Experimental influence of storm-surge salinity on soil greenhouse gas emissions from a tidal salt marsh.
Storm surges can substantially alter the water level and salinity in tidal salt marshes. Little is known about how changes experienced during storm surges affect greenhouse gas emissions (GHG; CO2, CH4, N2O) from tidal salt marsh soils. Understanding how storm surges influence ecosystem processes is critical for evaluating the ecosystem's sensitivity to sea level rise. To explore how hurricane-induced changes in salinity affect GHG emissions, we exposed intact soil mesocosms (0-9 cm depth) from a Mid-Atlantic temperate salt marsh to pulse changes in salinity experienced at the site before, during, and after Hurricane Joaquin in 2015. Soil temperature, oxygen, and water level were kept constant to avoid confounding effects throughout the experiment. Automated measurements (hourly resolution) of soil GHG emissions were recorded in control (i.e., no salinity changes) and treatment mesocosms, and combined with soil pore water chemistry (i.e., SO42-, S2-, Fe2+, TNb, redox potential, pH) to characterize the biogeochemical responses. Using mixed effects models, we found that the role of different biogeochemical processes, such as sulfur cycling, changed throughout the experiment, underscoring the complex nature of GHG emissions in tidal salt marsh soils. Overall, soils subjected to a salinity decrease had greater GHG emissions than control soils, which were maintained at 17 ppt. The treatment soils had a 24% and 23% increase in global warming potential (20- and 100-year scenarios, respectively) indicating that storm surges can produce pulses of GHG emissions. However, both CH4 and N2O emissions returned to baseline values (following hysteresis responses) when initial conditions were reestablished. The results support the fact that tidal salt marshes are resilient ecosystems, as soil GHG emissions recovered relatively quickly from the pulse event.


Testicular microliths: their origin and structure.
Light and electron microscopic studies were done on microliths in unilateral undescended testes to determine the origin and structure. The microliths seem to originate from degenerating intratubular cells and consist of a central calcified core surrounded by concentric layers of connective fibers.


Comparison of cholinergic drug effects on regional brain glucose consumption in rats and humans by means of autoradiography and position emission tomography.
Cholinergic mechanisms have been extensively studied in animals and have been implicated in the pathogenesis of human disorders such as Alzheimer's disease. However, few investigations have directly evaluated the validity of extrapolating the results of animal studies to humans. As a component of a continuing examination of the contribution of cholinergic deficits to the alterations in brain metabolism that occur in Alzheimer's disease, we have compared the effects of scopolamine and physostigmine on regional brain energy metabolism in both rats and humans, using a common region of interest atlas. In Alzheimer's patients and in rodents, physostigmine increased glucose metabolism in several regions (e.g. thalamus) and decreased it in others. Overall, there was a significant positive correlation for the effects of physostigmine in the nineteen brain regions studied in both species (r = 0.51, P < 0.05). In normal humans, scopolamine induced a metabolic increase in most brain regions except in the thalamus. Outside this structure, the regional effects of scopolamine were significantly and negatively correlated (r = 0.58, P < 0.01) between rat and human. These results suggest that: (1) cholinergic mechanisms have a similar anatomic distribution in both species, (2) muscarinic receptor-mediated cholinergic effects could predominate outside the thalamus, (3) muscarinic mechanisms are inhibitory in humans but are more complex and possibly excitatory in rats, (4) nicotinic stimulatory effects are found in the thalamus of both species, and (5) physostigmine, but not scopolamine, alters glucose consumption similarly in both species.


Treatment of TASC C and D Femoropoliteal Lesions with Paclitaxel eluting Stents: 12 month Results of the STELLA-PTX Registry.
The aim was to evaluate the safety and the efficacy of primary stenting with paclitaxel eluting stents for TASC C and D femoropopliteal lesions. Patients with TASC C/D de novo femoropopliteal lesions were treated by implanting paclitaxel eluting stents. Patients were included in a single center registry and prospectively followed by clinical and ultrasound evaluation. X-ray of the stented zone was systematically performed 12 months after implantation. The primary endpoint was primary sustained clinical improvement after 12 months. A total of 45 patients (48 limbs) suffering from claudication (25 limbs) or CLI (23 limbs) were enrolled. Lesions were either TASC C (28 limbs) or TASC D (20 limbs). The mean length of the treated segment was 252 ± 90 mm. The mean number of stents was 2.9 ± 1 (2-5). Mean follow up was 12.7 months. No patient was lost to follow up. At 1 year post procedure, primary and secondary sustained clinical improvements were 56.3 ± 7.4% and 80.1 ± 5.9% respectively. Freedom from target lesion and target extremity revascularization were 63.6% and 90.1%, respectively. Primary and secondary patency rates were 52.5% and 79.6%. One year primary sustained clinical improvement rates for TASC C/D were 63.3 ± 9.2% and 45.6 ± 11.7%, respectively (p = .34). One year primary sustained clinical improvement rates for claudication/CLI patients were 68 ± 9.3% and 41.6 ± 11.1%, respectively (p = .13). The incidence of in stent re-stenosis and in stent thrombosis were 25% and 14%, respectively. The incidence of stent fracture was 12.5% on a limb basis and 9% on a per stent basis. The paclitaxel eluting stent did not achieve its goal in terms of prevention of in stent re-stenosis for TASC C/D femoropopliteal lesions. It requires frequent re-interventions during the first year to maintain satisfactory clinical results.


Chronic suicidal thoughts and implicit memory: hypothesis and practical implications.
This paper outlines a hypothesis linking the development of implicit memory in infants and chronic suicidal thoughts in adults. In order to do this, the developmental trajectory of memory is reviewed, as well as how attachment experiences are encoded in implicit memory. The cognitive/emotional capacity of infants is then compared to the subjective experience of the chronically suicidal patient. This is used to develop the hypothesis that chronic suicidal thoughts are located in implicit memory, encoded very early in life. This idea is then used to explain why common responses by mental health workers to the chronically suicidal patient may inadvertently reinforce suicidal thoughts. Finally, understanding these concepts helps us to understand how psychotherapy can change chronic suicidal ideation. A hypothesis is proposed to link infant memory systems with adult chronic suicidal thoughts, and is used to understand helpful responses for patients who suffer with chronic suicidal ideation.


Patterns of sequence evolution at epitopes for host antibodies and cytotoxic T-lymphocytes in human immunodeficiency virus type 1.
Analysis of published sequence data from the nine protein-coding genes of human immunodeficiency virus type 1 (HIV-1) showed striking differences in evolutionary pattern between epitopes for host neutralizing antibodies (Ab) and epitopes for cytotoxic T cells (CTL). In all sequences analyzed, the greatest median amino acid residue diversity was seen at sites that formed part of Ab epitopes, but not of CTL epitopes. By contrast, sites belonging to CTL epitopes but not to Ab epitopes showed reduced median amino acid sequence diversity not only in comparison to sites in Ab epitopes but also in comparison to non-epitope sites. Ab epitopes that did not overlap CTL epitopes showed the highest frequency of comparisons in which the rate of nonsynonymous (amino acid-altering) nucleotide substitution exceeded that of synonymous nucleotide substitution, supporting the hypothesis that much of the diversity at Ab epitopes results from positive selection exerted by the host immune system. Though less frequent than that at Ab epitopes, there was evidence of such selection at certain CTL epitopes as well; and amino acid differences between sister pairs of sequences in CTL epitopes were more likely to be convergent than those in Ab epitopes. The pattern seen at CTL epitopes may represent the result of conflicting pressures favoring conservation of the amino acid sequence for functional reasons and amino acid replacements for reasons of CTL escape.


Effects of freshwater leaching on potential bioavailability of heavy metals in tidal flat soils.
Leaching experiments were conducted to investigate the effects of desalination levels and sediment depths on potential bioavailability of heavy metal (Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn) in tidal flat soils. The data showed that both the desalination levels (p < 0.001) and soil depths (p < 0.001) had significant effects on the concentrations of acid-volatile sulfide (AVS). AVS concentrations generally exhibited increasing trends with an increase in depth and decreasing trends with enhanced desalination levels. The desalination levels had significant (p < 0.05) effects on the concentrations of simultaneously extracted metal (SEM; Cd, Cr, Cu, Fe, Mn, Pb, and Zn). Moreover, the concentrations of SEM (Cd, Cr, Cu, Fe, Mn, Pb, and Zn) generally tended to decrease with an increase in the desalination level. The desalination treatment significantly reduced the ratios of SEM/AVS compared with control. However, the ratios of SEM/AVS increased with enhanced desalination levels in treatments. Results reveal that low desalination treatment is better for reducing toxicity to benthic organisms than high desalination treatment. Since these reclaimed tidal flats with low desalinisation are suitable for saline water aquaculture, transforming the present land use of reclaimed tidal flats from fresh water aquaculture into saline water aquaculture may reduce health risk of heavy metals remained in sediments. These results will also contribute to our understanding of the dynamic behavior of heavy metals in the reclamation of tidal flats during leaching and the role of the ratio of SEM/AVS predictions on assessing the ecological risks of reclaimed tidal flats.


