Successful nucleofection of rat adipose-derived stroma cells with Ambystoma mexicanum epidermal lipoxygenase (AmbLOXe).
Adipose-derived stroma cells (ASCs) are attractive cells for cell-based gene therapy but are generally difficult to transfect. Nucleofection has proven to be an efficient method for transfection of primary cells. Therefore, we used this technique to transfect ASCs with a vector encoding for Ambystoma mexicanum epidermal lipoxygenase (AmbLOXe) which is a promising bioactive enzyme in regenerative processes. Thereby, we thought to even further increase the large regenerative potential of the ASCs. ASCs were isolated from the inguinal fat pad of Lewis rats and were subsequently transfected in passage 1 using Nucleofector® 2b and the hMSC Nucleofector kit. Transfection efficiency was determined measuring co-transfected green fluorescent protein (GFP) in a flow cytometer and gene expression in transfected cells was detected by reverse transcription polymerase chain reaction (RT-PCR). Moreover, cell migration was assessed using a scratch assay and results were tested for statistical significance with ANOVA followed by Bonferroni's post hoc test. High initial transfection rates were achieved with an average of 79.8 ± 2.82% of GFP positive cells although longer cultivation periods reduced the number of positive cells to below 5% after four passages. Although successful production of AmbLOXe transcript could be proven the gene product had no measureable effect on cell migration. Our study demonstrates the feasibility of ASCs to serve as a vehicle of AmbLOXe transport for gene therapeutic purposes in regenerative medicine. One potential field of applications could be peripheral nerve injuries.


Effects of anaesthesia method and tourniquet use on recovery following total knee arthroplasty: a randomised controlled study.
We investigated the effects of spinal and general anaesthesia and surgical tourniquet on acute pain and early recovery after total knee arthroplasty (TKA). Patients (n=413) were randomised to four parallel groups: spinal anaesthesia with or without tourniquet, and general anaesthesia with or without tourniquet. The primary outcome was patient-controlled i.v. oxycodone consumption over 24 postoperative hours. Results from 395 subjects were analysed. Median i.v. oxycodone consumption did not differ between the four groups (spinal anaesthesia without [36.6 mg] and with tourniquet [38.0 mg], general anaesthesia without [42.3 mg] and with tourniquet [42.5 mg], P=0.42), between spinal (37.7 mg) and general anaesthesia (42.5 mg) groups (median difference -3.1, 95% confidence interval [CI] -7.4 to 1.2, P=0.15) and between tourniquet and no-tourniquet groups (40.0 vs 40.0 mg, median difference -0.8, CI -5.1 to 3.5, P=0.72). Vomiting incidence was higher with spinal than with general anaesthesia (21% [42/200] vs 13% [25/194], CI 1.05 to 3.1, P=0.034). The mean haemoglobin decrease was greater without than with tourniquet (-3.0 vs -2.5 g dl-1, mean difference -0.48, CI -0.65 to -0.32, P<0.001). No differences were observed in pain, pain management, incidences of blood transfusions, in-hospital complications, or length of hospital stay. For TKA, spinal and general anaesthesia with or without tourniquet did not differ in 24-h postoperative opioid consumption, pain management, blood transfusions, in-hospital complications, and length of hospital stay. Vomiting incidence was higher in the spinal than in the general anaesthesia group. Tourniquet use caused smaller decreases in haemoglobin levels. EudraCT 2016-002035-15.


Metal binding to modified bleomycins. Zinc and ferrous complexes with an acetylated bleomycin.
We have studied the DNA- and metal-binding properties of a bleomycin A2 derivative in which the alpha-amino group of the beta-aminoalanine moiety has been N-acetylated. The modified antibiotic has been shown to be without activity in mediating the in vitro release of [3H]thymine from Pm-2 DNA. Fluorescence experiments indicate that the degree of quenching by DNA of the bithiazole fluorescence is unaffected by N-acetylation of bleomycin. Furthermore, 1H NMR experiments demonstrate that N-acetylation does not alter the stoichiometry of metal binding. The Fe(II)--Ac-bleomycin A2 complex, however, has been found to be stable in the presence of both O2 and CO, and thus inactivation appears to be accounted for by the loss of the ability to bind and/or reduce O2. Comparison of the 1H NMR spectra of the Fe(II)--bleomycin and Fe(II)--Ac-bleomycin A2 complexes indicates that either a drastic reorganization of the ligands with respect to the central iron atom has occurred or that an altered spin state is stabilized. These experiments establish that the ability of bleomycin to cause DNA damage is sensitive to even minor structural alterations within the antibiotic.


Aseptic cavernous sinus thrombosis after internal carotid arterial occlusion in polycythaemia vera.
Two patients with untreated polycythaemia vera developed intracranial internal carotid arterial occlusion followed by monocular blindness and the characteristic features of ipsilateral cavernous sinus thrombosis. Primary septic source and signs of systemic infection were absent. It is suggested that the predisposing factors in this unusual syndrome were hyperviscosity and venous sludging induced by the basic haematological disorder and progression of the thrombotic process within the internal carotid artery towards its intracavernous portion with occlusion of the ophthalmic artery and of the arterial branches which supply the walls of the sinus.


Tumors of the nail unit. A review. Part I: acquired localized longitudinal melanonychia and erythronychia.
The article aims to be a guide to the interpretation of tumors specific to the nail, that is, tumors presenting peculiar histological features linked specifically to the nail unit. Therefore, the classical epithelial, fibroepithelial, and fibrous skin tumors occurring in the nail region are not analyzed. The interpretation of nail biopsies requires the identification and integration of the 2 main clinical modes of presentation of nail tumors, the acquired localized (monodactylous) longitudinal (ALL) band pattern, and the "masked" nail tumor. The ALL band pattern often allows the recognition of a nail tumor in its early phase of progression, with a limited differential diagnosis. The masked nail tumor mimics an inflammatory nail process, as a clinically misleading reactive benign lesion, which delays diagnosis with the subsequent development of partial nail loss and a locally destructive evolution. ALL band pattern appears as a longitudinal band starting at the matrix and extending to the tip of the nail plate. The band is usually single, rarely bifid. This clinical pattern can divided into 2 presentations. The generic term of ALL maculonychia could be proposed to define the macular aspect of the colored band of the nail plate. It encompasses 3 syndromes: longitudinal melanonychia, longitudinal erythronychia, and longitudinal leukonychia. ALL pachyonychia is a rare presentation. Pachyonychia indicates a localized thickening of the nail plate specific to the matrical nail tumor. In this group, there is differentiation toward cells of the nail matrix. The prototype tumor is the onychomatricoma, which present classically with a yellow (xantholeukonychia) band pattern. Recently, a new clinical band pattern has been described as longitudinal pachymelanonychia with 2 etiologies: pigmented onychomatricoma and onychocytic matricoma. The first part of this review delineate, in the first section, the distinctive microanatomical features of the nail unit and the second is dedicated to the most important pitfalls in pathological diagnosis of nail tumors because of nail surgery techniques. In the third section, the histopathology of ALL melanonychia and ALL erythronychia is discussed in a detailed description.


A Metallo-molecular Cage That Can Close the Apertures with Coordination Bonds.
We designed a novel tricobalt(III) metallo-molecular cage in which its apertures can be closed with bifunctional ligands via coordination bonds. A closed-cage complex was easily formed by ligand exchange of its open-cage analogue. Guest uptake/release by the open-cage complex was sufficiently fast to quickly reach guest-binding equilibrium, while that by the closed-cage complex was extremely slow and took about 1 week to reach equilibrium. The guest uptake was retarded by at least 2000 times by introduction of the bifunctional ligands at the cage apertures.


Targeting of protein kinase Calpha to caveolae.
Previously, we showed caveolae contain a population of protein kinase Calpha (PKCalpha) that appears to regulate membrane invagination. We now report that multiple PKC isoenzymes are enriched in caveolae of unstimulated fibroblasts. To understand the mechanism of PKC targeting, we prepared caveolae lacking PKCalpha and measured the interaction of recombinant PKCalpha with these membranes. PKCalpha bound with high affinity and specificity to caveolae membranes. Binding was calcium dependent, did not require the addition of factors that activate the enzyme, and involved the regulatory domain of the molecule. A 68-kD PKCalpha-binding protein identified as sdr (serum deprivation response) was isolated by interaction cloning and localized to caveolae. Antibodies against sdr inhibited PKCalpha binding. A 100-amino acid sequence from the middle of sdr competitively blocked PKCalpha binding while flanking sequences were inactive. Caveolae appear to be a membrane site where PKC enzymes are organized to carry out essential regulatory functions as well as to modulate signal transduction at the cell surface.


High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes.
It has been proposed that liver dysfunction may contribute to the development of type 2 diabetes. The aim of the present study was to examine whether elevated hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or gamma -glutamyltranspeptidase [GGT]) are associated with prospective changes in liver or whole-body insulin sensitivity and/or insulin secretion and whether these elevated enzymes predict the development of type 2 diabetes in Pima Indians. We measured ALT, AST, and GGT in 451 nondiabetic (75-g oral glucose tolerance test) Pima Indians (aged 30 +/- 6 years, body fat 33 +/- 8%, ALT 45 +/- 29 units/l, AST 34 +/- 18 units/l, and GGT 56 +/- 40 units/l [mean +/- SD]) who were characterized for body composition (hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M), and hepatic insulin sensitivity (hepatic glucose output [HGO] during the low-dose insulin infusion of a hyperinsulinemic clamp) and acute insulin response (AIR) (25-g intravenous glucose challenge). Sixty-three subjects developed diabetes over an average follow-up of 6.9 +/- 4.9 years. In 224 subjects, who remained nondiabetic, follow-up measurements of M and AIR were available. At baseline, ALT, AST, and GGT were related to percent body fat (r = 0.16, 0.17, and 0.11, respectively), M (r = -0.32, - 0.28, and -0.24), and HGO (r = 0.27, 0.12, and 0.14; all P < 0.01). In a proportional hazard analysis with adjustment for age, sex, body fat, M, and AIR, higher ALT [relative hazard 90th vs. 10th centiles (95% CI): 1.9 (1.1-3.3), P = 0.02], but not AST or GGT, predicted diabetes. Elevated ALT at baseline was associated prospectively with an increase in HGO (r = 0.21, P = 0.001) but not with changes in M or AIR (both P = 0.1). Higher ALT concentrations were cross-sectionally associated with obesity and whole-body and hepatic insulin resistance and prospectively associated with a decline in hepatic insulin sensitivity and the development of type 2 diabetes. Our findings indicate that high ALT is a marker of risk for type 2 diabetes and suggest a potential role of the liver in the pathogenesis of type 2 diabetes.


