before residency training was completed by 134 first-year family practice residents. Participation in a family practice clerkship or preceptorship during the third and fourth years of medical school and association with family physicians during or before medical school were perceived as most beneficial. Generally, students' experiences during the first three years were perceived as detrimental to selecting family practice. Also, data indicated that 75 percent of the students select their specialty during years three and four. Medical schools wishing to increase the number of their graduates entering family practice should strongly consider requiring clinical rotations in family medicine and providing maximum exposure to family practice residents and faculty members as role models.


Do calcium antagonists affect platelets?
Inappropriate platelet activation is thought to have a pathophysiological role in several cardiovascular disorders, including ischaemic heart disease and hypertension. Calcium antagonists are increasingly used in the therapy of these diseases. An inhibitory effect on platelet activation would clearly be a useful component of their therapeutic effect. Since a raised intracellular calcium concentration is crucial for platelet activation, and much of the calcium enters from the extracellular medium, such an effect might be anticipated. In fact, calcium antagonists consistently inhibit platelet activation in vitro, and somewhat less consistently ex vivo. However, many unanswered questions remain. Clinically attained drug concentrations in plasma may be too low to be effective, there appear to be no calcium antagonist receptors on the platelet, and the mechanism of action of the drugs is unclear. More importantly, it is not known whether an anti-platelet effect, if it occurs, is of practical rather than theoretical, value to the patient. These problems will need much more investigation.


Patient experiences of anxiety, depression and acute pain after surgery: a longitudinal perspective.
This study sought to explore the impact of the psychological variables anxiety and depression, on pain experience over time following surgery. Eighty-five women having major gynaecological surgery were assessed for anxiety, depression and pain after surgery. To gain further understanding, 37 patients participated in a semi-structured taped telephone interview 4-6 weeks post-operatively. Pre-operative anxiety was found to be predictive of post-operative anxiety on Day 2, with patients who experienced high levels of anxiety before surgery continuing to feel anxious afterwards. By Day 4 both anxiety and depression scores increased as pain increased and one-third of the sample experienced levels of anxiety in psychiatric proportions whilst under one-third experienced similar levels of depression. These findings have significant implications for the provision of acute pain management after surgery. Future research and those managing acute pain services need to consider the multidimensional effect of acute pain and the interface between primary and secondary care.


Hypertrophic gastropathy symptoms responsive to prednisone. A case report and a review of the literature.
We describe a 33-year-old man with giant hypertrophic gastropathy (Menetrier's disease), which, on operative biopsy of the stomach, showed a significant inflammatory component. The patient was treated with prednisone and quickly responded. Although a review of the literature revealed only two cases similarly treated, with equivocal results, spontaneous remission, does occur. Symptoms associated with this disease may respond to corticosteroids, which may offer effective therapy while awaiting involution of the gastropathy. Thus total gastrectomy may be avoided.


Immobilization of Keggin polyoxovanadoniobate in crystalline solids to produce effective heterogeneous catalysts towards selective oxidation of benzyl-alkanes.
Two ionic organic-inorganic hybrid compounds, [CuII(C2N2H8)2]4[CuII(C2N2H8)2(H2O)2]2[PNb12O40VVVIVO2]·(OH)2·11H2O (1) and [CoIII(C2N2H8)3]2[CoIII(C2N2H8)2(H2O)2]0.5[H2.5PNb12O40 VVVIVO2]·20H2O (2), based on P-centered dicapped polyoxoniobates and organometallic cations were isolated and structurally characterized by routine techniques. The trivalent cobalt complex-containing compound exhibits a looser arrangement compared with its divalent copper complex-containing counterpart, with a space volume of 34.9% for the former and 17.0% for the latter. The two compounds were proved to be effective in facilitating the oxidation of benzyl-alkanes to ketone products in a heterogeneous manner, evidencing the feasiblity of the strategy of self-immobilization of catalytically active, readily soluble PNb12O40(VO)2 species in crystalline solids.