Objective Derivation of the Morphology and Staging of Visual Field Loss Associated with Long-Term Vigabatrin Therapy.
The morphology and between-eye symmetry of the visual field loss associated with the antiepileptic drug vigabatrin (VAVFL) has received little attention. Our objective was to model the appearance and ensuing staging of VAVFL derived with the European Medicines Agency-approved perimetric protocol. This was a retrospective, cross-sectional, observational study that identified 123 adults who had received vigabatrin for refractory seizures and who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality. A further 38 adults with refractory seizures and identical inclusion criteria but no exposure to vigabatrin acted as controls. For each group, the median outcome at each stimulus location in each eye (of absolute loss, relative loss or Pattern Deviation probability level, as appropriate) was derived for each successive ten pairs of fields, ranked for severity. Between-eye symmetry was quantified by an index that accounted for severity of loss and that was referenced to the likelihood of the occurrence of symmetry due to chance. The modelled VAVFL was bilateral and highly symmetrical and was described by six stages that were all independent of the extent of vigabatrin exposure. The loss originated in the extreme temporal periphery and encroached centripetally along all meridians towards fixation. The initial appearance within the central field (Stage 2) occurred inferior-nasally. Subsequent stages exhibited increasing loss, which was greater nasally than temporally. Stage 6 described concentric loss extending to approximately 15° eccentricity from fixation. The model exhibited a consistent pattern of VAVFL. The staging of the loss could assist the risk:benefit analysis of vigabatrin for the treatment of epilepsy.


Treatment of phenol-contaminated soil by Corynebacterium glutamicum and toxicity removal evaluation.
Biodegradation of phenol-contaminated soils using Corynebacterium glutamicum, was optimized in this study. Phenol degradation by C. glutamicum was observed in soil supplemented with 1% yeast extract as a substrate. We determined the optimal inoculation size of C. glutamicum (7.4 log(10) CFU mL(-1)) for the degradation of phenol-contaminated soil. Under optimal conditions (1% yeast extract and 7.4 log(10) CFU mL(-1) of C. glutamicum), the efficiency of phenol degradation in soil was greater than 94% at three days after treatment. The degradation of phenol-contaminated soil by C. glutamicum was evaluated using acute toxicity assays with Daphnia magna. Based on the acute toxicity assays, we found that the residual toxicity of contaminated soil was removed completely after three days of C. glutamicum treatment.


Diabetes and pregnancy.
Despite improvement in perinatal outcome over the past several decades, controversy still exists regarding both the management and pathophysiology of pregnancy complicated by diabetes mellitus. In this article, potential factors contributing to morbidity observed in the offspring of diabetic women are considered. The clinical management of insulin-dependent and gestational diabetes is also discussed.


Exercise-induced stress enhances mammary tumor growth in rats: beneficial effect of the hormone melatonin.
We hypothesized that intense exercise training (forced swimming for 30 min, 5 days/week) may enhance the progression of mammary carcinogenesis through the involvement of stress hormones, such as catecholamines and prolactin, which can promote breast cancer. After the appearance of the DMBA-induced tumors in Sprague-Dawley rats, the effect was evaluated of exercise-induced stress (with or without administration of the hormone melatonin) on the survival time, tumor multiplicity, and tumor growth until the death of the animals. In a second set of experiments, after one month of exercise, the NK cells count in blood, and the plasma concentrations of catecholamines and prolactin were determined. Although no significant change was found in either the survival time of the rats or the tumor multiplicity, exercise significantly increased the tumor growth rate. Stress was confirmed by the enhanced adrenaline and prolactin concentrations in the blood of the exercised rats. Exercise-induced stress did not change the percentage of NK cells in the tumor-bearing rats. Melatonin counteracted the increased tumor growth, returning the prolactin and adrenaline concentrations to their optimal physiological levels in the exercised tumor-bearing rats, thus confirming an "anti-stress" role of this hormone. In conclusion, intense exercise-induced stress enhances mammary carcinogenesis through the involvement of adrenaline and prolactin. The results also confirmed a role of melatonin as a therapeutic aid against breast cancer in general, and in particular during situations of stress.


Regulation of the human biotin transporter hSMVT promoter by KLF-4 and AP-2: confirmation of promoter activity in vivo.
The mechanism of biotin uptake in human intestine has been well characterized and involves the human sodium-dependent multivitamin transporter (hSMVT), yet little is known about the molecular/transcriptional regulation of the system. Previous investigations cloned the 5' regulatory region of the hSMVT gene and identified the minimal promoter. To expand these investigations, we compared activity of the hSMVT promoter in three human intestinal epithelial cell lines (NCM460, Caco-2, and HuTu-80) and contrasted a renal epithelial cell line (HEK-293). We analyzed the role of putative cis-elements in regulating promoter activity and confirmed activity of the cloned hSMVT promoter in vivo. In vitro studies demonstrated that all cell lines utilized the same minimal promoter region, and mutation of specific cis-regulatory elements [Kruppel-like factor 4 (KLF-4) and activator protein-2 (AP-2)] led to a decrease in promoter activity in all intestinal cell types but not in renal cells. Using electrophoretic mobility shift assays, we identified two specific DNA/protein complexes. Using oligonucleotide competition and antibody supershift analysis, we determined that KLF-4 and AP-2 were involved in forming the complexes. In HEK-293 cells, overexpressing KLF-4 increased the endogenous hSMVT message levels threefold and activated a cotransfected hSMVT promoter-reporter construct. In vivo studies using hSMVT promoter-luciferase transgenic mice established physiological relevance and showed the pattern of hSMVT promoter expression to be similar to endogenous mouse SMVT mRNA expression. The results demonstrate, for the first time, the importance of KLF-4 and AP-2 in regulating the activity of the hSMVT promoter in the intestine and provide direct in vivo confirmation of hSMVT promoter activity.


Vascular access: comparison of US guidance with the sonic flashlight and conventional US in phantoms.
To prospectively evaluate whether ultrasonography (US)-guided vascular access can be learned and performed faster with the sonic flashlight than with conventional US and to demonstrate sonic flashlight-guided vascular access in a cadaver. Institutional review board approval and oral and written informed consent were obtained. The sonic flashlight replaces the standard US monitor with a real-time US image that appears to float beneath the skin and is displayed where it is scanned. In studies 1 and 2, participants performed sonic flashlight-guided needle insertion tasks in vascular phantoms. In study 1, 16 participants (nine women, seven men) with no US experience performed 60 simulated vascular access trials with sonic flashlight or conventional US guidance. With analysis of variance (ANOVA) and power-curve fitting, improvement with practice rate and mean differences between techniques and tasks were examined. In study 2, 14 female nurses (mean age, 50.1 years) proficient with conventional US performed simulated vascular access trials on three tasks with the sonic flashlight and conventional US. With random assignment, half the participants used the sonic flashlight first and half used conventional US first. Mean performance with each technique and that with each task were compared by using ANOVA. In study 3, feasibility of sonic flashlight guidance for access to internal jugular and basilic veins was demonstrated in a cadaver. For study 1, learning rates (ie, decrease in access time over trials) did not differ for vascular access with sonic flashlight and conventional US. Overall, participants achieved faster vascular access times with sonic flashlight guidance (P < .007). In study 2, participants performed procedures faster overall with the sonic flashlight (P < .02) and found the sonic flashlight easier to use. In study 3, sonic flashlight-guided vascular access was gained in the cadaver. Learning and performance of vascular access were significantly faster with the sonic flashlight than with conventional US, and vascular access could be gained in a cadaver; the sonic flashlight is ready for clinical trials.


Catheter ablation of incessant ventricular tachycardia: acute and long-term results.
Seventeen patients with incessant ventricular tachycardia refractory to anti-arrhythmic therapy underwent catheter ablation between 1987 and 1993. Fifteen patients had coronary heart disease and two had dilated cardiomyopathy. The mean age of the patients was 65 +/- 8 and the mean left ventricular ejection fraction was 31 +/- 9%. Ablation sites were selected on the basis of endocardial activation mapping, concealed entrainment or bundle branch mapping. Catheter ablation was performed with direct current in nine patients and with radiofrequency energy in eight patients. Incessant ventricular tachycardia was terminated by catheter ablation in all 17 patients. One patient died after the ablation procedure due to pericardial tamponade. During electrophysiological testing 5-14 days later, 7 of 16 patients (44%) had inducible sustained or non-sustained ventricular tachycardia. Five of them underwent implantation of an automatic cardioverter/defibrillator, and three of these experienced discharges of the device during a mean follow-up of 30 +/- 12 months. another patient underwent implantation of a cardioverter/defibrillator after spontaneous recurrence of ventricular tachycardia. Out of the nine patients without inducible ventricular tachycardia, one died as a result of sudden cardiac death, and another had spontaneous ventricular tachycardia. Thus, ventricular tachycardia recurred clinically in 6 of 16 patients (38%), in whom ventricular tachycardia with the same morphology as that of the ablated ventricular tachycardia could be determined only in one patient. Catheter ablation is the method of choice for the emergency treatment of patients with incessant ventricular tachycardia. Due to the high risk of recurrence, additional anti-arrhythmic management, such as the implantation of a cardioverter/defibrillator, has to be considered.