Sibling bereavement and continuing bonds.
Historically, from a Freudian and medical model perspective, emotional disengagement from the deceased was seen as essential to the successful adaptation of bereavement. A major shift in the bereavement literature has occurred and it is now generally accepted that despite the permanence of physical separation, the bereaved remains involved and connected to the deceased and can be emotionally sustained through continuing bonds. The majority of literature has focused on adults and on the nature of continuing bonds following the death of a spouse. In this article, the authors demonstrate how the continuing bonds concept applies to the sibling relationship. We describe the unique continued relationship formed by bereaved children and adolescents following a sibling loss, highlight the factors that influence the siblings continuing bonds expressions, and offer clinical interventions. In our view, mental health professionals can play an important role in helping parents encourage activities that may facilitate the creation and maintenance of continuing bonds in their children.


Adolescents' physical activity habits--results from a national health survey.
The MABAT Youth National Health and Nutrition Survey was conducted in Israel by the Ministry of Health and the Center for Disease Control. This article presents results of physical activity (PA) habits in Israel, in relation to recommendations by world health organizations. Participants were 6274 adolescents, grades 7-12, enrolled in a cross-sectional, representative, school-based survey. Sufficient level of PA was defined as any moderate and vigorous level of PA that adds up daily to 60 min/day. Light PA was considered to be an insufficient level of PA. Only 10.5% of the participants reported performing sufficient PA. Large gender differences were found, with 17.7% of boys versus only 4.6% of girls meeting the guidelines. Results highlight the need to develop programmes for school children in Israel to promote PA. Such programmes have been initiated in many countries that have a large percentage of adolescents with a sedentary lifestyle.


Phase I to III trials of anti-B cell therapy in non-Hodgkin's lymphoma.
Led by the anti-CD20 antibody rituximab, therapeutic monoclonal antibodies have dramatically altered the treatment of patients with non-Hodgkin's lymphoma. As the understanding of the biology of this novel therapy improves, so does the potential for further progress. There are currently four monoclonal antibodies approved by the Food and Drug Administration for the treatment of B-cell malignancies and dozens more are in various stages of development. The indications for the currently available antibodies, both labeled and unlabeled, are being expanded to include first-line treatment, maintenance strategies, and combinations with chemotherapy. Newer agents are being engineered to target novel antigens, and to interact more specifically with the host immune system. These promising therapeutics face a significant challenge in evaluation and integration in the post-rituximab world.


Methods for decoding Cas9 protospacer adjacent motif (PAM) sequences: A brief overview.
Recently the Cas9, an RNA guided DNA endonuclease, emerged as a powerful tool for targeted genome manipulations. Cas9 protein can be reprogrammed to cleave, bind or nick any DNA target by simply changing crRNA sequence, however a short nucleotide sequence, termed PAM, is required to initiate crRNA hybridization to the DNA target. PAM sequence is recognized by Cas9 protein and must be determined experimentally for each Cas9 variant. Exploration of Cas9 orthologs could offer a diversity of PAM sequences and novel biochemical properties that may be beneficial for genome editing applications. Here we briefly review and compare Cas9 PAM identification assays that can be adopted for other PAM-dependent CRISPR-Cas systems.


The role of nutrition in influencing mechanisms involved in environmentally mediated diseases.
Human exposure to environmental contaminants such as persistent chlorinated organics, heavy metals, pesticides, phthalates, flame retardants, electronic waste and airborne pollutants around the world, and especially in Southeast Asian regions, are significant and require urgent attention. Given this widespread contamination and abundance of such toxins as persistent organic pollutants (POPs) in the ecosystem, it is unlikely that remediation alone will be sufficient to address the health impacts associated with this exposure. Furthermore, we must assume that the impact on health of some of these contaminants results in populations with extraordinary vulnerabilities to disease risks. Further exacerbating risk; infectious diseases, poverty and malnutrition are common in the Southeast Asian regions of the world. Thus, exploring preventive measures of environmental exposure and disease risk through new paradigms of environmental toxicology, optimal and/or healthful nutrition and health is essential. For example, folic acid supplementation can lower blood arsenic levels, and plant-derived bioactive nutrients can lower cardiovascular and cancer risks linked to pollutant exposure. Data also indicate that diets enriched with bioactive food components such as polyphenols and omega-3 polyunsaturated fatty acids can prevent or decrease toxicant-induced inflammation. Thus, consuming healthy diets that exhibit high levels of antioxidant and anti-inflammatory properties, is a meaningful way to reduce the vulnerability to non-communicable diseases linked to environmental toxic insults. This nutritional paradigm in environmental toxicology requires further study in order to improve our understanding of the relationship between nutrition or other lifestyle modifications and toxicant-induced diseases. Understanding mechanistic relationships between nutritional modulation of environmental toxicants and susceptibility to disease development are important for both cumulative risk assessment and the design and implementation of future public health programs and behavioral interventions.


Gonadotropins, serum, and amino acids alter nuclear maturation, cumulus expansion, and oocyte morphology in hamster cumulus-oocyte complexes in vitro.
Glucose, lactate, and pyruvate (the substrate triad), gonadotropins, serum, and amino acids were tested on maturation of cumulus-oocyte complexes (COCs) using a simple defined medium, Tyrode's-PVA (T-PVA). In experiment 1, effects of FSH (2 microg/ml) and the substrate triad were tested using a 2 x 2 factorial design. After 12-13 h, nuclear maturation was depressed in the absence of the triad or with FSH (0-14% metaphase II [MII]) compared with the triad alone (92% MII, p < 0.05). Subsequent experiments used as the base medium Tyrode's solution with the triad (TLP-PVA): adding 10% bovine calf serum (BCS) and gonadotropins (10 microg/ml FSH, 10 microg/ml LH, or both) yielded nuclear maturation equivalent to that in medium alone (88-100% post-metaphase I [post-MI] oocytes). Responses with glutamine, or with 11 but not 20 amino acids, were equivalent to the response in BCS with gonadotropins (93-100% post-MI oocytes). Some cumulus expansion occurred in COCs matured with gonadotropins and BCS, or glutamine, or 11 amino acids, but was less extensive than for in vivo-matured COCs. Oocytes matured with gonadotropins and BCS, or glutamine, or 11 amino acids plus gonadotropins, but not medium alone, had normal-appearing first polar bodies. Another cytoplasmic marker, cortical distribution of microfilaments (detected by confocal microscopy), did not differ between in vitro- and in vivo-matured oocytes. We conclude that effects of gonadotropins on hamster nuclear maturation, cumulus expansion, and oocyte morphology are modulated by serum or amino acids; maturation conditions producing normal oocyte and cumulus morphologies are predicted to yield developmentally competent oocytes.


Basal and ACTH-stimulated cortisol and aldosterone release from adrenocortical adenomas in vitro.
Basal and ACTH-stimulated release of aldosterone and cortisol was studied in slices of adrenocortical adenomas and adrenal cortex from 16 consecutive patients with Conn's syndrome (n = 7), Cushing's syndrome (n = 5) or no signs of steroid hypersecretion (n = 4). Clinical data were reviewed and histologic examination was repeated. The adrenal cortex and all tumours but one (non-hyperfunctioning) secreted cortisol. Cortisol release increased after addition of ACTH in 13/15 tumours and all cortex slices. Aldosterone was secreted from the adrenal cortex in all patients and was increased by ACTH in 75% of the tissue specimens. Adenomas from patients with hyperaldosteronism showed the highest basal aldosterone secretion. This secretion was further increased by ACTH. Tumours from patients without signs of corticosteroid excess also released steroids and responded to ACTH. It is concluded that in vitro studies of steroids released from adrenocortical tumours contribute to their diagnostic and functional evaluation.


Measuring emergency physician productivity and work patterns.
I propose a methodology to compare individual emergency physician (EP) work patterns. This is intended to generate discussion within the specialty. A work pattern graph shows individual EP productivity and, assuming the EPs case selection is similar, can be used to compare group activity. Using a simple mathematical model, an averaged calculation can be made of the number of patients needed to be seen by each treating clinician during a standard shift.


Learning and memory effects of neonatal methamphetamine exposure in rats: Role of reactive oxygen species and age at assessment.
In utero methamphetamine (MA) exposure leads to a range of adverse effects, such as decreased attention, reduced working-memory capability, behavioral dysregulation, and spatial memory impairments in exposed children. In the current experiment, preweaning Sprague-Dawley rats-as a model of third trimester human exposure-were administered the spin trapping agent, N-tert-butyl-α-phenylnitrone (PBN), daily prior to MA. Rats were given 0 (SAL) or 40 mg/kg PBN prior to each MA dose (10 mg/kg, 4× per day) from postnatal day (P) 6-15. Littermates underwent Cincinnati water maze, Morris water maze, and radial water maze assessment beginning on P30 (males) or P60 (females). Males were also tested for conditioned contextual and cued freezing, while females were trained in passive avoidance. Findings show that, regardless of age/sex, neonatal MA induced deficits in all tests, except passive avoidance. PBN did not ameliorate these effects, but had a few minor effects. Taken together, MA induced learning deficits emerge early and persist, but the mechanism remains unknown.


Predictors of change in quality of life in older adults with generalized anxiety disorder.
Quality of life (QOL) is lower in older adults with generalized anxiety disorder (GAD). QOL generally improves following cognitive-behavioral treatment for GAD. Little is known, however, about additional variables predicting changes in QOL in older adults with GAD. This study examined predictors of change in QOL among older participants in a randomized clinical trial of cognitive behavioral therapy (CBT) for GAD, relative to enhanced usual care (EUC). Hierarchical multilevel mixed-model analyses were used to examine inter-individual and intra-individual factors that predicted QOL over time. Predictors were categorized into treatment, personal and clinical characteristics. QOL improved over time, and there was significant variability between participants in change in QOL. Controlling for treatment condition, baseline general self-efficacy, baseline social support, within-person variation in worry and depression and average levels of depression across different time points predicted changes in QOL. QOL has increasingly been used as an outcome measure in treatment outcome studies to focus on overall improvement in functioning. Attention to improvement in symptoms of depression and worry, along with psychosocial variables, such as social support and self-efficacy, may help improve QOL in older adults with GAD. This study was a secondary study of data from a randomized clinical trial (NCT00308724) registered with clinical.trials.gov.