Effects of sodium lactate on isolated rabbit corneas.
Corneal stromal lactate accumulation may result from epithelial hypoxia and contact lens wear, but the possible corneal toxicity of lactate has not been reported. Isolated superfused whole rabbit corneas were examined for thickness changes during exposure to neutral sodium lactate (NaL) or excess sodium chloride (NaCl) in Krebs-bicarbonate Ringer's solution for a 3-hr period. Placed in the tears side bath, 5 mM NaL significantly thinned corneas (swelling rates of 1 +/- 1 micron/hr in Ringer's controls vs -11 +/- 1 micron/hr in lactate-treated corneas; mean +/- SD). Excesses of 5 mM NaCl had essentially identical effects (0 +/- 1 micron/hr in controls vs -13 +/- 3 micron/hr in experimentals). When placed on the aqueous side of normal-thickness corneas, neither 20 mM NaL nor 20 mM excess NaCl affected corneal thickness, but both solutions stimulated endothelium-mediated deswelling in preswollen deepithelialized corneas. When "loaded" into the stroma of deepithelialized corneas, Ringer containing 20 mM lactate caused more swelling than Ringer's alone (491 +/- 18 microns in controls vs 558 +/- 20 microns in loaded corneas; mean +/- SEM). A similar swelling occurred when 20 mM excess NaCl was loaded into the stroma (483 +/- 15 vs 565 +/- 20 microns in controls and loaded corneas, respectively), due to fluid uptake into the hypertonic stroma across the endothelium from the aqueous side (Ringer's) bath. Corneas both loaded and superfused with either NaL or excess NaCl swelled and subsequently deswelled similar to controls swollen and superfused in Ringer's.(ABSTRACT TRUNCATED AT 250 WORDS)


An intelligent dual stimuli-responsive photosensitizer delivery system with O2-supplying for efficient photodynamic therapy.
The effects of photodynamic therapy (PDT) are limited by the hypoxic tumor microenvironment (TME). In this paper, a new type of biocompatible multifunctional photosensitizer delivery system was fabricated to relieve tumor hypoxia and improve the efficacy of PDT. The photosensitizer hematoporphyrin monomethyl ether (HMME) and catalase (CAT) were encapsulated in the pores of mesoporous graphitic-phase carbon nitride nanosheets (mpg-C3N4). Next, hyaluronic (HA) was coated on the surface of the mpg-C3N4 via an amide linkage to construct the tumor-targeting HAase/CAT dual activatable and mpg-C3N4/HMME response photosensitizer delivery system (HA@mpg-C3N4-HMME/CAT). Upon intravenous injection, HA@mpg-C3N4-HMME/CAT shows high tumor accumulation owing to the tumor-targeting HA coating. Meanwhile, CAT within mpg-C3N4 could trigger decomposition of endogenic TME H2O2 to increase oxygen supply in-situ to relieve tumor hypoxia. This effect together with mpg-C3N4/HMME dual response is able to dramatically improve PDT efficiency. The hypoxia status of tumors was evaluated in vivo to demonstrate the success of the O2-supplying. And the in vitro and in vivo results showed the excellent therapeutic effect of the HA@mpg-C3N4-HMME/CAT photosensitizer delivery system. O2-supplying PDT may enable the enhancement of traditional PDT and future PDT design.


Longitudinal in vivo imaging of cones in the alert chicken.
To demonstrate the feasibility of in vivo measurements of cones and their distributions as a function of normal growth without adaptive optics (AO) and also discuss the potential advantages and disadvantages of AO imaging in the chick, an animal model of myopia. Chicks were obtained on the day of hatching. Axial length and retinoscopy measurements were performed on days 0 and 14. Chicks were imaged on the day of hatching and 14 days later in a custom-built confocal scanning laser ophthalmoscope. Angular densities, linear cone spacings, and cone packing arrangements were determined. Four subarrays of hexagonally packed cones were identified on both days and, from their angular spacings, appear to correspond to different cone types. There were no significant changes in angular cone density with growth and linear spacings of cones increased with growth. This is true for both overall densities and those of the cone subtypes. There was no change in the percent of hexagonally packed cones with growth. Cones can be imaged longitudinally in vivo in the awake chick. The packing arrangement of cones is 40% hexagonally packed. Although AO is not necessary to visualize the cones, including the subarrays of like cones, some closely spaced cones of different types may not be resolved. Most importantly, there is a need to use a larger pupil with growth to maintain the same linear resolution in the larger eye. Novel longitudinal imaging techniques and methods in animal models are shown here to give insights into normal development and, in future, will give insights into visual disorders and diseases, including myopia.