Pulmonary sarcoidosis in the Nordic countries 1950-1982. II. Course and prognosis.
The review is based on studies of pulmonary sarcoidosis from Denmark, Finland and Sweden during 1950-1982, focusing on the course and prognosis of the disease. Cases with acute onset with chest X-ray stage I, fever, arthritis and erythema nodosum had a 85-90% remission rate during the first two years. The overall 5 year remission rate for stage I was 82%, stage II 66% and stage III 30%. Among cases with stage I, 2-5%, and among cases with stage II and III, 6-10% developed chronic pulmonary disease. Patients with stage I had a normal mortality rate, whereas those with stage II, III and IV had a rate threefold higher than expected due to sarcoidosis-related cardiopulmonary complications.


Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features.
Although uterine fibroids are very common, their pathogenesis and clinical behaviour are poorly understood. Since they may be prevalent in some families, we investigated whether such a prevalence was associated with distinctive clinical and molecular features. A case-control questionnaire study of 300 multi-ethnic women with uterine fibroids at a London university hospital was undertaken, with review of case notes and immunohistochemical determination of vascular endothelial growth factor (VEGF-A) in fibroids. When compared with families with sporadic fibroids, familial prevalence of fibroids was associated with a higher incidence of abdominal swelling (59.1% versus 41.6%; P=0.037), menorrhagia (84.4% versus 51.9%; P=0.042), dysmenorrhoea (64.4% versus 46.3%; P=0.004), dyspareunia (43.2% versus 27.9%; P=0.012) and family history of cancers (52.3% versus 32.4%; P<0.01). The fibroids were also more multiple (mean +/- SEM: 7 +/- 0.86 versus 3 +/- 0.42; P<0.011) and strong VEGF-A expression in fibroids was more common in the familial group (64% versus 28%). Racial distribution was the same in both groups (blacks 49%, whites 33.4%, others 18.6%). Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features that differ from those found when fibroids occur sporadically in families.


[Clinical relevance of immunoglobulin M antibody fraction against hepatitis B core antigen (anti-HBc-IgM) (author's transl)].
Forty-four anti-HBc positive patients with various liver diseases were followed up over 2-3 years with enzyme-immunological determinations of the IgM fraction of anti HBc (anti-HBc-IgM). Patients with acute virus hepatitis B (n = 10) had anti-HBc-IgM titres greater than or equal to 10(-3) in the acute phase. In the reconvalescent phase the titre decreased significantly but was still detectable at a level of 10(-1) two years after the onset of the disease. In patients with HBs-antigen positive chronic active hepatitis (n = 25) the anti-HBc-IgM was always detectable when HBe-antigen was positive. Patients with HBe-antigen negative chronic active hepatitis B showed various anti-HBc-IgM findings. Patients with liver diseases not due to hepatitis B virus infections (n = 9) were always anti-HBc-IgM negative. Thus with the help of anti-HBc-IgM determinations acute hepatitis B virus infection can be diagnosed in HBs-antigen negative people. On the other hand it is not suitable for differentiation between acute and chronic hepatitis B infections in HBs-antigen positive persons.


Intracortical 5,7-dihydroxytryptamine depletes brain serotonin concentrations without affecting spontaneous activity.
Microinjections of either 2 or 4 micrograms of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) were made into either the right or left frontal cortex of male rats pretreated with desmethylimipramine. Although both the 2 and 4 micrograms doses produced significant depletions of serotonin concentrations in the cortex and median raphe, neither dose produced a significant increase in spontaneous activity. This is in contrast to our findings with the noradrenergic neurotoxins, 6-hydroxydopamine and DSP-4, which produced hyperactivity following right but not left hemisphere injections. These findings do not rule out the involvement of 5-HT in the asymmetrically elicited hyperactivity but they do suggest some transmitter and neural pathway specificity to the lateralized response to cortical injury.


Characterization of PknC, a Ser/Thr kinase with broad substrate specificity from the cyanobacterium Anabaena sp. strain PCC 7120.
Eukaryotic-like protein Ser/Thr and Tyr kinases have only recently been discovered in prokaryotes. In most cases, their biochemical properties have been poorly characterized. The nitrogen-fixing and heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120 houses a family of eukaryotic-like Ser/Thr kinases. Some of these enzymes are required for cell growth or development under certain conditions. None of them, however, has been shown experimentally to possess Ser/Thr kinase activity. A gene, pknC, encoding a novel putative Ser/Thr kinase was isolated from Anabaena sp. PCC 7120. The recombinant PknC was shown to be phosphorylated on a Thr residue. This phosphorylation was probably due to the autophosphorylation activity of PknC itself because mutation of two amino acid residues within the subdomain II of its catalytic domain eliminated the phosphorylation of PknC. PknC displayed also a Ser kinase activity towards several nonspecific substrates, and the two residues needed for PknC autophosphorylation was equally required for the phosphorylation of other substrates. PknC is thus a Ser/Thr kinase with broad substrate specificity. The activity of PknC is likely to be regulated in vivo in order to limit the spectrum of its substrate specificity.


Structure-activity relationships of novel neuritogenic steroid glycosides from the Okinawan starfish Linckia laevigata.
Six new steroid glycosides, linckosides F-K, and a related metabolite were isolated from the Okinawan blue starfish Linckia laevigata as mimics or enhancers of nerve growth factor (NGF). Their structures and stereochemistry were elucidated by spectroscopic methods and chemical derivatization. Structure-activity relationships suggest that both a carbon branch modified by a pentose at the side chain and 2'-O-methylxylopyranose at C-3 of the aglycon are important for neuritogenic activity.


Heterogeneity of serum peptides with immunoactivity detected by a radioimmunoassay for proinsulin-like growth factor-II E domain: description of a free E domain peptide in serum.
We have reported that normal human sera contain immunoactivity (IA) detected by a RIA directed against the first 21 amino acids of the E domain of proinsulin-like growth factor-II (pro-IGF-II). Marked elevations of E-21 IA were found in the serum of patients with nonislet cell hypoglycemia (NICTH) and patients with renal failure receiving chronic hemodialysis. In this paper we describe some of the properties of the E-21 IA of normal and abnormal sera. The E-21 IA eluted from a calibrated acid Sephadex G-50 column as two major peaks. In normal serum the first major peak had a mol wt (Mr) between 14,000-15,000, and the second peak had a Mr between 5,000-6,000. When E-21 IA from serum of a patient with NICTH was similarly studied, most of the IA was present as a Mr 11,000 peak and only a small amount was present as a 5,000-6,000 Mr peak. In contrast, most of the E-21 IA present in the sera of patients on hemodialysis was present in the smaller molecular form, which eluted from a reverse phase column as a single component. This small Mr peak lacked determinants for the IGF-II monoclonal antibody (Amano), for pooled serum IGF-binding proteins, and for the IGF-I receptors on human placental membranes. We suggest that the 15- and 11-kilodalton peaks represent the glycated and unglycated forms of pro-IGF-II (E-21) reported by others. The glycated form appears to predominate in normal serum, whereas the nonglycated form predominates in the serum of patients with NICTH and renal failure. The 5,000-6,000 Mr E-21 IA probably represents a fragment of the free E domain of pro-IGF-II. Its size is consistent with cleavage of the free E domain between Arg46 and Arg47. The accumulation of this E-21 IA in renal failure is evidence that the kidney has a major role in the clearance of this fragment, which is not accomplished by the membranes used in hemodialysis.


[Torsades de pointes ventricular tachycardia induced by intravenous amiodarone].
The authors report on the case history of a 61 year old woman with hyperthyroidism induced atrial fibrillation, tachycardiomyopathy and congestive heart failure, in whom life threatening ventricular proarrhythmia (torsades de pointes) developed in response to intravenous amiodarone. The patient in a septic state was resuscitated because of ventricular fibrillation. The atrial fibrillation complicated by a high ventricular frequency was slowed down with intravenous amiodarone; additionally, the iodine-containing antiarrhythmic drug was expected to counter thyrotoxicosis. In response to amiodarone (2 x 300 mg), the sinus rhythm was restored, but the excessive post-cardioversion bradycardia led to the development of extreme QT interval prolongation and torsades de pointes ventricular tachycardias that often degenerated into ventricular fibrillation. In connection with this case, the authors survey those electropharmacological and pathophysiological factors which may have played a role in the emergence of ventricular proarrhythmia based on a lengthening of repolarization through the exhaustion of the repolarization reserve.