Endometrial stromal sarcoma with selective polyvinyl alcohol embolization of a pulmonary metastasis after recurrent hemoptysis and expansive growth.
A 63-year-old female with a well-vascularized pulmonary metastasis of an endometrial stromal sarcoma (ESS) of 6×6 cm received selective embolization with 150-250 μm polyvinyl alcohol (Contour; Boston Scientific, Natick, MA, USA) via a bronchial artery. Post-interventional loss of perfusion was qualitatively estimated to be >80%. The lesion was located in direct proximity to the pulmonary hilar vessels. Owing to recurrent and sudden hemoptyses, an interdisciplinary tumor board assessed the risk of life-threatening blood loss to be greater than that of angiography with particle embolization and agreed on an endovascular approach. Hemoptysis did not recur in a follow-up period of six months. Initial clinical symptoms were noted 25 years ago. However, establishing a definite diagnosis has, for a long time, remained a histopathological challenge.


Hand wound caused by an active sting with a toxin spine of a catfish (Heteropneustes fossilis)--a case report.
A case of a 33-years-old aquarist admitted to the Clinic with a painful wound caused by a Stinging Catfish (Heteropneustes fossilis) was presented. While cleaning the aquarium the fish actively stung him in the hand. After irrigating and debriding of the wound the patient was given tetanus anatoxin and antibiotic course. The opioid analgesia and local anesthesia had to be provided to relieve the pain. The follow up after 2 weeks showed healed wound of the hand and the patient had no subjective complaints. There is an urgent need for a bill about venomous and poisonous animals which will be allowed to be kept at home. The registration of venomous and poisonous animals in the Regional Poison Control Centers should be compulsory. There is a need for initiating educational activity among people who keep dangerous animals at home as their pets.


Nasal Administration of Cholera Toxin as a Mucosal Adjuvant Damages the Olfactory System in Mice.
Cholera toxin (CT) induces severe diarrhea in humans but acts as an adjuvant to enhance immune responses to vaccines when administered orally. Nasally administered CT also acts as an adjuvant, but CT and CT derivatives, including the B subunit of CT (CTB), are taken up from the olfactory epithelium and transported to the olfactory bulbs and therefore may be toxic to the central nervous system. To assess the toxicity, we investigated whether nasally administered CT or CT derivatives impair the olfactory system. In mice, nasal administration of CT, but not CTB or a non-toxic CT derivative, reduced the expression of olfactory marker protein (OMP) in the olfactory epithelium and olfactory bulbs and impaired odor responses, as determined with behavioral tests and optical imaging. Thus, nasally administered CT, like orally administered CT, is toxic and damages the olfactory system in mice. However, CTB and a non-toxic CT derivative, do not damage the olfactory system. The optical imaging we used here will be useful for assessing the safety of nasal vaccines and adjuvants during their development for human use and CT can be used as a positive control in this test.


The effect of a marathon run on plasma and urine mineral and metal concentrations.
Little data exist on the requirements of trace metals and minerals for endurance athletes. Changes in body status of these elements must be examined before specific nutritional recommendations can be made. This study was designed to determine whether a marathon run was associated with changes in serum and urine metal and mineral concentrations. Forty subjects who planned to complete the 1996 Houston-Tennaco marathon were recruited. Subjects had blood and urine samples collected 2 weeks prior to the race and immediately following the race. Blood and urine specimens were analyzed for copper, iron, magnesium and zinc concentrations. Blood was also analyzed for calcium concentration and ceruloplasmin activity. Twenty-six subjects (24 male, 2 female) completed the marathon. Finish times varied between 2 hours 43 minutes and 5 hours 28 minutes. There was no significant change in serum calcium, copper or zinc concentrations or ceruloplasmin activity. Serum and urine magnesium concentration decreased significantly (19.55+/-1.73 to 16.55+/-1.53 ppm, p=0.00001; 34.02+/-8.64 to 21.80+/-12.24 ppm, p=0.003, respectively). Serum iron concentration increased significantly (1.06+/-0.48 to 1.35+/-0.42 ppm, p=0.006), while urine copper and iron concentrations were below the limits of detection, zinc concentration did not change. Serum and urinary magnesium concentrations decrease during endurance running, consistent with the possibility of magnesium deficiency. This may be related to increased demand in skeletal muscle. Serum iron concentration increases, possibly related to tissue injury. The exact etiology for these observations, as well as their clinical significance, requires further investigation.


Pharmacological ascorbate and ionizing radiation (IR) increase labile iron in pancreatic cancer.
Labile iron, i.e. iron that is weakly bound and is relatively unrestricted in its redox activity, has been implicated in both the pathogenesis as well as treatment of cancer. Two cancer treatments where labile iron may contribute to their mechanism of action are pharmacological ascorbate and ionizing radiation (IR). Pharmacological ascorbate has been shown to have tumor-specific toxic effects due to the formation of hydrogen peroxide. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of hydrogen peroxide; labile iron can also react with hydrogen peroxide. Here we have investigated the magnitude of the labile iron pool in tumor and normal tissue. We also examined the ability of pharmacological ascorbate and IR to change the size of the labile iron pool. Although a significant amount of labile iron was seen in tumors (MIA PaCa-2 cells in athymic nude mice), higher levels were seen in murine tissues that were not susceptible to pharmacological ascorbate. Pharmacological ascorbate and irradiation were shown to increase the labile iron in tumor homogenates from this murine model of pancreatic cancer. As both IR and pharmacological ascorbate may rely on labile iron for their effects on tumor tissues, our data suggest that pharmacological ascorbate could be used as a radio-sensitizing agent for some radio-resistant tumors.


Urine Xanthine Crystals in Hematologic Malignancies with Tumor Lysis Syndrome.
Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.


The effect of impulse noise on distortion product otoacoustic emissions.
The aim of this study was the evaluation of distortion product otoacoustic emissions (DPOAEs) before and after noise exposure from shooting, and the comparison of DPOAEs with pure-tone audiometry. Thirteen young male police officers were exposed to impulse noise from shooting, without using earplugs. Standard pure-tone audiometry, tympanometry, and DPOAEs were performed before exposure and at one hour post- and 24 hour post-exposure. In the one hour post-exposure testing mean pure-tone thresholds were elevated in the 1-8 kHz frequency zone and DPOAE levels were reduced at several frequencies. DPOAEs were more affected at 3 kHz or lower, whereas pure-tone thresholds were more affected at higher frequencies. After the final examination, non-significant partial shifts at high frequencies on both tests remained. Pure-tone audiometry was overall more sensitive, but DPOAEs provided additional information about the cochlear status of certain ears. These data suggest that besides behavioral testing, DPOAEs may play a role as a fast, objective, and easy to perform test for monitoring subjects exposed to impulse noise.


[Extracorporeal Membrane Oxygenation in Lung Transplantation].
Multiple situations necessitate extracorporeal membrane oxygenation( ECMO) during lung transplantation. ECMO can also be used as a bridge to lung transplantation. We describe five cases in which bridging ECMO was successfully utilized, including three cases of living donor lung transplantation. ECMO can also be used as an alternative to cardiopulmonary bypass for intraoperative support during lung transplantation, and postoperatively, primary graft dysfunction, rejection, and infection can cause reversible respiratory failure which warrants ECMO. It can also be used for patients with pulmonary arterial hypertension in the early postoperative period to help their hearts adjust to new circulation. Eight patients with pulmonary arterial hypertension who underwent lung transplantation at our institu-tion received intraoperative and early postoperative ECMO support and their postoperative courses were uneventful. In this report, we review the indications for ECMO and the type of ECMO required for each of the various issues that can arise during lung transplantation, based on the literature and our experiences.


Review of advanced nursing practice: the international literature and developing the generic features.
The aim of this article is to review the nursing literature on the notion of advanced nursing practice (ANP) and consequently provide clarifications on the concept of advanced nurse practitioner by developing its' generic features. This paper commences by critically reviewing the concept of advanced nursing practice as it is portrayed within the literature. From this review, a series of contradictions emerged in terms of definitions and roles. On further analysis of the literature the core aims and goals of the ANP are revealed. An informative and narrative systematic literature review was undertaken, using specific inclusion and exclusion criteria. The mass of retrieved material was carefully screened and methods of data saturation were used. Consequently, the material was read, re-read and indexed as to develop seven thematic units that formed the generic features of the ANP. The generic features that emerged are: (i) the use of knowledge in practice, (ii) critical thinking and analytical skills, (iii) clinical judgement and decision-making skills, (iv) professional leadership and clinical inquiry, (v) coaching and mentoring skills, (vi) research skills and (vii) changing practice. Reviewing the literature on the concept of ANP, a great variety of definitions, conceptualizations and roles emerged. Nonetheless, on a closer reading, a common goal was identified, which was the attainment of practice and professional autonomy via ANP roles for enhanced practice provision. Eventually, from the reviewed literature, seven generic features of the ANP were developed, thus providing clarification to the role and the characteristics of the ANP. Clarifying the confusion surrounding advanced nursing practice and gaining an in-depth understanding of its' generic features would facilitate practitioners, practice educators and clinical managers to develop those skills that would allow them or their staff or students to practise at an advanced level.