Towards a four-dimensional analysis of meteorological data.
Rapid advances in the gathering of meteorological data and the design of atmospheric models are making the conventional two-dimensional analysis inadequate. This article describes some progress towards a four-dimensional analysis system.


Structure-property relationships of fluorinated donor/acceptor tetrakis(phenylethynyl)benzenes and bis(dehydrobenzoannuleno)benzenes.
Nine new bisdonor/bisacceptor-functionalized tetrakis(phenylethynyl)benzene (TPEB) and six new bis(dehydrobenzoannuleno)benzene (DBA) chromophores have been synthesized. The compounds consist of electron-donating dibutylaniline groups connected through a conjugated phenyl-acetylene scaffold to benzotrifluoride, bis(trifluoromethyl)phenyl, or pentafluorophenyl acceptor groups. In comparison to previously reported analogues utilizing nitrophenyl or benzonitrile acceptor groups, the weaker acceptor groups exhibit visibly fluorescent intramolecular charge transfer (ICT) behavior, moderately narrow optical band gaps, moderately high quantum yields, and strong fluorescence solvatochromism. In this series of molecules, the strongly inductive fluoro acceptor groups result in optical properties similar to the resonance acceptor analogues, making them promising candidates for optical materials device components. The data also support recent investigations that question the utility of using UV/vis spectroscopy alone as a qualitative measure of conjugation. The bisDBAs exhibit weaker ICT behavior and self-association in solution than their corresponding nitro analogues, but show greater stability to decomposition via polymerization and smaller optical band gaps than their acyclic analogues.


The transient ventilatory response to carbon dioxide at rest and in exercise in man.
A new technique has been developed to measure the transient response to inhaled CO2 using 30 sec pulses at constant inflow. Multiple experiments are ensemble-averaged in order to define the resulting small signals. We measured the peak changes in ventilation (delta V') and in PCO2 (delta PCO2), taking the ratio (delta V'/delta PCO2) as an index of response. Six healthy volunteers performed experiments at rest, 50 W and 100 W exercise. Three runs, each containing three pulses, were performed at each workload and subsequently averaged. Analysis of variance showed no significant difference between successive pulses or among subjects. delta V' did not differ significantly with workload, but delta PCO2 was progressively smaller as workload increased, and hence the response, delta V'/delta PCO2, greater. The delay between the rise in PCO2 and the rise in ventilation was also progressively shorter as workload increased, being 16-18 sec at rest, 7-13 sec at 50 W, and 3-6 sec at 100 W. Our results suggest that there is increased sensitivity to CO2 in exercise, which may be due to progressive activation of the peripheral chemoreceptors as work load increases. The delay at rest is too long for the peripheral chemoreceptor. Therefore, with these small stimuli, the central chemoreceptor must account for the CO2 response at rest.


Anaesthesia with alphaxalone plus alphadolone acetate blocks the oestrogen-stimulated LH surge and impairs pulsatile LH secretion in ovariectomized female rats.
Two experiments were undertaken to assess further the action of the steroid anaesthetic alphaxalone upon LH secretion in chronically ovariectomized female rats. For the first experiment, 31 rats were given two injections of oestradiol benzoate (20 micrograms/100 g body weight), each 72 h apart, to stimulate an LH surge 6 h after the second injection. However, one group of seven rats was anaesthetized with alphaxalone throughout the 6-h period and a second group of eight was similarly anaesthetized only for the last 2 h of the 6-h period. The steroid-stimulated LH surge was blocked in both groups of rats anaesthetized with alphaxalone. The second experiment involved a comparison of pulsatile LH secretion in animals which were either unanaesthetized (n = 8) or anaesthetized with alpha xalone (n = 9). In six out of nine rats the anaesthetic did not affect the maximum or minimum plasma LH concentrations but significantly slowed the frequency at which LH pulses were measured. In the remaining three anaesthetized rats the drug blocked pulsatile LH secretion. The experiments confirm that some secretion of LH continues during alphaxalone anaesthesia but indicate also that the drug has a more deleterious action upon the oestrogen-stimulated LH surge than believed hitherto.