Activation of the melanocortin-4 receptor mobilizes intracellular free calcium in immortalized hypothalamic neurons.
At least 4% of childhood obesity is due to mutations in the hypothalamic melanocortin-4 receptor. The melanocortin-4 receptor, a seven transmembrane G-protein-coupled receptor, is important in the regulation of feeding behavior and body weight. The specific pathways of intracellular signaling remain in investigative stages. To further understand its function, we hypothesized that the melanocortin-4 receptor activates the Galphaq/phospholipase C signaling pathway, resulting in alterations of cytoplasmic calcium in immortalized hypothalamic (GT1-1) neurons. Changes in intracellular calcium were measured after loading GT1-1 cells with fura-2-AM. Cells were treated with NDP-alphaMSH, an alpha-melanocortin stimulating hormone analogue, and intracellular calcium changes were recorded. Cells treated with NDP-alpha-MSH were also treated with the melanocortin-4 receptor antagonist, SHU-9119. To assess the specific G-protein subunit involved, GT1-1 neurons were treated with the phospholipase C inhibitor U73122 and its inactive analogue, U73433. Experiments were also performed after inhibition of IP3 receptors with 2-aminoethoxydiphenylborate (2APB). Additional experiments were conducted in a calcium-depleted buffer environment. Data were analyzed by ANOVA with statistical significance of P < 0.05. Agonist treatment (0.01-1000 nm) of GT1-1 neurons resulted in dose-dependent increases in intracellular calcium. SHU-9119 (0.01-1000 nm) abolished the calcium response. Treatment with U73122 (10 microm) attenuated the calcium response, while U73433 (10 microm) had minimal effect. 2APB (200 microm) inhibited the calcium transient, and the use of calcium-free buffer did not affect the amplitude of the calcium spike. Our study demonstrates that, upon agonist binding, the melanocortin-4 receptor mediates increases in intracellular calcium through the Galphaq-protein/phospholipase C dependent signaling pathway. Understanding the physiological importance of calcium signaling by the melanocortin-4 receptor may be important for future development of therapeutic targets.


First-Line Systemic Therapy for Metastatic Clear-Cell Renal Cell Carcinoma: Critical Appraisal of Emerging Options.
Until recently, a dichotomy existed in the front-line approach of metastatic clear-cell renal cell carcinoma (mRCC). Specifically, patients received either targeted therapy or immunotherapy. Targeted therapy entailed use of agents blocking signaling through the vascular endothelial growth factor (VEGF) receptor, such as cabozantinib, sunitinib, or pazopanib. Immunotherapy entailed dual therapy with nivolumab and ipilimumab, both checkpoint inhibitors for intermediate/poor International Metastatic RCC Database Consortium (IMDC)-risk disease patients. Within the past year, two datasets have emerged that led to recent approvals of combined therapy with VEGF and checkpoint inhibitors. These regimens (axitinib with either avelumab or pembolizumab) are among several that have been or will be evaluated for patients with newly diagnosed mRCC. We aim to facilitate treatment decisions through this comprehensive and contextualized overview of recent datasets in this therapeutic space.


Fabrication of vascularized and scaffold-free bone tissue using endothelial and osteogenic cells differentiated from bone marrow derived mesenchymal stem cells.
Over-dependence on existing synthetic scaffolds and insufficient vascularization limit the development of tissue engineered bone (TEB). The purpose of this study is to fabricate vascularized and scaffold-free bone tissue using cell sheet technology and to assess its feasibility to repair critical-sized calvarial defects in rats. Firstly, the pre-vascularized cell sheet was formed by seeding BMSC-derived endothelial cells (ECs) on an undifferentiated BMSCs cell sheet layer in vitro. After 3 days of co-culture, ECs migrated and rearranged to form lumens on the BMSC sheet. Secondly, osteogenic cell sheet was formed by inducing osteogenic differentiation of high density BMSCs. Then, the pre-vascularized cell sheet was stacked on BMSC-derived osteogenic cell sheet to fabricate a scaffold-free construct for bone regeneration. Finally, the scaffold-free construct with both angiogenic and osteogenic potential was implanted into critical-sized calvarial defects in adult Wistar rats. Results showed that more functional perfused blood vessels and new bone tissue formed in the pre-vascularized group than that in the controls (both empty and non-pre-vascularized cell sheet group). This study indicates a new promising strategy for bone tissue regeneration.


Mycobacterium psychrotolerans sp. nov., isolated from pond water near a uranium mine.
An acid-fast, rapidly growing, psychrotolerant short rod was isolated from pond water near a uranium mine. Phylogenetic analysis of the 16S rRNA gene sequence grouped this strain with the rapidly growing mycobacteria. The 16S rRNA gene sequence of isolate WA101T showed highest similarity to that of Mycobacterium sphagni DSM 44076T; however, DNA-DNA relatedness between the two strains was less than 30 %. Chemotaxonomic analyses, which included fatty acid and mycolic acid patterns, confirmed the classification of strain WA101T in the genus Mycobacterium. Physiological data, including antibiotic resistance, NaCl tolerance, carbon sources, temperature growth range and enzyme activities, were also determined. Based on the genotypic and phenotypic results it is proposed that isolate WA101T represents a novel Mycobacterium species. The name Mycobacterium psychrotolerans sp. nov. is proposed, with type strain WA101T (= DSM 44697T = LMG 21953T).


Plant powder teabags: a novel and practical approach to resolve culturability and diversity of rhizobacteria.
We have developed teabags packed with dehydrated plant powders, without any supplements, for preparation of plant infusions necessary to develop media for culturing rhizobacteria. These bacteria are efficiently cultivated on such plant teabag culture media, with better progressive in situ recoverability compared to standard chemically synthetic culture media. Combining various plant-based culture media and incubation conditions enabled us to resolve unique denaturing gradient gel electrophoresis (DGGE) bands that were not resolved by tested standard culture media. Based on polymerase chain reaction PCR-DGGE of 16S rDNA fingerprints and sequencing, the plant teabag culture media supported higher diversity and significant increases in the richness of endo-rhizobacteria, namely Gammaproteobacteria (Enterobacteriaceae) and predominantly Alphaproteobacteria (Rhizobiaceae). This culminated in greater retrieval of the rhizobacteria taxa associated with the plant roots. We conclude that the plant teabag culture medium by itself, without any nutritional supplements, is sufficient and efficient for recovering and mirroring the complex and diverse communities of rhizobacteria. Our message to fellow microbial ecologists is: simply dehydrate your plant canopy, teabag it and soak it to prepare your culture media, with no need for any additional supplementary nutrients.


Quadriceps activity and physical activity profiles over long durations in patients with osteoarthritis of the knee and controls.
Exercise is recommended as a non-pharmacological, non-invasive intervention for osteoarthritis (OA) of the knee. Physiological data concerning the duration and intensity of muscle activity or physical activity profiles during normal daily activity for this population is lacking. Our aim was to explore this using surface Electromyography (EMG) and accelerometer-based activity monitoring. Thirty-four patients with knee OA, mean (SD) age 63.2 (9.8) years and 30 aged-matched asymptomatic controls 64.1 (10.9) years participated. The duration of recording was similar in knee OA and control groups - median (IRQ range) 12:34 (10:11-14:17)h and 13:10 (12:02-14:56)h, respectively (p=0.514). VM and VL were quiescent for 81.8 (75.3-91.0) to 89.2 (81.5-94.7)% of the time. VM was active for significantly longer durations than VL in the highest intensity band for those with knee OA (p=0.00), and for longer durations in those with knee OA compared to controls (p=0.027). The median (IRQ range) percentage of the total recording time spent in an upright posture was 32.4 (28.3-43.9)% and 38.8 (33.6-45.8)%, and time spent stepping or walking was 12.7 (9.7-16.4)% and 16.0 (11.9-19.6)% for those with knee OA and controls respectively. These novel data may prove useful for designing therapeutic exercise programmes and lifestyle changes for those with knee OA.


Effects of advanced glycosylation endproducts on perlecan core protein of glomerular epithelium.
Perlecan is one of major heparan sulfate proteoglycans in the glomerular basement membrane and is reduced in the renal parenchyma of diabetic patients and animals with proteinuria. To examine the effects of glucose and advanced glycosylated end-products (AGE) on perlecan, we cultured rat glomerular epithelial cells (GEpC) on AGE- or bovine serum albumin (BSA)-coated plates under normal (NG, 5 mM) and high-glucose (HG, 30 mM) conditions and measured the change in perlecan core protein production by a sandwich ELISA and northern blot analysis. We observed significant decreases of perlecan core protein under HG conditions at 1 week incubation, specifically on the AGE-coated compared with the BSA-coated surface, by 22.2% and 4.7%, respectively. The expression of mRNA for perlecan promoter was decreased under HG conditions on AGE-coated surfaces by 19.7% at 2 days and 61.1% at 1 week. Even under NG condition, the expression of mRNA was reduced by 30% at 1 week if GEpC were grown on an AGE-coated surface. In conclusion, HG and AGE have an additive effect in reducing the production of perlecan core protein by GEpC in vitro. AGE had a greater effect than HG, implying that the inhibition of AGE formation may be more effective than short-term glucose control in the prevention of diabetic proteinuria.