Biomarkers in the lung cancer diagnosis: a clinical perspective.
The propensity for tumor biomarkers to be detected in serum at an early disease stage has become an area of interest for clinicians. This study aimed to evaluate the efficiency of 7 tumor biomarkers, namely, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin 19 (CYFRA-21-1), alpha-fetoprotein, carbohydrate antigen-125 (CA-125), carbohydrate antigen-19.9 (CA-19.9), and ferritin, independently or in combination for the diagnosis of lung cancer. Electrochemiluminescence immunization was used to determine biomarker levels expressed in 530 patients with pulmonary disease and 229 healthy subjects. The observed levels of CEA, NSE, CYFRA-21-1, CA-125, and CA-19.9 in patients with pathologically confirmed lung cancer were significantly higher than those in patients with benign pulmonary disease or control subjects. Adenocarcinoma, squamous cell carcinoma, and small cell carcinoma of the lung were associated with the highest observed levels of CA-125, CYFRA-21-1, and NSE, respectively. Combining biomarkers successfully led to the diagnosis of lung cancer. CEA + NSE + CA-125 showed the highest sensitivity for small cell carcinoma, at 83.33%, whereas CEA + NSE + CYFRA-21-1 + CA-125 showed 94.11% sensitivity for squamous cell carcinoma. The combination of 6 biomarkers, namely, CEA + NSE + CYFRA-21-1 + CA-125 + ferritin + CA-19.9, showed 80.49% sensitivity for adenocarcinoma. Combining biomarkers significantly aided in the diagnosis of lung cancer. However, this increased sensitivity on combination was accompanied by a decreased specificity for lung cancer subtypes. Combining biomarkers appropriately increases their sensitivity and helps with the diagnosis of lung cancer.


Origin of OXA-181, an emerging carbapenem-hydrolyzing oxacillinase, as a chromosomal gene in Shewanella xiamenensis.
Plasmid-mediated carbapenem-hydrolyzing β-lactamases are becoming emerging threats with Enterobacteriaceae. In particular, the carbapenem-hydrolyzing class D β-lactamase OXA-48 and its derivative OXA-181 have been reported increasingly worldwide. Using a PCR-based strategy, environmental samples were screened for bla(OXA-48)-like genes. Shewanella xiamenensis, an environmental species from marine and freshwater, was identified as the progenitor of the bla(OXA-181) gene. This work identifies the reservoir of an emerging carbapenemase gene that is clinically significant.


Baseline Neurocognitive Impairment (NCI) Is Associated With Incident Frailty but Baseline Frailty Does Not Predict Incident NCI in Older Persons With Human Immunodeficiency Virus (HIV).
Neurocognitive impairment (NCI) and frailty are more prevalent among persons with human immunodeficiency virus (HIV, PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well established. AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI. In total, 929 participants were included with a median age of 51 years (interquartile range [IQR] 46-56). At study entry, 16% had NCI, and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR] = 2.06; 95% confidence interval [CI] = .94, 4.48; P = .07). Further adjustment for confounding strengthened this association (OR = 2.79; 95% CI = 1.21, 6.43; P = .02). Baseline frailty however was not associated with NCI development. NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.


Evidence that p53 and bcl-2 are regulators of a common cell death pathway important for in vivo lymphomagenesis.
Multistep lymphomagenesis involves the deregulation of oncogenes and inactivation of tumor suppressor genes resulting in altered rates of proliferation as well as apoptotic cell death in tumor cells. The contribution of bcl-2 and p53 to the regulation of cell death during lymphomagenesis is assessed using bcl-2-1g, p53 'knock-out' (p53 KO), and p53 KO/bcl-2 hybrid mice. PCR-SSCP and DNA sequence analysis demonstrated that p53 somatic mutations are uncommon in lymphomas arising in bcl-2-Ig transgenic mice. Reduction in tumor latency was not observed in p53 KO/bcl-2 hybrid mice compared to p53 KO mice. Furthermore, overexpressed bcl-2 suppressed wild-type p53 associated apoptosis following gamma-radiation. These findings indicate that bcl-2 and p53 serve a suppressor and effector function, respectively, of a common cell death pathway. These findings also suggest that p53 somatic mutations provide no selective advantage during in vivo multistep lymphomagenesis in the context of bcl-2 gene deregulation.


Up-regulation of Plasma Hexosylceramide (d18: 1/18: 1) Contributes to Genotype 2 Virus Replication in Chronic Hepatitis C: A 20-Year Cohort Study.
The aim of the present study was to explore the relationship between plasma sphingolipids and hepatitis C virus (HCV) replication in chronic hepatitis C (CHC) patients.A cohort of 120 treatment-naïve CHC patients was included. Liver biopsies and the Scheuer scoring system were used to assess hepatic inflammatory activity. Blood biochemical indicators, HCV-RNA load, and immunological markers were also measured. Forty-four plasma sphingolipids were identified and quantified using high-performance liquid chromatography-tandem mass spectrometry.The hexosylceramide (HexCer) (d18:1/18:1) level was significantly different between patients with a low HCV load (<10 IU/mL) and a high HCV load (≥10 IU/mL), and it was positively correlated with the HCV-RNA load (r = 0.337, P = 0.001) in CHC patients. Additionally, the plasma HexCer (d18:1/18:1) level (odds ratio 1.302, 95% confidence interval 1.129-1.502) was an independent factor for a high HCV-RNA load. For patients with hepatic inflammation grade ≤2 or HCV genotype 2, HexCer (d18:1/18:1) was independently related to a high HCV-RNA load.Plasma HexCer (d18:1/18:1) might be involved in the high viral replication level in chronic HCV infection, especially for CHC patients with genotype 2.


Dexamethasone inhibits ovine corticotrophin-releasing factor (oCRF), arginine vasopressin (AVP), and oCRF + AVP stimulated release of ACTH during the last third of pregnancy in the sheep fetus.
We examined the hypothesis that in fetal sheep during late pregnancy exogenous glucocorticoids might affect differentially the pituitary response, measured as changes in plasma ACTH concentrations, to the systemic administration of ovine corticotrophin-releasing factor (oCRF), arginine vasopressin (AVP), or oCRF + AVP. At d 113-116 of pregnancy, equimolar injections of oCRF and AVP given separately provoked similar significant increases in plasma ACTH; the change in ACTH over basal values was significantly greater than the sum of the two separate responses when AVP + oCRF were given together. Exogenous dexamethasone did not affect basal ACTH concentrations, but suppressed significantly the responses to oCRF, AVP, and oCRF + AVP. At d 126-130, there was a significant ACTH response to CRF alone and to AVP + oCRF, but not to AVP alone. The response during the first 30 min postinjection to oCRF was significantly less than that to AVP + oCRF. Plasma cortisol rose after each peptide injection. Exogenous dexamethasone suppressed both basal and stimulated responses to each peptide. At the amounts injected, there was no significant ACTH or cortisol response to oCRF, AVP, or oCRF + AVP at d 136-140, but dexamethasone suppressed basal ACTH and cortisol concentrations at this time. We conclude that stimulated, but not basal, release of ACTH is subject to the negative feedback effect of exogenous glucocorticoid by d 113-116 of gestation in fetal sheep. Both basal and stimulated release of ACTH and cortisol are suppressed after d 125. At the amount of exogenous dexamethasone given, oCRF, AVP, and oCRF + AVP-stimulated responses are affected similarly.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of intravenous verapamil on exercise tolerance and left ventricular function in patients with severe exertional angina pectoris.
The hemodynamic effects of 0.1 mg/kg verapamil given intravenously to 7 patients with angina pectoris were studied at rest and during exercise in the supine position. Cardiac output was measured with the thermodilution technique, which permitted measurements every 30 sec during exercise. Maximal exercise tolerance increased significantly after verapamil. Verapamil had no effect on heart rate at rest, but significantly increased it at the end of the exercise. Left ventricular systolic pressure was reduced by verapamil at rest and during submaximal exercise. Left ventricular end-diastolic pressure was not influenced by verapamil at rest, but was significantly lowered during submaximal exercise. Stroke work index and left ventricular power index were not influenced by verapamil. Rate pressure product was lowered by verapamil during submaximal exercise but had a tendency to be increased at the breaking point. Verapamil had no negative inotropic effect as judged from the left ventricular function curve. It is suggested that the beneficial effect of verapamil relates mainly to a reduction of left ventricular pre- and after-load. The slightly higher rate pressure product after verapamil may also suggest a slight improvement of myocardial perfusion.


Prognostic values of chromosome 18q microsatellite alterations in stage II colonic carcinoma.
To investigate the prognostic value of chromosome 18q microsatellite alterations (MA) in stage II colon cancer. One hundred and six patients with sporadic stage II colon cancer were enrolled in this study. DNA was extracted from formalin-fixed, paraffin-embedded tumor and adjacent normal mucosal tissue samples. MA, including loss of heterozygosity (LOH) and microsatellite instability (MSI), was analyzed by polymerase chain reaction, polyacrylamide gel-electrophoresis and DNA sequencing at 5 microsatellite loci on chromosome 18q (D18S474, D18S55, D18S58, D18S61 and D18S64). Among the 102 patients eligible for MA information, the overall frequencies of LOH, high and low frequency MSI/microsatellite stable were 49.0%, 17.6% and 82.4%, respectively. The high frequency of 18q-LOH was significantly associated with the poor 5-year overall survival (OS) (P = 0.008) and disease free survival (P = 0.006). High levels of MSI were significantly associated with a longer 5-year OS (P = 0.045) while the higher frequency of 18q-LOH at the loci of D18S474 and D18S61 was significantly associated with a poorer 5-year OS (P = 0.010 and 0.005, respectively). But multivariate analysis showed that only the frequency of 18q-LOH was significantly associated with the prognosis of the disease. High frequency of 18q-LOH is an independent prognostic factor indicating poor prognosis of the patients with stage II colon cancer.


Treatment of Hypertension in Complex Older Adults: How Many Medications Are Needed?
Background: Many older adults with hypertension receive multiple antihypertensives. It is unclear whether treatment with several antihypertensive classes results in greater cardiovascular benefits than fewer antihypertensive classes. Objectives: We investigated (a) the longitudinal associations between treatment with ≥ 3 versus 1-2 classes and death and major adverse cardiovascular events (MACE) and (b) whether these associations varied by the presence of mobility disability. Methods: We included 6,011 treated hypertensive adults ≥65 from the Medical Expenditure Panel Survey (MEPS), a nationally representative community sample. Times to MACE and death were compared between those receiving ≥3 versus 1-2 classes using multivariable proportional hazards regression. We used inverse probability of treatment weighting to account for indication and contraindication bias. Results: There were no significant differences in the risk of mortality (hazard ratio [HR] = 0.96, p = .769) or MACE (HR = 1.10, p = .574) between the exposure groups, and there were no significant exposure × mobility disability interactions. Discussion: We found no benefit of ≥3 versus 1-2 antihypertensive classes in reducing mortality and cardiovascular events in a representative cohort of older adults, raising concern about the added benefit of additional antihypertensives in the real world.