Molecules to migration: pressures of life.
The highly successful Fourth International Conference in Africa for Comparative Physiology and Biochemistry (ICA-CPB) was held in the Maasai Mara National Reserve in July 2008. The theme of the meeting was "Molecules to Migration: Pressures of Life." To enhance the theme, the venue and timing of the meeting were chosen to coincide with the arrival of approximately 1.4 million wildebeest on their annual migration from the Serengeti National Park in Tanzania. Like the three previous ICA-CPB meetings, the discussion topics and the resulting collection of synthesia presented here were very diverse. The articles in this special collection reflect the authors' interest in broadening our understanding of the field of comparative physiology and biochemistry and their commitment to engaging in global research with international colleagues. These articles are brief, synthetic reviews integrating information presented at and inspired by the meeting. From seasonal migration and reproduction in birds, to cardiovascular system development in vertebrates, to strategies for hypoxia survival, papers range from specific to broad interactions. What they all have in common: they increase our understanding of how animals are affected by and respond to the pressures of life.


Outcome after surgical repair of congenital cardiac malformations at school age.
To explore the long-term physical, educational, behavioural, and emotional outcome of patients undergoing surgical correction of congenital cardiac disease at school age, and to investigate the relation, if any, between the outcome and comorbidity, age and sex, and level of complexity of the cardiac surgery. Information was obtained concerning 101 patients who underwent open-heart surgery for correction of congenital cardiac malformations between 1992 and 2000 whilst aged from 6 to 16 years. The patients, and their parents, completed the questionnaire "Outcome of congenital heart disease and surgery", the RAND 36-Item Health Survey, and the Child Behaviour Checklist/Youth Self-Report/Young Adult Self-Report. Of the patients, 26% had comorbidity. Of those without comorbidity, 39% had frequent physical complaints, and 28% experienced limitations due to the cardiac disease. Nevertheless, the patients reported a good subjective state of health, and did not report any behavioural or emotional problems. Patients did show academic difficulties. They had received special education more frequently than their healthy peers, and many had needed to repeat a grade, or had received remedial teaching. Consequently, the educational level of patients was lower than that of their healthy peers. Patients with comorbidity, female patients, and patients who underwent complex surgery, seemed to be most at risk for physical, behavioural, and emotional problems. It is necessary to distinguish between physical state and its appraisal, and clinicians should be aware of this. Further research is needed to find out the cause and nature of the academic difficulties. Groups of patients at risk should be followed closely to enable early interventions.


Simple Designs for the Construction of Complex Trans-Fused Polyether Toxin Frameworks. A Convergent Strategy Based on Hydroxy Ketone Cyclization of C-Linked Oxacycles.
A single, unified convergent strategy for the stereocontrolled synthesis of trans-fused polyethers was developed. It was demonstrated that the epimerization and reductive intramolecular coupling of hydroxy ketones in reactions with silane-Lewis acids (SI-LA) to generate ethers in C-linked oxacycles is affected by its conformational preference in a predictable manner. The obtained results make evident that the influence of hydrogen bonding between a hemiketal hydroxyl and a 1,3-diaxial C-O bond is regular and predictable and that convergent synthesis of trans-fused polyethers may confidently be conducted on driving ring closure to oxane rings under thermodynamic conditions


Formation of nanostructured silica materials templated with nonionic fluorinated surfactant followed by in situ SAXS.
The formation of two-dimensional (2D)-hexagonal (p6m) silica-based hybrid materials from concentrated micellar solutions (10 wt %) of two nonionic fluorinated surfactants, R(7)(F)(EO)(8) and R(8)(F)(EO)(9), is investigated in situ using synchrotron time-resolved small angle X-ray scattering (SAXS). The two surfactants form direct micelles with different structures prior to the silica precursor addition as demonstrated by SAXS and SANS. R(8)(F)(EO)(9) gives spherical micelles and R(7)(F)(EO)(8) more complex ones, modeled here as short wormlike micelles. The in situ SAXS experiments reveal that both surfactants form well-ordered 2D-hexagonal hybrid materials after the addition of the silica precursor, in coexistence with an excess of surfactant micelles. The structures of both 2D-hexagonal phases are compared just after precipitation, and it is found that more robust and larger silica walls are formed for R(8)(F)(EO)(9) than for R(7)(F)(EO)(8). This could explain why only the material obtained with R(8)(F)(EO)(9) is stable upon washing, as observed previously. Moreover, it is proposed that in both cases, only a part of the micelles interact with the silica oligomers and undergo structural modifications before forming the 2D-hexagonal mesophase. The obtained results are finally discussed in the more general framework of the templating mechanism for nonionic surfactants.