Distribution and Population of Free-Living Cells Related to Endosymbiont A Harbored in Oligobrachia mashikoi (a Siboglinid Polychaete) Inhabiting Tsukumo Bay.
Beard worms (Siboglinidae, Polychaeta), which lack a mouth and a digestive tract, harbor thioautotrophic or methanotrophic bacteria in special cells called bacteriocytes. These endosymbionts have been considered to be trapped at a specific larval stage from the environment. Although many species of beard worms have been discovered in various abyssal seas, Oligobrachia mashikoi inhabits Tsukumo Bay which is only 25 m deep. At least seven types of endosymbionts (endosymbiont A-G) have been distinguished in O. mashikoi. In this study, we investigated the distribution pattern of free-living cells related to the major endosymbiont (endosymbiont A) in Tsukumo Bay by quantitative PCR targeting the 16S rRNA gene. The endosymbiont A-related phylotype was detected in almost all sediment samples collected from 23 points in Tsukumo Bay, ranging in copy number of the 16S rRNA gene from 2.22×10(4) to 1.42×10(6) copies per gram of dry-sediment. Furthermore, the free-living cells made up less than 9% of the total eubacterial population, suggesting that the O. mashikoi larvae precisely select candidates for their endosymbiont from bacterial flora in the environment. This is the first report on the ecological characterization of a free-living bacterium related to the endosymbiont of the siboglinid polychaete, O. mashikoi.


Endovascular Treatment of Intracranial Aneurysms: Long-Term Follow-up.
Endovascular treatment of intracranial aneurysms is increasingly used and has evolved as an alternative to surgical clipping. However, its long-term efficacy has yet to be established. This retrospective hospital based (tertiary teaching hospital) study aimed to identify factors that might be important in predicting initial efficacy of this treatment and a long-term follow-up to study the clinical and angiographic results of treated aneurysms. A total of 80 aneurysms in 78 patients were treated and analyzed, and the percentage of occlusion calculated. Overall, 51/80 (64 %) cases were treated with selective endovascular coil occlusion and 29/80 (36 %) by parent artery occlusion. The shape of the aneurysm rest was noted on the immediate post treatment and follow-up angiograms. Immediate and follow-up clinical status was also noted using the Glasgow outcome scale. The clinical and radiological changes on follow-up were assessed and possible factors involved were analyzed. Of the 50 patients of intracranial aneurysms that underwent selective aneurysm coiling, good immediate outcome (Glasgow outcome scale 1 and 2) was seen in 36/50 (72 %) cases. Narrow necked aneurysms showed a good immediate result (90-100 % packing) in all cases 28/28 (100 %). Amongst the wide necked aneurysms, good packing (90-100 %) was achieved in 17/23 (73 %) cases. Amongst the cases treated with parent artery occlusion, complete occlusion was noted in 20/29 (69 %) cases. No subarachnoid hemorrhage was seen in any of the followed up cases of coiled aneurysms. A statistically significant relationship was noted between aneurysm neck size and immediate angiographic outcome. Long-term angiographic recurrences were found more often in large aneurysms. Endovascular treatment of intracranial aneurysms is a safe and effective treatment modality that offers protection from recurrent subarachnoid hemorrhage.


Deletion of EphA4 enhances deafferentation-induced ipsilateral sprouting in auditory brainstem projections.
Axonal selection of ipsilateral and/or contralateral targets is essential for integrating bilateral sensory information and for coordinated movement. The molecular processes that determine ipsilateral and contralateral target choice are not fully understood. We examined this target selection in the developing auditory brainstem. Ventral cochlear nucleus (VCN) axons normally project to the medial nucleus of the trapezoid body (MNTB) only on the contralateral side. However, after unilateral removal of cochlear input in neonates, we found that axons from the unoperated VCN sprout and project to MNTB bilaterally. We found that EphA4 is expressed in the mouse auditory brainstem during development and during a sensitive period for ipsilateral sprouting, so we hypothesized that deletion of the Eph receptor EphA4 would impair target selection in these auditory pathways. Lipophilic dyes were used to evaluate quantitatively the brainstem projections in wild-type and EphA4-null mice. VCN-MNTB projections in EphA4-null mice were strictly contralateral, as in wild-type mice. However, after deafferentation, EphA4-null mice had a significant, threefold increase in the proportion of axons from the intact VCN that sprouted into ipsilateral MNTB compared with wild-type mice. Heterozygous mice had a twofold increase in these projections. These results demonstrate that EphA4 influences auditory brainstem circuitry selectively in response to deafferentation. Although this axon guidance molecule is not by itself necessary for appropriate target choice during normal development, it is a strong determinant of ipsilateral vs. contralateral target choice during deafferentation-induced plasticity.


Interleukin-10 in combination with interferon-gamma and tumor necrosis factor-alpha enhances in vitro production of nitric oxide by murine resident paritoneal macrophage.
Resident peritoneal macrophages obtained from CBA/J mice were cultured in the presence of recombinant interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10). IFN-gamma-stimulated nitric oxide (NO) formation, IL-10 substantially enhanced the production of NO generated by IFN-gamma + TNF-alpha, irrespective of the timing and dosing of any of the three cytokines. Increased levels of iNOS mRNA after the triple combination of IFN-gamma + TNF-alpha + IL-10 versus IFN-gamma + TNF-alpha suggest that the NO-enhancing effect is mediated, at the least partially, at the transcriptional level. Collectively, the present data support the view that IL-10 is not a general macrophage deactivating factor or a suppressor of gene expression.


Perioperative death in Malaysia: the transition phase from a developing nation to a developed one.
This paper examines the surgical pathology associated with perioperative deaths in a country that is undergoing the transition from a developing to a developed nation status. The data from an ongoing nation-wide perioperative mortality study was prospectively collected for the period July 1996 to December 1997 and analyzed. The surgical pathology related to perioperative deaths in Malaysia is different from other developing and developed countries. While death from trauma and the late presentation of surgical conditions are similar to developing countries, infective gastrointestinal conditions were rarely encountered. Diseases associated with advanced age such as colorectal cancer, peptic ulcer, urological diseases and vascular conditions are beginning to emerge. As the country races towards a developed nation status, increasing life expectancy and changing life-styles are expected to influence the disease pattern. The planning of surgical facilities and manpower development must recognize the changes taking place.


Lipocalin-2 contributes to experimental atherosclerosis in a stage-dependent manner.
Lipocalin-2 (Lcn2) is a glycoprotein which can be secreted by immune cells. Several studies in humans have suggested Lcn2 can be used as a biomarker for the detection of unstable atherosclerotic lesions, partly as it is known to interact with MMP-9. In this study, we generated Ldlr-/-Lcn2-/- mice to assess the functional role of Lcn2 in different stages of atherosclerosis. Atherosclerotic lesions were characterized through histological analysis and myeloid cell populations were examined using flow cytometry. We show that Ldlr-/-Lcn2-/- mice developed larger atherosclerotic lesions during earlier stages of atherosclerosis and had increased circulating Ly6Chi inflammatory monocytes compared to Ldlr-/- mice. Advanced atherosclerotic lesions from Ldlr-/-Lcn2-/- mice had decreased necrotic core area, suggesting Lcn2 deficiency may affect lesion stability. Furthermore, MMP-9 activity was diminished in plaques from Ldlr-/-Lcn2-/- mice. Altogether, these findings suggest that Lcn2 deficiency promotes lesion growth in earlier stages of the disease while it decreases MMP-9 activity and necrotic core size in advanced atherosclerosis.


Effect of hepatitis C virus treatment in fibrosis progression rate (FPR) and time to cirrhosis (TTC) in patients co-infected with human immunodeficiency virus: a paired liver biopsy study.
Patients with hepatitis C and human immunodeficiency virus coinfection have rapid fibrosis progression. The effect on fibrosis progression rate and time to cirrhosis of HCV treatment has not been extensively studied. First aim of the study was to assess changes in FPR and TTC and staging after HCV therapy vs. no treatment. Secondary aim was to study changes in FPR/staging of sustained viral responders and non-responders to Peg-IFN alfa-2a and RBV. Seventy-four (74) co-infected patients were grouped in three according to HCV treatment, Group 1 - None (n=9), Group 2 - IFN (n=30), Group 3-Peg-IFN alfa-2a (n=35). Paired liver biopsies were analyzed and FPR/TTC calculated for each biopsy. Baseline characteristics, duration of treatment and time between biopsies were similar among groups. HCV therapy, improved grading, but only Peg-IFN alfa-2a therapy resulted in staging decrease. Group 2 had significant staging increase and Group 1 had doubling of FPR and (TTC) reduction from 22.7 to 9.09 years. Peg-IFN alfa-2a treated patients had negative change in FPR and stabilization in TTC. SVR and NR with Peg-IFN alfa-2a/RBV had same FPR and staging. In patients with HIV/HCV co-infection Peg-IFN alfa 2a based treatment produced regression or stable fibrosis in contrast to accelerated progression in those without treatment.