Follicle-stimulating hormone amplifies insulin-like growth factor I-mediated activation of AKT/protein kinase B signaling in immature rat Sertoli cells.
FSH and IGF-I are both important determinants of testicular development and Sertoli cell function. The present studies were performed to determine the actions of FSH and IGF-I on PI3K/AKT protein kinase signaling in immature rat Sertoli cells. Primary cultures of rat Sertoli cells were prepared from 10-d-old rats. After 7 d in culture, Sertoli cells were treated with IGF-I, FSH, or IGF-I plus FSH. In some experiments cultures were treated with 8-bromo-cAMP (40 microM), (Bu)(2)cAMP (40 microM), or forskolin (10 microM). After treatments, cell lysates were prepared, and the activation state of AKT and cAMP response element-binding protein (CREB) was determined by Western blot analysis using phosphorylation site-specific antibodies. IGF-I had little effect on CREB phosphorylation, but rapidly increased the phosphorylation of AKT in a concentration-dependent manner. Maximal stimulatory effects of IGF-I were observed at 10-20 ng/ml. Treatment with FSH (0.9 IU/ml) or forskolin for 20 min increased CREB phosphorylation, but had little effect on AKT phosphorylation. However, FSH caused a concentration-dependent increase in IGF-I-induced AKT phosphorylation. Longer incubations (1-4 h) with FSH alone resulted in the elevation of AKT phosphorylation concomitant with an increased secretion of IGF-I and decreased production of IGF-binding protein-3, implicating endogenous IGF-I in the action of FSH on AKT phosphorylation. IGF-I- and FSH-dependent AKT phosphorylation was inhibited by LY29400 (10 microM), a PI3K inhibitor, and by IGF-binding protein 3, but not by a PKA inhibitor (H89). The present study demonstrates that immature rat Sertoli cells possess multiple protein kinase signaling cascades that are regulated by FSH. Furthermore, FSH amplifies IGF-I-mediated PI3K/AKT signaling in Sertoli cells. The results provide evidence for intracellular signaling mechanisms that may be required for the proliferation and differentiation of Sertoli cells.


The 23 and 17 kDa extrinsic proteins of photosystem II modulate the magnetic properties of the S1-state manganese cluster.
An S1-state parallel polarization "multiline" EPR signal arising from the oxygen-evolving complex has been detected in spinach (PSII) membrane and core preparations depleted of the 23 and 17 kDa extrinsic polypeptides, but retaining the 33 kDa extrinsic protein. This S1-state multiline signal, with an effective g value of 12 and at least 18 hyperfine lines, has previously been detected only in PSII preparations from the cyanobacterium sp. Synechocystis sp. PCC6803 [Campbell, K. A., Peloquin, J. M., Pham, D. P., Debus, R. J., and Britt, R. D. (1998) J. Am. Chem. Soc. 120, 447-448]. It is absent in PSII spinach membrane and core preparations that either fully retain or completely lack the 33, 23, and 17 kDa extrinsic proteins. The S1-state multiline signal detected in spinach PSII cores and membranes has the same effective g value and hyperfine spacing as the signal detected in Synechocystis PSII particles. This signal provides direct evidence for the influence of the extrinsic PSII proteins on the magnetic properties of the Mn cluster.


Developing a Tailored Texting Preventive Intervention: A Card Sort Methodology.
Intervention content written by adults for youth can result in miscommunication due to generational and cultural differences. Inviting at-risk youth to participate in the creation of intervention material can augment acceptability for their peers. To improve intervention messaging, the present study examines the utility of a card sort technique when creating cellular phone text messages to be used in a preventive substance use intervention. During focus groups with 24 youth who are exiting the foster care system - a population with distinct cultural attributes - participants were asked to rate stage of change-specific health messages rooted in Motivational Interviewing and the Transtheoretical Model. Participants unanimously favored content that encouraged autonomy and choice. Statements that invited a "look to the future" were also rated favorably. Messages that referenced the past were not rated well, as were suggestions for professional assistance. Finally, encouragement to receive social support for change was met with ambivalence. While some participants regarded support as helpful, many others felt a severe lack of support in their lives, possibly prompting further substance use. Youth exiting foster care constitute a unique population whose voice is paramount in the development of interventions. The content present in traditional approaches to substance use prevention (e.g., increasing social support) may not apply to this group of vulnerable youth. The card sort technique has strong potential to evoke youth-specific intervention content that is more readily understood and accepted by target audiences.


Greater functional similarity in mobile compared to sessile assemblages colonizing artificial coastal habitats.
Among anthropogenic habitats built in the marine environment, floating and non-floating structures can be colonized by distinct assemblages. However, there is little knowledge whether these differences are also reflected in the functional structure. This study compared the functional diversity of sessile and mobile invertebrate assemblages that settle over three months on floating vs. non-floating artificial habitats, in two Chilean ports. Using morphological, trophic, behavioral, and life history traits, we found differences between mobile and sessile assemblages regarding the effect of the type of habitat on the functional diversity. Compared to sessile assemblages, a greater functional similarity was observed for mobile assemblages, which suggests that their dispersal capacity enables them to balance the reduced connectivity between settlement structures. No traits, prevailing or selected in one or the other habitat type, was however clearly identified; a result warranting for further studies focusing on more advanced stages of community development.


Structure and dioxygen-reactivity of copper(I) complexes supported by bis(6-methylpyridin-2-ylmethyl)amine tridentate ligands.
The structure and dioxygen-reactivity of copper(I) complexes R supported by N,N-bis(6-methylpyridin-2-ylmethyl)amine tridentate ligands L2R[R (N-alkyl substituent)=-CH2Ph (Bn), -CH2CH2Ph (Phe) and -CH2CHPh2(PhePh)] have been examined and compared with those of copper(I) complex (Phe) of N,N-bis[2-(pyridin-2-yl)ethyl]amine tridentate ligand L1(Phe) and copper(I) complex (Phe) of N,N-bis(pyridin-2-ylmethyl)amine tridentate ligand L3(Phe). Copper(I) complexes (Phe) and (PhePh) exhibited a distorted trigonal pyramidal structure involving a d-pi interaction with an eta1-binding mode between the metal ion and one of the ortho-carbon atoms of the phenyl group of the N-alkyl substituent [-CH2CH2Ph (Phe) and -CH2CHPh2(PhePh)]. The strength of the d-pi interaction in (Phe) and (PhePh) was weaker than that of the d-pi interaction with an eta2-binding mode in (Phe) but stronger than that of the eta1 d-pi interaction in (Phe). Existence of a weak d-pi interaction in (Bn) in solution was also explored, but its binding mode was not clear. Redox potentials of the copper(I) complexes (E1/2) were also affected by the supporting ligand; the order of E1/2 was Phe>R>Phe. Thus, the order of electron-donor ability of the ligand is L1Phe<L2R<L3Phe. This was reflected in the copper(I)-dioxygen reactivity, where the reaction rate of copper(I) complex toward O2 dramatically increased in the order of R<R<R. The structure of the resulting Cu2/O2 intermediate was also altered by the supporting ligand. Namely, oxygenation of copper(I) complex R at a low temperature gave a (micro-eta2:eta2-peroxo)dicopper(II) complex as in the case of Phe, but its O-O bond was relatively weakened as compared to the peroxo complex derived from Phe, and a small amount of a bis(micro-oxo)dicopper(III) complex co-existed. These results can be attributed to the higher electron-donor ability of L2R as compared to that of L1Phe. On the other hand, the fact that Phe mainly afforded a bis(micro-oxo)dicopper(III) complex suggests that the electron-donor ability of L2R is not high enough to support the higher oxidation state of copper(III) of the bis(micro-oxo) complex.


The effect of re-dosing of vasodilators on the intracavernosal pressure and on the penile rigidity.
To study the effect of re-dosing of vasodilators on cavernous smooth muscle relaxation. The intracavernosal pressure (ICP) was measured in 48 patients undergoing an intracavernosal injection test followed by gravity cavernosometry before and after administration of 1 or 2 booster injections with 20 micrograms prostaglandin E1 after an initial injection of a trimix of vasodilators. When submitted to Duplex scanning on another occasion, the injection of the trimix was followed by squeeze of the corpora. The occurrence of clinical full erection during the examinations was registered. The mean values of the ICP changed little, albeit statistically significant, after the first booster injection (+3.47 mm Hg) but not after the second one. With cavernosometry, a false diagnosis of cavernous leakage was made in at least 14 patients. During Duplex scanning, after the corpora were squeezed, 12 patients developed a clinical full erection, but none did during the intracavernosal injection test, even after re-dosing. A minimal drop in blood pressure was observed in 15 subjects after a booster injection. Administration of booster injections of 20 micrograms prostaglandin E1 after an initial injection of trimix did not induce sufficient cavernous smooth muscle relaxation. Squeezing of the corpora after injection of trimix was more successful.


Plasticity of epidermal adult stem cells derived from adult goat ear skin.
Here we report the isolation and characterization of pluripotent stem cells from adult goat skin. We found that these primary cells have the properties of embryonic stem cells (ESC), including the expression of appropriate immunological markers and the capability of forming embryoid bodies. The subcultured cells also show the characteristics of stem cells, such as the expression of CK19, beta(1-)integrin, P63, and formation of holo-clones in culture. Therefore, we termed these cells epidermal adult stem cells (EpiASC), although their origin was not identified. We have shown that clones of individual EpiASC proliferate and differentiate in culture to produce neurons, cardiomyocytes, osteoblasts, and occytes. Further, we cultivated EpiASC on bioengineered dermis and denuded human amniotic membrane (HAM), to reconstruct artificial skin and corneal epithelium. We successfully transplanted those artificial tissues in goats with acute full-thickness skin defect (AFTSD) and limbal stem cell deficiency (LSCD), respectively. Our results showed that indeed EpiASC reconstructed the skin (hair was observed in restored areas), and repaired the damaged cornea of goats with total LSCD. These data confirm that EpiASC can differentiate into different functional cell types in vivo or in vitro. Due to their high degree of inherent plasticity, and to their easy accessibility for collection from the skin, EpiASC are excellent candidate sources for diverse cell therapies.