Association of virulent and avirulent strains of bluetongue virus serotype 11 with premature births of late-term bovine fetuses.
Two strains of bluetongue virus serotype 11 (BTV 11), UC-2 avirulent and UC-8 neurovirulent in newborn mice, were inoculated into late-term bovine fetuses to investigate whether infection with these two BTV strains in late gestation would produce congenital infection and pathological changes. Fetuses were inoculated by intramuscular injection through the uterine wall at 243 days gestation and recovered after spontaneous delivery. In calves inoculated with UC-8, births occurred 15 to 27 days before expected parturition, resulting in small, weak calves. These calves had a mild encephalitis and were unthrifty at birth. Calves inoculated with UC-2 appeared healthy when born 7 to 11 days prior to expected parturition. No lesions were found in these calves at necropsy. All calves seroconverted by the time of birth. Viraemia was present in the calves inoculated with UC-8 and in one calf inoculated with UC-2. Plasma cortisol concentrations were prematurely elevated, particularly in the calves inoculated with UC-8, indicating that they were stressed by the infection. The elevated cortisol, associated with an active congenital infection caused by bluetongue virus serotype 11 strain UC-8, is capable of causing premature delivery of low birth-weight, weak calves.


Neuropeptides and airway submucosal gland secretion.
Our study using feline tracheal isolated submucosal gland preparation has revealed that substance P (SP) produces an increase in submucosal gland secretion through the actions of both mucus ejection by glandular contraction and macromolecule secretion from secretory cells, and that the two actions are both mediated by a peripheral cholinergic action. In contrast, SP has no significant effect on macromolecule secretion from secretory cells in tracheal explants, probably because of epithelial suppression. Our study using an isolated gland preparation has also indicated that VIP potentiates mucous glycoprotein secretion induced by cholinergic stimulation through an interaction between muscarinic and VIP receptors in secretory cells. However, VIP failed to induce any significant glandular contraction or relaxation, indicating a lack of VIP receptors or a difference in the subtypes of muscarinic receptors in myoepithelial cells in submucosa glands.


Anesthetic management of a patient with Bartter's syndrome.
Bartter's syndrome is a rare disorder characterized by normal or low arterial blood pressure (BP), despite marked elevation in plasma renin activity, angiotensin II (Ang-II), and aldosterone, along with hypokalemic metabolic alkalosis. Perioperative changes in the cardiovascular and renin-angiotensin-aldosterone (RAA) systems in Bartter's syndrome patients are not well understood. We managed a 44-year-old Japanese man with rectal cancer and Bartter's syndrome complicated by renal dysfunction. He underwent anterior resection of the rectum with general anesthesia (50% nitrous oxide-oxygen with 0.5% to 0.8% isoflurane, supplemented with intravenous midazolam and butorphanol). Epidural morphine was given postoperatively. Although BP tended to be lower (75/35 to 110/60 mmHg) during surgery, there were no profound perioperative hemodynamic derangements. Plasma renin activity. Ang-II, and aldosterone values were highest during surgery. These responses of the RAA system to anesthesia and surgery were the same as previously noted in otherwise healthy surgical patients.


[Sepsis in emergency medicine--pre-hospital and early in-hospital emergency treatment].
Sepsis is a complex life threatening disease whose outcome decisively depends on a fast diagnosis and treatment. Emergency Medicine is confronted with the task to identify theses septic patients reliably and initiate early goal directed therapy and treatment with antibiotics as soon as possible to avoid a dangerous delay and reduce sepsis-related mortality. This article presents a review focused on the early steps of sepsis therapy in pre-hospital and early in-hospital emergency medicine.