Pattern of bacterial flora in local genital skin and surgical wounds in children undergoing hypospadias repair: a preliminary study.
To evaluate the pattern of bacterial flora in children undergoing hypospadias repair, the following swabs were sent for 60 consecutive subjects: perimeatal swabs at admission and immediately before surgical scrub, and intraoperative and postoperative wound swabs (after the first change of operative dressing). A pure or predominant growth of organism that was not part of the local flora was labelled 'infection'. The peak incidence of infection (53%) was detected in swabs taken at admission. This decreased to 30% in immediately preoperative skin swabs, following local preparations. Coliforms and Staphylococcus aureus were the most commonly grown pathogens and were sensitive to cephalosporin and aminoglycoside. Proximity to the anus, poor personal hygiene in our study subjects (who were of low socioeconomic status) and the high temperature and humidity in our geographic region probably led to the high incidence of infection. The authors feel that the results of preoperative perimeatal swabs could help dictate antibiotic therapy in patients awaiting hypospadias repair.


Prognostic factors and oncological outcomes of ovarian yolk sac tumors: a retrospective multicentric analysis of 99 cases.
To investigate the clinico-pathological prognostic factors and treatment outcomes in patients with ovarian yolk sac tumors (YST). A multicenter, retrospective department database review was performed to identify patients with ovarian YST who underwent surgery between 2000 and 2017 at seven Gynecologic Oncology Centers in Turkey. The study group consisted of 99 consecutive patients with a mean age of 23.9 years. While 52 patients had early stage (stage I-II) disease, the remaining 47 patients had advanced stage (stage III-IV) disease. The uterus was preserved in 74 (74.8%) of the cases. The absence of gross residual disease following surgery was achieved in 76.8% of the cases. Of the 54 patients with lymph node dissection (LND), lymph node metastasis was detected in 10 (18.5%) patients. Of the 99 patients, only 3 patients did not receive adjuvant therapy, and most of the patients (91.9%) received BEP (bleomycin, etoposide, cisplatin) chemotherapy. Disease recurred in 21 (21.2%) patients. The 5-year disease-free survival (DFS) and overall survival (OS) in the entire cohort were 79.2% and 81.3%, respectively. In multivariate analysis, only residual disease following initial surgery was found to be significantly associated with DFS and OS in patients with ovarian YST (p = 0.026 and p = 0.001, respectively). Our results demonstrate the significance of achieving no visible residual disease in patients with ovarian YST. Fertility-sparing approach for patients with no visible residual disease affected neither DFS nor OS. Although high lymphatic involvement rate was detected, the benefit of LND could not be demonstrated.


Selective noradrenaline reuptake inhibition enhances serotonergic neuronal activity and transmitter release in the rat forebrain.
Present pharmacotherapy of major depression is, in principle, based on enhancement of central monoaminergic neurotransmission. Clinical studies utilizing depletion experiments indicate that antidepressants which primarily enhance serotonergic or noradrenergic central activity, i.e. serotonin or nor-adrenaline reuptake inhibitors, largely work by two separate neuronal pathways. However, experimental studies have shown that noradrenaline may regulate serotonergic neurotransmission both at the serotonin cell body and nerve-terminal level. We therefore investigated the effects of the selective NRI reboxetine on serotonergic neuronal activity and extracellular levels of transmitter in the nerve-terminal area. In vivo electrophysiological experiments showed that low doses of reboxetine significantly enhance the firing rate of serotonergic neurons in the dorsal raphe nucleus of anaesthetized rats. Also, in the medial prefrontal cortex reboxetine (3 mg/kg s.c.) enhanced, whereas citalopram (3 mg/kg s.c.) reduced, extracellular concentrations of serotonin measured by means of microdialysis in awake rats, using a low dose of citalopram (0,5 micro M) in the perfusion solution. Local administration of reboxetine only induced an increase in cortical serotonin levels at very high concentrations (1000 micro M). Hence, NRIs may cause a secondary enhancement of central serotonergic activity by a mechanism separate from 5-HT reuptake inhibition; an effect that may contribute to their clinical antidepressant efficacy.


Development and validation of a stability-indicating HPLC method for the simultaneous determination of losartan potassium, hydrochlorothiazide, and their degradation products.
Losartan potassium was the first in a new class of potent angiotensin II receptor antagonists which are well-tolerated in the treatment of hypertension. Losartan potassium is the active ingredient in tablets COZAAR and is combined with diuretic co-active hydrochlorothiazide (HCTZ) in tablets HYZAAR for increased efficacy. Losartan potassium has one main impurity and two primary degradates. HCTZ has one major degradate as well as two common process impurities. Historically, separate methods have been used for the analysis of each active and their respective impurities and degradates. The ultimate goal of this work was to develop and validate a single high-performance liquid chromatography method selective for the eight main components of tablets HYZAAR. A single method was developed to afford simultaneous quantitation of actives and degradates for each of the two existing formulations. Each method is presented herein and demonstrated to be suitable for quantitation to 0.1% levels of all relevant degradates, as well as 100% levels of respective drug substances.


Contextualizing older women's body images: Time dimensions, multiple reference groups, and age codings of appearance.
The article sheds light on older women's body images and problematizes assumptions that women's aging is more painful and shameful than men's aging since men are not expected to live up to youthful beauty norms, the so-called double standard of aging hypothesis. Based on 12 qualitative interviews with women from the age of 75 from the Swedish capital area, I argue that older women have access to a double perspective of beauty, which means that they can relate to both youthful and age-related beauty norms. The results also illustrate that women's body image is created in a context where previous body images are central and that this time perspective can contribute toward a positive body image. Further, the results show how age codings of appearance-related qualities create a narrow framework for older women's body images and point to the benefits of shifting the analytical focus toward a material-semiotic body where corporeality and discourse are seen as interwoven.


Sensitivity to fairness and intentions of others in the ultimatum game in patients with ventromedial prefontal lesions.
This study aimed to examine the relationship between perspective-taking and impaired decision-making in patients with ventromedial prefrontal (VM) lesions, using the Ultimatum Game (UG). In the UG, two players split a sum of money and one player proposes a division while the other can accept or reject this. Eight patients with VM damage and 18 healthy controls participated as responders in a modified version of the UG, in which identical offers can generate different rejection rates depending on the other offers available to the proposer. Participants had to either accept or reject offers of 2:8 NIS (2NIS for them and 8 NIS for the proposer), which were paired with one of four different possible offers (5:5, 4:6, 2:8, 8:2). Results indicate that the controls more often rejected offers of 2:8 when the alternative was 4:6 (a greedy alternative) than when the alternative was 5:5 (fair alternative), whereas the VM patients showed the opposite pattern of decision-making. Additionally, the overall rejection rates were higher in patients as compared to controls. Furthermore, scores on a perspective-taking scale were negatively correlated with rejection rates in the patient group, suggesting that perspective-taking deficits may account for impaired decision-making in VM patients.


Brain (A) symmetry in monozygotic twins.
Origin and ontogenesis of human brain laterality are unknown. Using in vivo magnetic resonance morphometry we measured cerebral hemispheric asymmetry of the planum temporale, a structural substrate of functional laterality, in pairs of monozygotic twins concordant or discordant for handedness. In both groups, intraclass (i.e., within twin pair) correlations were low. The right-handers showed leftward asymmetry whereas the left-handers lacked asymmetry. The discordance for lateralized brain anatomy can be accounted for by ontogenetic models assuming twinning of an asymmetrical germ or differential action of nongenetic factors within twin pairs in utero. The findings confirm a coupling of lateralized structure and function of the human brain. At least in monozygotic twins, early epigenetic factors must play a role in anatomofunctional laterality development.


[Changes in the wrist joint in spontaneous course of scaphoid pseudarthrosis].
Scaphoid non-union always leads to carpal arthrosis. What is the natural history and course and sequence of development of arthrosis in scaphoid bone pseudarthrosis and what factors play a role in this? Forty-nine patients with scaphoid non-union were followed up; the period of observation was between three and 39 years. For comparison, 55 patients in whom a Matti-Russe reconstruction had been carried out successfully in the same period were followed up. Both the clinical and the radiological appearance seemed to be better in the operated patients than in the unoperated patients. The time factor, the position and form of the fracture appeared to be crucial for the development of arthrosis. No patient was free of arthrosis after ten years. The arthrosis begins in the radial part of the radiocarpal joint and progresses to the mediocarpal joint. The development of mediocarpal arthrosis takes about 20 years. Unstable and displaced fractures accelerate the development of arthrosis. Proximally located non-unions are unfavorable because of the danger of osteonecrosis of the proximal fragment. These non-unions should be treated surgically as soon as possible.


Differential effects of the computer-tailored FATaintPHAT programme on dietary behaviours according to sociodemographic, cognitive and home environmental factors.
To explore whether the effects on dietary behaviours of a computer-tailored intervention aimed to prevent excessive weight gain among adolescents, FATaintPHAT, were moderated by sociodemographic, cognitive and home environmental factors. A two-group cluster randomized trial. Potential moderation of the outcome measures (consumption of sugar-sweetened beverages, snacks, fruits and vegetables) was studied by gender, education level, ethnicity, awareness of risk behaviour, intention and home availability. Twenty schools in the Netherlands. Students (n 883) aged 12-13 years. Of the twenty-four interactions tested, only three were significant. The intervention effect on sugar-sweetened beverages was moderated by level of education (P = 0·009); intervention effects were found only among academic preparatory students. The intervention effects on fruit and vegetable intake were moderated by awareness of fruit intake (P < 0·001) and home availability of vegetables (P = 0·007); an effect on fruit intake was found only among students who were aware of their low fruit intake at baseline and an effect on vegetable consumption was found only among students who reported that vegetables were always available at their home. The effects of the intervention generally did not differ between sociodemographic subgroups. The moderation by home availability illustrates that the environment may influence the effects of educational interventions.