Obtainment and characterization of a potential functional ingredient from olive.
Current olive oil production methods generate huge amounts of polluting waste, containing most of the health-related compounds in olive. Here, a new product is obtained from olive after pitting, drying and oil extraction, without generating waste. Its characterization showed the presence, within a single matrix, of more than 90% of the polyphenols present in olive, including hydroyxtyrosols (commonly not transferred to olive oil), dietary fiber, oleic acid and polyalcohols. This product is a potential new functional ingredient, consumption of which may lead to additive and/or synergic activities among its constituents; some of which already have approved health claims. Additionally, the olive oil obtained exhibits profiles of fatty acids and phenolic compounds similar to those of commercial olive oil. The procurement of this potential functional ingredient may represent a new approach to the revalorization of olive that additionally decreases waste.


Risk perception bias, self-reporting of illness, and the validity of reported results in an epidemiologic study of recreational water associated illnesses.
Epidemiologic studies of water associated illness often have to rely on self-reported symptoms of the outcome illness(es) under study. Individual participant's perception of risk, in theory, can affect the validity of self-reported symptoms. The magnitude and effect of possible "risk perception bias" was evaluated as part of a series of randomized trials designed to assess infectious disease transmission via exposure to marine recreational waters with modest sewage contamination. All study subjects were blinded to both their individual indices of exposure and the outcome illnesses under study. Of the five outcome illnesses studied, the effect of "risk perception bias" only effected one: skin ailments. Although analysis of crude rates of skin ailments showed the exposed group (bathers) to be 3.5 times more likely to report skin ailments relative to the non-exposed (non-bathers), when the data was stratified by any perceived health risk of bathing in such waters, this association was shown to be spurious in nature. Bathers having pre-conceived notions of any health risk due to the exposure were 10.63 times more likely to report skin ailments relative to the unexposed (non-bathers) (95% CI 2.36-47.8, P = 0.0002), while bathers without any pre-conceived notion of risk were no more likely to report skin ailments relative to non-bathers (OR = 0.60, 95% CI 0.11-3.24, P = 0.71). Further stratification by exposure grouping showed bathers with pre-conceived notions of excess risk to be 4.78 times more likely to report skin ailments relative to bathers without any notion of excess risk (95% CI 1.04-21.86, P = 0.03), while among non-bathers those with pre-conceived notions of risk were 3.70 times less likely to report skin ailments relative to non-bathers without any pre-conceived notion of risk (95% CI 0.70-19.60, P = 0.10). This study shows that "risk perception bias" can be strong enough to lead to spurious associations in the presence of self-reported symptoms, and should be controlled for in future epidemiologic studies of recreational water associated illnesses and other water associated environmental exposures where the use of self-reported symptoms cannot be avoided.


Enhancing surface methane fluxes from an oligotrophic lake: exploring the microbubble hypothesis.
Exchange of the greenhouse gases carbon dioxide (CO2) and methane (CH4) across inland water surfaces is an important component of the terrestrial carbon (C) balance. We investigated the fluxes of these two gases across the surface of oligotrophic Lake Stechlin using a floating chamber approach. The normalized gas transfer rate for CH4 (k600,CH4) was on average 2.5 times higher than that for CO2 (k600,CO2) and consequently higher than Fickian transport. Because of its low solubility relative to CO2, the enhanced CH4 flux is possibly explained by the presence of microbubbles in the lake's surface layer. These microbubbles may originate from atmospheric bubble entrainment or gas supersaturation (i.e., O2) or both. Irrespective of the source, we determined that an average of 145 L m(–2) d(–1) of gas is required to exit the surface layer via microbubbles to produce the observed elevated k600,CH4. As k600 values are used to estimate CH4 pathways in aquatic systems, the presence of microbubbles could alter the resulting CH4 and perhaps C balances. These microbubbles will also affect the surface fluxes of other sparingly soluble gases in inland waters, including O2 and N2.


Low-Density Lipoprotein Receptor-Related Protein-1 Signaling in Angiogenesis.
Low-density lipoprotein receptor-related protein-1 (LRP1) plays multifunctional roles in lipid homeostasis, signaling transduction, and endocytosis. It has been recognized as an endocytic receptor for many ligands and is involved in the signaling pathways of many growth factors or cytokines. Dysregulation of LRP1-dependent signaling events contributes to the development of pathophysiologic processes such as Alzheimer's disease, atherosclerosis, inflammation, and coagulation. Interestingly, recent studies have linked LRP1 with endothelial function and angiogenesis, which has been underappreciated for a long time. During zebrafish embryonic development, LRP1 is required for the formation of vascular network, especially for the venous development. LRP1 depletion in the mouse embryo proper leads to angiogenic defects and disruption of endothelial integrity. Moreover, in a mouse oxygen-induced retinopathy model, specific depletion of LRP1 in endothelial cells results in abnormal development of neovessels. These loss-of-function studies suggest that LRP1 plays a pivotal role in angiogenesis. The review addresses the recent advances in the roles of LRP1-dependent signaling during angiogenesis.


Cimetidine disposition in obesity.
Cimetidine pharmacokinetics were studied in 13 otherwise healthy but obese volunteers, having a mean body weight of 113 kg and a mean percentage ideal body weight (IBW) of 179%. Sixteen healthy volunteers of normal body habitus (64 kg, 99% IBW) served as controls. All subjects had normal renal function and no laboratory or clinical evidence of hepatic or cardiac dysfunction. After administration of 200-300 mg of cimetidine by rapid intravenous injection, multiple plasma samples obtained over the next 24 h were analyzed for cimetidine concentration by high pressure liquid chromatography. Elimination half-life was not different between obese and control subjects (2.23 versus 2.08 h). Apparent volume of distribution was also similar between subject groups (120 versus 106), as was total metabolic clearance (616 versus 579 ml/min). Using percentage IBW as a measure of obesity, no relationship was found between percentage IBW and apparent volume of distribution (r = 0.29). Cimetidine similarly distributes into IBW in both obese and normal weight subjects, and there is minimal distribution of cimetidine into excess body weight over IBW. Furthermore, there is no difference in total metabolic clearance or half-life of cimetidine between obese and control subjects. Cimetidine dosage in clinical practice should therefore be calculated on the basis of IBW, which better reflects lean body mass, instead of total body weight, which reflects adipose tissue weight in addition to lean body mass.


Optical Trapping-Polarized Raman Microspectroscopy of Single Ethanol Aerosol Microdroplets: Droplet Size Effects on Rotational Relaxation Time and Viscosity.
Optical trapping-polarized Raman microspectroscopy of single ethanol (EtOH) microdroplets with a diameter (d) of 6.1-16.5 μm levitated in an EtOH vapor-saturated air/N2 gas atmosphere has been explored to elucidate the vibrational and rotational motions of EtOH in the droplets at 22.0 °C. The Raman spectral bandwidth of the C-C stretching vibrational mode observed for an aerosol EtOH microdroplet was narrower than that of bulk EtOH, suggesting that the vibrational/rotational motions of EtOH in the aerosol system were restricted compared to those in the bulk system. In practice, polarized Raman microspectroscopy demonstrated that the rotational relaxation time (τrot) of EtOH in an aerosol microdroplet with d = 16. 5 μm was slower (2.33 ps) than that in a bulk EtOH (1.65 ps), while the vibrational relaxation times (τvib) in the aerosol and bulk EtOH systems were almost comparable with one another: 0.86-0.98 ps. Furthermore, although the τvib value of an aerosol EtOH microdroplet was almost unchanged irrespective of d as described above, the τrot value increased from 2.33 to 3.57 ps with a decrease in d from 16.5 to 6.1 μm, which corresponded to the increase in EtOH viscosity (η) from 1.33 to 2.04 cP with the decrease in d. The droplet size dependences of τrot and η in an aerosol EtOH microdroplet were discussed in terms of the gas/droplet interfacial molecular arrangements of EtOH and Laplace pressure experienced by a spherical EtOH microdroplet in the gas phase.


Wet and Functional Adhesives from One-Step Aqueous Self-Assembly of Natural Amino Acids and Polyoxometalates.
Sessile organisms have undergone long-term evolution to develop the unique ability by positioning themselves on wet solid surface through secreting adhesive proteins. The present study reveals that natural amino acid monomers can also exhibit similar adhesion capacity. This kind of biomimetic adhesives were created by the one-step aqueous assembly of basic amino acids with assistance of anionic polyoxometalates. The polyoxometalates not only serve as multivalent scaffold to initiate the supramolecular cross-linking of amino acid molecules, but also function as a redox component, bestowing the wet adhesives with electrochromic features.


Stimulation of multiple MAPK pathways by mechanical overload in the perfused amphibian heart.
The mitogen-activated protein kinase (MAPK) signal transduction pathway activated by mechanical stress was investigated in the isolated perfused amphibian (Rana ridibunda) heart. High perfusion pressure induced the rapid (30 s) and prolonged (30 min) phosphorylation of a p43-extracellular regulated kinase, a response almost completely inhibited by 25 microM PD-98059. c-Jun NH2-terminal kinase (JNK) was also phosphorylated with maximal values attained at 15 min and remained elevated over 30 min. In-gel kinase assays verified that phosphorylated JNKs are active, phosphorylating the transcription factor c-Jun. Furthermore, pressure overload rapidly stimulated the p38-MAPK phosphorylation (30 s), a transient process (5 min) abolished by 1 microM SB-203580. In-gel kinase assays revealed that with phosphorylation, active p38-MAPKs phosphorylate their substrate MAP kinase-activated protein kinase 2. Biochemical analysis along with immunohistochemical studies showed that with activation, the three MAPK subfamily members examined are localized not only in the cytoplasm but in the nucleus as well. Present results therefore demonstrate for the first time in an amphibian species the involvement of multiple MAPK pathways in the mechanical overload-induced adaptive responses of the heart as well as their possible physiological roles.


The genus Ctenomelynthus (Hemiptera: Heteroptera: Coreidae: Acanthocephalini), with the description of three new species and key to the known species.
The genus Ctenomelynthus Breddin (1903) is redescribed, and three new species: C. sanchezi from French Guiana, and Venezuela, C. urbinus from Brazil, and C. venustulus from Suriname are described. Ctenomelynthus willineri (Kormilev, 1952), is synonymized under C. coxalis Breddin, 1903. One species, C. bridarollii (Kormilev) is designated as a nomen dubium. New distributional records for C. brunneiventris Breddin, C. coxalis Breddin, and C. inermibus (Distant) are included. Dorsal and ventral photographs and parameres of some species are included. A key to the six known species is given.