Potent expansion of human natural killer T cells using alpha-galactosylceramide (KRN7000)-loaded monocyte-derived dendritic cells, cultured in the presence of IL-7 and IL-15.
Natural killer T (NKT) cells have an extremely restricted T-cell receptor repertoire, in man consisting of a Valpha24 chain preferentially paired with a Vbeta11 chain, and play crucial roles in various immune responses. Characterization of circulating Valpha24(+)Vbeta11(+)-T cells is hampered by their low frequencies. The alpha-galactosylceramide KRN7000 was reported to be presented by CD1d to NKT cells. Since dendritic cells (DC) are potent antigen presenting cells, and have been shown to express CD1d, we analyzed whether these cells could efficiently mediate expansion of Valpha24(+)Vbeta11(+)-T cells. During a 7-day co-culture of peripheral blood mononuclear cells and KRN7000-loaded mature monocyte derived DC (moDC) in the presence of interleukin-7 (IL-7) and IL-15, we observed up to 76-fold expansion of Valpha24(+)Vbeta11(+)-T cells. The expanded Valpha24(+)Vbeta11(+)-T cells expressed the cytotoxic molecule granzyme B, showed negligible expression of Fas ligand and could be induced to express high levels of interferon-gamma, while retaining the capacity to produce IL-4. B cells, expressing CD1d, could also present KRN7000, but Valpha24(+)Vbeta11(+)-T cell expansion was only observed in the presence of IL-7 and/or IL-15. Considering the low frequency of circulating Valpha24(+)Vbeta11(+)-T cells, the present method for expansion of Valpha24(+)Vbeta11(+)-T cells using KRN7000-loaded mature moDC will be of value for the further characterization of this unique T cell subset.


Seaport as a source of hantavirus: a study on isolated isles.
Since small mammals from seaports have relative higher seroprevalences of hantavirus, this seroepidemiologic study was conducted on the isles in Kinmen and Lienchiang Counties along the coast of southern mainland China to determine whether seaport may play the role as a source of hantavirus. Among six species of small mammals trapped in Kinmen County, only male Mus musculus (6.7%) and Rattus losea (5.3%) were found to be positive. In Lienchiang County, five species of small mammals were trapped and positive findings were obtained only in male R. norvegicus (9.3%), male M. musculus (7.7%), and female R. losea (1.6%). There was no significant difference in the seroprevalence between the two counties (Kinmen 3.8% vs. Lienchiang 3.9%). The positive rate in Liaolo (17.9%) of Kinmen County was significantly higher than the remaining trapping stations and those in Matsu Distillery (10.3%) and Fushing (5.8%) of Lienchiang County were significantly higher than the remaining ones. Moreover, a significant inverse correlation was found between the seropositive rate and the distance of small mammal sampling sites to the seaport (p < 0.01). These findings suggest the role of seaport as a source of hantavirus.


[Expression and significance of NET-1 protein in hepatocellular carcinoma].
This study was designed to investigate the expression and significance of NET-1 in hepatocellular carcinoma (HCC) and analyze the relationship between NET-1 gene expression and clinicopathologic factors in HCC. NET-1 gene protein expression was detected by Western blot, fluorescence immunocytochemistry, confocal laser scanning microscopy and immunohistochemistry in 8 cases of HCC tissues, human hepatoma cell line SMMC-7721, and paraffin-embeded sections from 130 cases of HCC. NET-1 gene protein expressed in 8 cases of HCC tissues by Western blot. The NET-1 gene protein positively located in the cytoplasm as irregular granules near Golgi apparatus in SMMC-7721cells, detected by fluorescent immunocytochemistry and observed by confocal laser scanning microscopy. The positive rate of NET-1 protein expression revealed by immunohistochemistry was 96.9% in HCC (126/130). NET-1 Protein expression in HCC was clearly correlative with HCC cytological variants, there were pronounced higher expressions in clear cell type, pleomorphic cell type, and sarcomatous change than that in hepatocytic type (P < 0.05). NET-1 Protein expression in HCC was positively correlative with the histopathologic grading, clinical stages and HCC with hepatitis and cirrhosis (P < 0.05), respectively, and negatively correlated with the presence of patches of necrosis (P < 0.05). But NET-1 protein expression was not associated with AFP level, tumor size and growth patterns, respectively. NET-1 protein is expressed in cytoplasm of HCC cells as irregular granules near Golgi apparatus. NET-1 gene expression may promote the uncontrolled proliferation and abnormal differentiation in HCC cells.


Rare and unusual manifestations of Crohn's disease with pyoderma gangrenosum and sclerosing cholangitis.
Crohn's ileocolitis manifested in 2 Black patients with the exceptionally rare complications of pyoderma gangrenosum and sclerosing cholangitis. It is emphasized that Crohn's disease is very rare in the Black population of sub-Saharan Africa, and, as far as we are aware, no patient with large-bowel involvement has hitherto been reported.