Confidence interval reporting for measures of association in multivariable regression models in observational studies.
To assess the adherence to reporting confidence intervals (CI) for measures of association in multivariable regression models (MRM) in articles with observational design indexed in MEDLINE. A literature search was conducted using the MEDLINE bibliographic database to obtain a representative sample of studies with observational design and applying MRM (logistic, linear, and Cox regression) (n=428). Proportions and 95% CI of articles reporting CI for measures of association in MRM were calculated. Percentage ratios (PRs) were also calculated to describe the change in CI reporting before and after the publication of the STROBE statement. 188 of the 236 abstracts with measures of association (79.7%; 95% CI 74.5, 84.8) and 360 of the 428 main texts (84.1%; 80.6, 87.6) were provided with CI. A non-significant increase of 1% in the abstract, PR=1.01 (0.77, 1.29), and 7% in the main text, PR=1.07 (0.87, 1.28), occurred in the CI reporting after the publication of the STROBE guideline. The STROBE guideline recommendation on reporting CI should be more thoroughly followed.


The registration of slow ERG potentials of the perfused extracorporeal bull's eye.
Enucleated bull's eyes were perfused with blood and ERG recorded, with special attention paid to the slow components. When the blood flow was interrupted, the ERG components vanished in the following order: b wave, c wave, off-effect (d wave), and a wave. When the perfusion was continued afterward, we saw a variation in the standing potential that hinted at the biochemical activities causing slow electrical potentials of the retina.


Sodium butyrate attenuates soybean oil-based lipid emulsion-induced increase in intestinal permeability of lipopolysaccharide by modulation of P-glycoprotein in Caco-2 cells.
Down-regulation of intestinal P-glycoprotein (P-gp) by soybean oil-based lipid emulsion (SOLE) may cause elevated intestinal permeability of lipopolysaccharide (LPS) in patients with total parenteral nutrition, but the appropriate preventative treatment is currently limited. Recently, sodium butyrate (NaBut) has been demonstrated to regulate the expression of P-gp. Therefore, this study aimed to address whether treatment with NaBut could attenuate SOLE-induced increase in intestinal permeability of LPS by modulation of P-gp in vitro. Caco-2 cells were exposed to SOLE with or without NaBut. SOLE-induced down-regulation of P-gp was significantly attenuated by co-incubation with NaBut. Nuclear recruitment of FOXO 3a in response to NaBut was involved in P-gp regulation. Transport studies revealed that SOLE-induced increase in permeability of LPS was significantly attenuated by co-incubation with NaBut. Collectively, our results suggested that NaBut may be a potentially useful medication to prevent SOLE-induced increase in intestinal permeability of LPS.


A calorimetric study on the low temperature dynamics of doped ice V and its reversible phase transition to hydrogen ordered ice XIII.
Doped ice V samples made from solutions containing 0.01 M HCl (DCl), HF (DF), or KOH (KOD) in H(2)O (D(2)O) were slow-cooled from 250 to 77 K at 0.5 GPa. The effect of the dopant on the hydrogen disorder --> order transition and formation of hydrogen ordered ice XIII was studied by differential scanning calorimetry (DSC) with samples recovered at 77 K. DSC scans of acid-doped samples are consistent with a reversible ice XIII <--> ice V phase transition at ambient pressure, showing an endothermic peak on heating due to the hydrogen ordered ice XIII --> disordered ice V phase transition, and an exothermic peak on subsequent cooling due to the ice V --> ice XIII phase transition. The equilibrium temperature (T(o)) for the ice V <--> ice XIII phase transition is 112 K for both HCl doped H(2)O and DCl doped D(2)O. From the maximal enthalpy change of 250 J mol(-1) on the ice XIII --> ice V phase transition and T(o) of 112 K, the change in configurational entropy for the ice XIII --> ice V transition is calculated as 2.23 J mol(-1) K(-1) which is 66% of the Pauling entropy. For HCl, the most effective dopant, the influence of HCl concentration on the formation of ice XIII was determined: on decreasing the concentration of HCl from 0.01 to 0.001 M, its effectiveness is only slightly lowered. However, further HCl decrease to 0.0001 M drastically lowered its effectiveness. HF (DF) doping is less effective in inducing formation of ice XIII than HCl (DCl) doping. On heating at a rate of 5 K min(-1), kinetic unfreezing starts in pure ice V at approximately 132 K, whereas in acid doped ice XIII it starts at about 105 K due to acceleration of reorientation of water molecules. KOH doping does not lead to formation of hydrogen ordered ice XIII, a result which is consistent with our powder neutron diffraction study (C. G. Salzmann, P. G. Radaelli, A. Hallbrucker, E. Mayer, J. L. Finney, Science, 2006, 311, 1758). We further conjecture whether or not ice XIII has a stable region in the water/ice phase diagram, and on a metastable triple point where ice XIII, ice V and ice II are in equilibrium.


A bifurcated molecular pentad capable of sequential electronic energy transfer and intramolecular charge transfer.
An extended molecular array, comprising three distinct types of chromophores and two additional redox-active subunits, that harvests photons over most of the visible spectral range has been synthesized and characterised. The array exhibits a rich variety of electrochemical waves when examined by cyclic voltammetry but assignment can be made on the basis of control compounds and molecular orbital calculations. Stepwise electronic energy transfer occurs along the molecular axis, corresponding to a gradient of excitation energies, to populate the lowest-energy excited state of the ultimate acceptor. The latter species, which absorbs and emits in the far-red region, enters into light-induced charge transfer with a terminal amine group. The array is relatively stable under illumination with white light but degrades slowly via a series of well-defined steps, the first of which is autocatalytic. One of the main attributes of this system is the capability to harvest an unusually high fraction of sunlight while providing protection against exposure to UV light.


Involvement of DNA polymerase beta in proliferation of rat liver induced by lead nitrate or partial hepatectomy.
We have studied the expression pattern of DNA polymerase beta in two different models of in vivo cell proliferation. Both mRNA levels and enzyme activity of DNA polymerase beta markedly increased before and/or during DNA synthesis in proliferating hepatocytes in mitogen-treated and partially hepatectomized rats. The time-courses of the expression of the gene coding for DNA polymerase beta were significantly different in the two cell systems. A 5-fold increase in DNA polymerase beta mRNA was observed 8 h after lead nitrate administration, i.e. well before the onset of DNA synthesis. In the regenerative liver cells a 3-fold increase in the amount of mRNA was observed 24-48 h after partial hepatectomy, the event being coincident with extensive DNA synthesis. In both systems, the increase of mRNA levels was always paralleled by an increase in enzyme activity, suggesting that DNA polymerase beta activity may be regulated at a pre-translational level.


Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex.
A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.


Physical recovery after acute myocardial infarction: positive age self-stereotypes as a resource.
We considered whether positive and stable self-stereotypes of stigmatized group members can influence functioning (in contrast, stereotype threat theory suggests these influential self-stereotypes are limited to ones that are negative and situational). Specifically, we examined older individuals' positive age stereotypes after a life-threatening event, an acute myocardial infarction (AMI). Sixty-two persons, aged 50 to 96, participated. As expected, positive age stereotypes were found, even immediately after an AMI, and they did not significantly change over the next seven months. Also as expected, these self-stereotypes predicted physical recovery, after adjusting for potentially relevant covariates. Recovery expectations acted as a mediator. These findings suggest the importance of understanding the role that positive stereotypes may play in the health of stigmatized group members.


Should we be screening for colorectal cancer?
Mass population screening for asymptomatic neoplastic disease is now national policy in the UK for breast cancer and has been established for many years in the early diagnosis of carcinoma of the cervix. Cancer screening is based on the concept that treatment is more effective when the disease is localised and aims to detect it when it is at a less advanced clinico-pathological stage prior to the development of symptoms. Because colorectal cancer develops in benign adenomatous polyps which are often amenable to endoscopic resection, screening may both reduce the incidence of the disease as well as improving outcome from it. Flexible sigmoidoscopy screening focuses mainly on the detection of potentially malignant adenomas, their endoscopic removal producing a decrease in colorectal cancer incidence. It is a promising approach but conclusive data on effectiveness from a Medical Research Council-sponsored multicentre randomised controlled trial will not be available before 2006. Faecal occult blood testing aims to preferentially detect early stage invasive disease. Three randomised controlled trials of faecal occult blood screening show that the disease can be detected earlier in its development leading to reduced mortality from the disease--and that this is achieved at reasonable cost. The Department of Health is currently giving consideration to its national implementation.