Identification of insulin signaling elements in human beta-cells: autocrine regulation of insulin gene expression.
Although many studies using rodent islets and insulinoma cell lines have been performed to determine the role of insulin in the regulation of islet function, the autocrine effect of insulin on insulin gene expression is still controversial, and no consensus has yet been achieved. Because very little is known about the insulin signaling pathway in human islets, we used single-cell RT-PCR to profile the expression of genes potentially involved in the insulin signaling cascade in human beta-cells. The detection of mRNAs for insulin receptor (IR)A and IRB; insulin receptor substrate (IRS)-1 and IRS-2; phosphoinositide 3-kinase (PI3K) catalytic subunits p110alpha, p110beta, PI3KC2alpha, and PI3KC2gamma; phosphoinositide-dependent protein kinase-1; protein kinase B (PKB)alpha, PKBbeta, and PKBgamma in the beta-cell population suggests the presence of a functional insulin signaling cascade in human beta-cells. Small interfering RNA-induced reductions in IR expression in human islets completely suppressed glucose-stimulated insulin gene expression, suggesting that insulin regulates its own gene expression in human beta-cells. Defects in this regulation may accentuate the metabolic dysfunction associated with type 2 diabetes.


The placebo-nocebo response: controversies and challenges from clinical and research perspective.
Placebo and nocebo responses fascinate, confuse, mystify and challenge. They are genuine social, cultural and psychobiological phenomena which can significantly modify the overall treatment outcome. The placebo-nocebo phenomenon represents a very good model for our better understanding the role of treatment context and how the words, indices, symbols and icons act on our brains. Placebo response is associated with reward expectancy and relief of anticipatory anxiety, while nocebo response is related to lack of reward/positive expectancy and to increase of anticipatory anxiety. Placebo-nocebo responses are mediated through changes in various cortico-subcortical networks and psychophysiological systems. In spite of many existing complementary theories and still growing research on placebo and nocebo response, the implementation of our current knowledge to benefit basic research, clinical trials and routine clinical practice is still so scarce.


The prevalence and characteristics of battered women in a primary care setting.
Estimates are that 2 million women are battered each year by their male partner. To prevent battering and promote physical safety, Planned Parenthood of Houston and Southeast Texas added four abuse-assessment questions to the standard intake form for all initial and annual-visit clients. To establish the prevalence of battering, all intake forms completed at four clinics during a one-month period were analyzed. A total of 793 forms were reviewed. The prevalence of physical battering was 8.2 percent. When the characteristics of the battered women were compared with the non-battered, statistically significant differences existed. Information on the health consequences of battering are presented along with suggested assessment questions.


Exploring educational interventions to facilitate health professional students' professionally safe online presence.
To establish the most effective approach and type of educational intervention for health professional students, to enable them to maintain a professionally safe online presence. This was a qualitative, multinational, multi-institutional, multiprofessional study. Practical considerations (availability of participants) led us to use a combination of focus groups and individual interviews, strengthening our findings by triangulating our method of data collection. The study gathered data from 57 nursing, medical and paramedical students across four sites in three countries (Aotearoa/New Zealand, Australia and Wales). A content analysis was conducted to clarify how and why students used Facebook and what strategies they thought might be useful to ensure professional usage. A series of emergent codes were examined and a thematic analysis undertaken from which key themes were crystallized. The results illuminated the ways in which students use social networking sites (SNS). The three key themes to emerge from the data analysis were negotiating identities, distancing and risks. Students expressed the wish to have material about professional safety on SNS taught to them by authoritative figures to explain "the rules" as well as by peers to assist with practicalities. Our interactive research method demonstrated the transformative capacity of the students working in groups. Our study supports the need for an educational intervention to assist health professional students to navigate SNS safely and in a manner appropriate to their future roles as health professionals. Because health professional students develop their professional identity throughout their training, we suggest that the most appropriate intervention incorporate small group interactive sessions from those in authority, and from peers, combined with group work that facilitates and enhances the students' development of a professional identity.


Maximal intermittent handgrip strategy: design and evaluation of an exercise protocol and a grip tool.
Handgrip (HG) exercise has been prescribed as a lifestyle intervention to successfully reduce resting blood pressure (BP) among heterogeneous groups of participants. Current HG protocols have limited accessibility due to complicated exercise prescriptions and sophisticated required equipment. Therefore, this research describes the design and evaluation of the maximal intermittent (MINT) HG exercise strategy, consisting of both a novel exercise protocol (32×5 seconds maximal grip squeezes separated by 5 seconds of rest between sets) and an original grip tool. This research was a multistep progressive design that included 51 postmenopausal women as participants in three separate research studies. Part 1 of this research focuses on the MINT exercise protocol. A literature-informed rationale for the design of the protocol is described. This includes exercise intensity, work-to-rest ratio, and total exercise duration with reference to the unique physiology (mechanoreflex and metaboreflex) of postmenopausal women. Subsequent experimental analyses of acute responses to the MINT protocol revealed that women produced 50% of their maximum grip force with moderate cardiovascular responses (increases of systolic BP: 41.6 mmHg, diastolic BP: 20.1 mmHg, heart rate: 35.1 bpm) that remained far below the thresholds of concern identified by the American College of Sports Medicine. Part 2 of this research describes the creation of a novel grip tool, beginning with a mixed-methods assessment of participant opinions regarding two distinct in-laboratory grip tools, leading to the creation of four prototype MINT tools. Structured focus groups revealed a strong preference for MINT prototype 1 for all tool design features, including color, shape, size, and foam grip. Collectively, the result of this multistep research is a novel HG exercise strategy with enhanced accessibility by being easy to understand and simple to execute. The long-term training effectiveness of MINT as an exercise intervention for the reduction of resting BP has yet to be determined.


The Association between Maternal Reproductive Age and Progression of Refractive Error in Urban Students in Beijing.
To investigate the association between maternal reproductive age and their children' refractive error progression in Chinese urban students. The Beijing Myopia Progression Study was a three-year cohort investigation. Cycloplegic refraction of these students at both baseline and follow-up vision examinations, as well as non-cycloplegic refraction of their parents at baseline, were performed. Student's refractive change was defined as the cycloplegic spherical equivalent (SE) of the right eye at the final follow-up minus the cycloplegic SE of the right eye at baseline. At the final follow-up, 241 students (62.4%) were reexamined. 226 students (58.5%) with completed refractive data, as well as completed parental reproductive age data, were enrolled. The average paternal and maternal age increased from 29.4 years and 27.5 years in 1993-1994 to 32.6 years and 29.2 years in 2003-2004, respectively. In the multivariate analysis, students who were younger (β = 0.08 diopter/year/year, P<0.001), with more myopic refraction at baseline (β = 0.02 diopter/year/diopter, P = 0.01), and with older maternal reproductive age (β = -0.18 diopter/year/decade, P = 0.01), had more myopic refractive change. After stratifying the parental reproductive age into quartile groups, children with older maternal reproductive age (trend test: P = 0.04) had more myopic refractive change, after adjusting for the children's age, baseline refraction, maternal refraction, and near work time. However, no significant association between myopic refractive change and paternal reproductive age was found. In this cohort, children with older maternal reproductive age had more myopic refractive change. This new risk factor for myopia progression may partially explain the faster myopic progression found in the Chinese population in recent decades.


Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts.
Enzymes sample multiple conformations during their catalytic cycles. Chemical shifts from Nuclear Magnetic Resonance (NMR) are hypersensitive to conformational changes and ensembles in solution. Phosphomannomutase/phosphoglucomutase (PMM/PGM) is a ubiquitous four-domain enzyme that catalyzes phosphoryl transfer across phosphohexose substrates. We compared states the enzyme visits during its catalytic cycle. Collective responses of Pseudomonas PMM/PGM to phosphosugar substrates and inhibitor were assessed using NMR-detected titrations. Affinities were estimated from binding isotherms obtained by principal component analysis (PCA). Relationships among phosphosugar-enzyme associations emerge from PCA comparisons of the titrations. COordiNated Chemical Shifts bEhavior (CONCISE) analysis provides novel discrimination of three ligand-bound states of PMM/PGM harboring a mutation that suppresses activity. Enzyme phosphorylation and phosphosugar binding appear to drive the open dephosphorylated enzyme to the free phosphorylated state, and on toward ligand-closed states. Domain 4 appears central to collective responses to substrate and inhibitor binding. Hydrogen exchange reveals that binding of a substrate analogue enhances folding stability of the domains to a uniform level, establishing a globally unified structure. CONCISE and PCA of NMR spectra have discovered novel states of a well-studied enzyme and appear ready to discriminate other enzyme and ligand binding states.


Similarities and differences between the effects of amino acids and nitroprusside on peritoneal permeability during CAPD.
Intraperitoneal administration of amino acid based dialysis solutions affects the surface area available for diffusion, with almost no effect on the intrinsic permeability to macromolecules. Intraperitoneally administered nitroprusside affects the vascular surface area and the intrinsic permeability without effect on the peritoneal blood flow. In the present study, these differences were translated into different effects on the radii of the pores in the peritoneal membrane. Effects of amino acid based dialysate and nitroprusside on peritoneal permeability characteristics were evaluated in standard peritoneal permeability analyses with L-arginine-containing amino acid dialysate (10 patients) or with 1.36% glucose dialysate with nitroprusside (10 patients). In each patient a control experiment with 1.36% glucose was performed. Kinetic modeling was done to analyze the effects in terms of the pore theory. Both interventions increased the mass transfer area coefficients of low molecular weight solutes. This is in accordance with an increase in the unrestricted area over diffusion distance found with modeling. With amino acids almost no effect was found on the protein clearances; the increase in the large-pore radius was only small. Nitroprusside induced a marked increase in protein clearances. This was in accordance with an evident increase in the average large-pore radius. Amino acids affect the radii of the small pores and the large pores to the same extent. Nitroprusside influences especially the large pores. Both amino acids and nitroprusside are vasoactive, although the effects on the peritoneal microcirculation are different.