Relation Between Renin-Angiotensin System Blockers and Survival Following Isolated Aortic Valve Replacement for Aortic Stenosis.
Renin-angiotensin system blockers (RASb) improve cardiac remodeling, but their clinical utility after surgical aortic valve replacement (SAVR) for aortic stenosis (AS) is unclear. We aimed to assess the impact of RASb on short- and long-term survival following isolated SAVR for severe AS. From January 2005 to January 2014, 508 consecutive patients had isolated SAVR for severe AS. Patients with RASb (n = 286; 53%) were more often female (p = 0.039), hypertensive (p < 0.0001), and diabetic (p = 0.004), with higher body mass index (p < 0.0001) and EuroSCORE II (p = 0.025), and lower mean aortic pressure gradient (p = 0.011). The 30-day mortality was similar in both groups (RASb: 3% vs no RASb: 5.8%, p = 0.13), but lower under angiotensin receptor blockers (ARB) than angiotensin-converting enzyme inhibitors (ACEi; 0.7% vs 5.6%, p = 0.017). Patients under RASb had a better 8-year survival than those without RASb (83 ± 3% vs 52 ± 5%, p < 0.0001), confirmed in a propensity score-matched pairs analysis (82 ± 4% vs 50 ± 7%, p < 0.0001). Regarding different types of RASb, patients under ARB had lower mortality than those under ACEi (87 ± 3% vs 79 ± 4%, p = 0.028). In multivariate analysis, the use of RASb was associated with improved survival (hazard ratio = 0.31, 95% confidence interval 0.20 to 0.47, p < 0.0001), with lower mortality under ARB than under ACEi (hazard ratio = 0.39, 95% confidence interval 0.18 to 0.85, p = 0.018). In this observational study, the use of RASb was associated with improved long-term outcome after isolated SAVR for severe AS. A randomized clinical trial is mandatory.


Allogeneic hemopietic stem cell transplants for the treatment of B cell acute lymphocytic leukemia.
Explore the feasibility of allo- hemopietic stem cell transplants in treating patients with B cell acute lymphocytic leukemia. Between september 2006 and February 2011, fifteen patients with B cell acute lymphocytic leukemia (ALL) were treated by allo-hemopietic stem cell transplants (HSCT). Stem cell sources were peripheral blood. Six patients were conditioned by busulfan (BU) and cyclophosphamide (CY) and nine patients were conditioned with TBI and cyclophosphamide (CY). Graft versus host disease (GVHD) prophylaxis regimen consisted of cyclosporine A (CSA), methotrex ate (MTX) and mycophenolatemofetil (MMF). Patients received a median of 7.98×10⁸·kg⁻¹ (5.36-12.30×10⁸·kg⁻¹) mononuclear cells (MNC). The median time of ANC>0.5×10⁹/L was day 12 (10-15), and PLT>20.0×10⁹/L was day 13 (11-16). Extensive acute GVHD occurred in 6 (40.0%) patients, and extensive chronic GVHD was recorded in 6 (40.0%) patients. Nine patients were alive after 2.5-65 months follow-up. Allogeneic stem cell transplant could be effective in treating patients with B cell acute lymphocytic leukemia.


Facile enzymatic synthesis of sugar 1-phosphates as substrates for phosphorylases using anomeric kinases.
Three sugar 1-phosphates that are donor substrates for phosphorylases were produced at the gram scale from phosphoenolpyruvic acid and the corresponding sugars by the combined action of pyruvate kinase and the corresponding anomeric kinases in good yields. These sugar 1-phosphates were purified through two electrodialysis steps. α-D-Galactose 1-phosphate was finally isolated as crystals of dipotassium salts. α-D-Mannose 1-phosphate and 2-acetamido-2-deoxy-α-D-glucose 1-phosphate were isolated as crystals of bis(cyclohexylammonium) salts.


Implications of prospective payment under DRGs for hospital marketing.
The authors analyze the hospital marketing implications of Medicare's prospective payment system under DRGs. They take an appropriately broad view of marketing and consider related impacts on culture, structure, and management, in addition to the traditional marketing mix. The article serves to present in one place the ideas and discussions on the subject from a wide and disparate literature. The aim throughout is to identify those marketing responses warranting recommendation. The recommendations are assembled in a concluding section. Though many of the ideas are not new, they have yet to be widely adopted by hospitals. Hence they represent untapped marketing opportunities attributable to the advent of the DRG system. The authors conclude with suggestions for future research.