Testosterone normalizes plasma vasopressin response to osmotic stimuli in men with hypogonadism.
We studied plasma vasopressin concentrations during hypertonic saline infusions in 5 men with hypogonadism and 10 normal men to investigate the effect of gonadal steroid on hypothalamo-neurohypophyseal function. All the subjects received the infusion of 5% saline, and plasma vasopressin concentrations were determined by radioimmunoassay (RIA). Three of the 5 men were patients with isolated hypogonadotropic hypogonadism (IHH) and the other two were patients with Klinefelter's syndrome. None of them had any symptoms of diabetes insipidus. Although there was no difference between basal plasma osmolality in the patients and the normal subjects (287.2 +/- 2.1 vs. 285.3 +/- 1.8 mmol/kg), the basal level of plasma vasopressin in the patients was lower than that in the normal subjects (0.62 +/- 0.17 vs. 1.36 +/- 0.15 pg/ml, P < 0.05). Hypertonic saline infusion revealed varying degrees of subnormal vasopressin responses in the patients except one patient with Klinefelter's syndrome. The mean vasopressin response to osmotic stimuli (delta plasma vasopressin/delta plasma osmolality) in the 5 patients was lower than in the normal subjects (0.04 +/- 0.01 vs. 0.16 +/- 0.02, P < 0.05). Three patients with IHH and one patient with Klinefelter's syndrome were re-examined after pulsatile gonadotropin-releasing hormone (GnRH) infusion or testosterone enanthate i.m. injection. After the treatment with testosterone or GnRH, the response of plasma vasopressin to hypertonic saline infusion was normalized in three patients who had subnormal vasopressin response before treatment (delta plasma vasopressin/delta plasma osmolality: 0.04 +/- 0.01 vs. 0.09 +/- 0.01, P < 0.05). These results suggest that testosterone improves the subnormal vasopressin response to osmotic stimuli in men with hypogonadism.


Renal nerve stimulation augments effect of intraluminal angiotensin II on proximal tubule transport.
The proximal tubule synthesizes and secretes angiotensin II into the lumen, where it regulates transport. Renal denervation abolishes the effect of angiotensin II on proximal tubule transport. Using in vivo microperfusion, we examined whether renal nerve stimulation modulates the effect of angiotensin II on transport. The effect of angiotensin II was assessed by measuring the decrease in volume reabsorption with the addition of 10(-4) M luminal enalaprilat. Luminal enalaprilat did not alter volume reabsorption (2.80 +/- 0.18 vs. 2.34 +/- 0.14 nl x mm(-1) x min(-1)). However, with renal nerve stimulation, enalaprilat decreased volume reabsorption (3.45 +/- 0.22 vs. 1.67 +/- 0.20 nl x mm(-1) x min(-1), P < 0.0005). The absolute and percent decrements in volume reabsorption with luminal enalaprilat were higher with renal nerve stimulation than with native innervation (1.78 +/- 0.19 vs. 0.46 +/- 0.23 nl x mm(-1) x min(-1), P < 0.02, and 51.8 +/- 5.0 vs. 14.6 +/- 7.4%, P < 0.05, respectively). Renal nerve stimulation did not alter the glomerular filtration rate or renal blood flow. Renal nerve stimulation augments the stimulatory effect of intraluminal angiotensin II. The sympathetic renal nerves modulate the proximal tubule renin-angiotensin system and thereby regulate proximal tubule transport.


[Non-allergic drug exanthemas].
Drug reactions similar to allergic reactions according to the differentiation by Coombs and Gell--type I to type V--can be triggered by drugs without the interaction of antibodies and lymphocytes. The immediate hypersensitivity reaction (type I) is imitated in three ways: 1. Histamine release from mast cells or basophiles by drugs without regines (IgE, IgG4), 2. complement activation by a drug via the classic or alternative pathway without reaction with an antibody. 2. intolerance reaction, that means a chronic urticaria triggered by an inhibitor of the prostaglandin synthesis (Aspirin, other analgesics, food additives and dyes). In contrast to the above reactions, non-immune mechanisms mimicking type II to type V reactions are of inferior clinical importance.


Wolff on duties of esteem in the law of peoples.
The role that the desire for self-worth plays in international relations has become a prominent topic in contemporary political theory. Contemporary accounts are based on the notion of national self-worth as a function of status; therefore, the desire for national self-worth is seen as a source of anxiety and conflict over status. By contrast, according to Christian Wolff, there exists a duty to take care that both one's own and other political communities deserve to be esteemed. In his view, this duty is grounded in the duty of self-perfection because the qualities for which communities deserve to be esteemed are those that promote the self-perfection of individuals. From this perspective, he argues that duties of esteem toward political communities should not be seen as an outcome of power relations but rather as an outcome of the fulfillment of functions of the law of peoples. Wolff's line of argument draws attention to the possibility that anger over a violation of the desire for honor could be mistaken for an expression of specific culture-specific sensitivities, while what really may be expressed is a diverging interpretation of the implications of dependence in international relations.


Genotyping of Cryptosporidium isolates from Chamelea gallina clams in Italy.
Chamelea gallina clams collected from the mouths of rivers along the Adriatic Sea (central Italy) were found to harbor Cryptosporidium parvum (genotype 2), which is the lineage involved in zoonotic transmission. The clams were collected from the mouths of rivers near whose banks ruminants are brought to graze. This paper reports the environmental spread of C. parvum in Italy and highlights the fact that genotyping of seaborne Cryptosporidium isolates is a powerful tool with which to investigate the transmission patterns and epidemiology of this microorganism.


Avian species functional diversity and habitat use: The role of forest structural attributes and tree diversity in the Midlands Mistbelt Forests of KwaZulu-Natal, South Africa.
Forest transformation has major impacts on biodiversity and ecosystem functioning. Identifying the influence of forest habitat structure and composition on avian functional communities is important for conserving and managing forest systems. This study investigated the effect of forest structure and composition characteristics on bird species community structure, habitat use and functional diversity in 14 Mistbelt Forest patches of the Midlands of KwaZulu-Natal in South Africa. We surveyed bird communities using point counts. We quantified bird functional diversity for each forest patch using three diversity indices: functional richness, functional evenness and functional divergence. We further assessed species-specific responses by focussing on three avian forest specialists, orange ground-thrush Geokichla gurneyi, forest canary Crithagra scotops and Cape parrot Poicephalus robustus. We found that bird community and forest-specialist species responses to forest structure and tree species diversity differed. Also, forest structural complexity, canopy cover and tree species richness were the main forest characteristics better at explaining microhabitat influence on bird functional diversity. Forest patches with relatively high structural complexity and tree species richness had higher functional richness. Different structural characteristics influenced habitat use by the three forest specialists. Tree species diversity influenced C. scotops and G. gurneyi positively, while P. robustus responded negatively to forest patches with high tree species richness. Our study showed that site-scale forest structure and composition characteristics are important for bird species richness and functional richness. Forest patches with high tree species diversity and structural complexity should be maintained to conserve forest specialists, bird species richness and functional richness.


Control of two-electron four-center (2e-/4c) C-C bond formation observed for tetracyanoethenide dimerization, [TCNE]2(2-).
Cu(PPh3)3(TCNE) (TCNE = tetracyanoethylene) and 14 other examples form [TCNE]22- dimers possessing a long 2.89 +/- 0.05 A two-electron four-center (2e-/4c) C-C bond in the solid state. This bond arises from the overlap of the b2g pi* singly occupied molecular orbital (SOMO) on each [TCNE]*- fragment, forming a filled bonding orbital of b2u symmetry, and the stabilizing effect of the cation...anion interactions in the crystal that exceed the anionic repulsion. In contrast, Mn(C5H5)(CO)2(TCNE) exhibits a related, but different, [TCNE]*-...TCNE]*- motif in the solid state that lacks the 2e-/4c C-C bonding. To better understand the unusual nature of 2e-/4c C-C bonding, the genesis of the differences between their respective pi-[TCNE]*-...TCNE]*- interactions was sought. The lack of 2e-/4c C-C bond formation is attributed to the weaker radical character of the [TCNE]*- ligand, which has a total spin population of only 0.5 electron, half of that required for two S = 1/2 [TCNE]*- moieties to form a [TCNE]22- dimer. Hence, the antiferromagnetic MnII-[TCNE]*- intramolecular interaction (between the formally S = 1/2 Mn-bound [TCNE]*- and the paramagnetic Mn(II)) dominates over the intermolecular pi-[TCNE]*--[TCNE]*- spin coupling (between two S = 1/2 [TCNE]*- needed to form [TCNE]22-). Therefore, by selecting specific metal ions that can interact with sigma-[TCNE]*-, dimerization forming [TCNE]22- can be favored or disfavored.


Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging.
Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress. We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence. They are selectively down-regulated in cultured fibroblasts after oxidative stress, and, in vivo, in proliferating tissues and during physiological aging. Selectivity is imposed by p66 expression and activation of p44/p53 (also named Delta40p53), a p53 isoform that accelerates aging and prevents mitosis after protein damage. p66 deletion retards aging and increases longevity of p44/p53 transgenic mice. Thus, oxidative stress activates a specific p53 transcriptional response, mediated by p44/p53 and p66, which regulates cellular senescence and aging.


Exposure to peers who smoke moderates the association between sports participation and cigarette smoking behavior among non-white adolescents.
Adolescent sports participants are less likely to smoke cigarettes, and sports participation may prevent young people from smoking. Research suggests that the relationship between sports participation and smoking may vary by race/ethnicity and is also possibly moderated by exposure to peer smoking. We investigated these relationships in a sample of 311 adolescents ages 13-21 presenting for well-visit medical appointments. Participants completed valid assessments of demographics, sports participation, exposure to peer smoking, and smoking behavior. The primary outcome was smoking status (never smoked, tried smoking, experimental/current smoker). Ordinal logistic regression was used separately for non-Hispanic White (n=122) and non-white (n=189; 70.4% black, 14.3% Hispanic, and 15.3% other) adolescents. Among White adolescents, sports participants had significantly lower odds of smoking than non-sports participants, independent of age, gender, and peer smoking. For non-Whites, the adjusted effect of sports participation on smoking depended upon exposure to peers who smoke. Compared with non-sport participants with no exposure to peer smoking, sports participants with no exposure to peer smoking had significantly lower odds of smoking, whereas sports participants with exposure to peer smoking had significantly higher odds of smoking. Sports appear to be protective against smoking among non-Hispanic White adolescents, but among non-White adolescents exposure to peer smoking influences this protection. Interventions incorporating sports to prevent smoking should consider these racial/ethnic differences to address disparities in smoking-related disease.