Examination of rotational fixation of the femoral component in total hip arthroplasty. A mechanical study of micromovement and acoustic emission.
Rotational loosening has recently emerged as an important cause of failure of the femoral component of total hip arthroplasties. This study was designed to investigate the role played by torsional loads in loosening of cementless femoral components and to evaluate three cementing techniques involving a combination of canal irrigation, manual insertion, and vacuum mixing combined with pressure injection of the cement for their ability to improve rotational fixation. Rotational micromotion and subsidence were measured in 24 preserved human anatomic specimen femora. Acoustic emission (AE) technique was applied as a non-destructive method for evaluating material failure during loading. From the micromovement data, torque to 50 mu subsidence and torque to failure were surprisingly low with cementless fixation and with poor cement technique but were markedly improved with pulsed irrigation. Further improvement was achieved by pressure injection and vacuum mixing of the cement. However, AE was detected even in the most carefully performed cement specimens under torsional-loading conditions commonly occurring in daily activities. These signs of microfailure of the cement mantle at relatively low torsional loads suggest that the mode of failure of deeply penetrated cement is by microfracture of the cement mantle. The poor performance suggests that cementless fixation of intramedullary stems provides unsatisfactory fixation against torsional loading. There is need for major improvements in fixation mechanisms and techniques. The signs of failure of the cement mantle at normally occurring torsional loads suggest that even the best cement technique is prone to failure in torsion when exposed to normal daily use.


Use of the intramuscular route to administer pentamidine isethionate in Leishmania guyanensis cutaneous leishmaniasis increases the risk of treatment failure.
New world cutaneous leishmaniasis (NWCL) can be found in French Guiana as well as in several other parts of Central and South America. Leishmania guyanensis accounts for nearly 90% of cases in French Guiana and is treated with pentamidine isethionate, given by either intramuscular or intravenous injection. The military population is particularly exposed due to repeated missions in the rainforest. The purpose of the present study was to identify the factors associated with pentamidine isethionate treatment failure in a series of service members with L. guyanensis NWCL acquired in French Guiana. All the French service members reported as having acquired leishmaniasis in French Guiana from December 2013 to June 2016 were included. Seventy-three patients infected with L. guyanensis were included in the final analysis. Patients treated with IV pentamidine isethionate had better response rates than those treated with IM pentamidine isethionate (p = 0.002, adjusted odds ratio (AOR) = 0.15, 95% CI [0.04-0.50]). The rate of treatment success was 85.3% (95% CI [68.9-95.0]) for IV pentamidine isethionate and 51.3% (95% CI [34.8-67.6]) for IM pentamidine isethionate. The use of intramuscular pentamidine isethionate in the treatment of Leishmania guyanensis cutaneous leishmaniasis is associated with more treatment failures than intravenous pentamidine isethionate.


Fulminant peripartum cardiomyopathy rescue with extracorporeal membranous oxygenation.
We report the successful use of extracorporeal membranous oxygenation in a previously healthy parturient with fulminant peripartum cardiomyopathy. Native cardiac function recovered rapidly, with weaning from extracorporeal membranous oxygenation after only 68 h. This case highlights the potential of this lifesaving treatment, in appropriately selected patients, where death seems inevitable. No major complications of extracorporeal membranous oxygenation occurred in this patient.


Intrinsic dynamics in neuronal networks. II. experiment.
Neurons in many regions of the mammalian CNS remain active in the absence of stimuli. This activity falls into two main patterns: steady firing at low rates and rhythmic bursting. How these firing patterns are maintained in the presence of powerful recurrent excitation, and how networks switch between them, is not well understood. In the previous paper, we addressed these issues theoretically; in this paper we address them experimentally. We found in both studies that a key parameter in controlling firing patterns is the fraction of endogenously active cells. The theoretical analysis indicated that steady firing rates are possible only when the fraction of endogenously active cells is above some threshold, that there is a transition to bursting when it falls below that threshold, and that networks becomes silent when the fraction drops to zero. Experimentally, we found that all steadily firing cultures contain endogenously active cells, and that reducing the fraction of such cells in steadily firing cultures causes a transition to bursting. The latter finding implies indirectly that the elimination of endogenously active cells would cause a permanent drop to zero firing rate. The experiments described here thus corroborate the theoretical analysis.


Diurnal changes in paraventricular hypothalamic alpha1 and alpha2-adrenoceptors and food intake in rats.
The prominent feeding rhythm evident in rats may reflect circadian variation in activity of feeding-relevant adrenoceptors within the hypothalamic paraventricular nucleus (PVN). In the present study, separate groups of rats were sacrificed at six time points (ZT0, ZT4, ZT8, ZT12, ZT16, ZT20) over a diurnal cycle. Food intakes were recorded during the 4-h period prior to sacrifice in each group. Brain sections were incubated with either an alpha1-adrenoceptor ligand (3H)-prazosin [(3H)-PRZ] or an alpha2-adrenoceptor ligand (3H) para-aminoclonidine [(3H)-PAC] prior to autoradiography analyses. Binding of (3H)-PRZ within the PVN varied as a function of the diurnal cycle, with significantly greater binding evident during the light phase of ZT0 (first 4 h of the light phase) and at ZT4, compared to nadir binding during the dark phase at ZT16 (first 4 h of the dark phase). Binding of (3H)-PAC within the PVN also varied as a function of the diurnal cycle, with significantly greater binding evident during the first 8 h of the dark phase (ZT16 and ZT20) than during the light phase. Food intake and alpha1-adrenergic binding were inversely related across the diurnal cycle. These results support the hypothesis that PVN adrenergic systems may be organized in an antagonistic fashion so as to modulate feeding in the rat.


A phase III randomized trial of gemcitabine-oxaliplatin versus carboplatin-paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer.
This phase III study compared the efficacy and tolerability of gemcitabine and oxaliplatin (GEMOX) with paclitaxel and carboplatin (PCb) in chemotherapy-naive patients with stage IIIB/IV non-small cell lung cancer. Patients aged 18 years or older were randomized to PCb (paclitaxel 225 mg/m followed by carboplatin area under the curve = 6 on day 1 every 3 weeks) or GEMOX (gemcitabine 1,000 mg/m on days 1 and 8 followed by oxaliplatin 130 mg/m on day 1 every 3 weeks) for up to six cycles. The primary end point was progression-free survival (PFS), with tumor response rate, overall survival (OS), and quality of life as secondary end points. : The study was terminated after 383 patients had been randomized (371 received treatment) as the incidence of adverse events had exceeded the protocol-specified safety threshold (≥ 20% in either arm). No formal statistical comparisons were conducted. Median PFS was 4.44 months and 4.67 months in the GEMOX and PCb groups, respectively. Objective response rates (complete or partial) were 15.2% and 22.4% in the GEMOX and PCb arms, respectively. Median OS was 9.90 months (GEMOX) and 9.24 months (PCb); post hoc analyses showed median OS in patients aged 70 years or older to be similar to those younger than 70 years. PFS was similar in both groups of patients with adenocarcinoma histology, although OS favored the GEMOX group. Quality of life was improved from baseline in both groups. Toxicity profiles were comparable between the groups. PFS, OS, and objective response rates with GEMOX were similar to PCb. Nevertheless, toxicities limit the adoption of this regimen for routine use in advanced non-small cell lung cancer.


Forefoot narrowing with external fixation for problem cleft wounds.
Healing of forefoot cleft wounds can be a difficult management problem in patients with peripheral vascular disease, diabetes or both. This is a prospective review of 15 patients with these conditions with nonhealing middle-ray cleft wounds managed with a temporary mini-external fixator to close the cleft wound. Fourteen (93%) of the 15 patients had a successful obliteration of the cleft and skin coverage. Twelve (80%) of 15 were able to resume their previous level of activity with the reconstructed, mechanically sound forefoot. Fourteen (93%) of the 15 patients received hyperbaric oxygen treatments as an adjunct to wound healing. All patients avoided a transmetatarsal or higher amputation.


The actions of three volatile general anaesthetics on withdrawal responses of the pond-snail Lymnaea stagnalis (L.).
1. The gastropod mollusc Lymnaea stagnalis (L.) is an ideal model system for studies on anaesthesia. It is reversibly anaesthetized by the general anaesthetics halothane, enflurane and isoflurane. 2. Criteria for "anaesthesia" in Lymnaea were established. The reflex used in ED50 trials was the whole animal withdrawal reflex. 3. ED50 values for halothane, enflurane and isoflurane were, 0.83% v.v. (volume for volume), 1.01% v.v. and 1.09% v.v. respectively. 4. Relationships between anaesthetic concentrations, weights of animals and mortality rates are reported.


[Kidney function test after partial nephrectomy (author's transl)].
A new method for testing the function of the kidney after partial nephrectomy is reported. By means of radioisotope renography, urography and radioisotope clearance ('single-shot' method) it is possible to prove the function of the single kidney. The clearance in regard to the size of the shadow of the kidney assessed by urography allows to estimate the specified kidney function. We used these methods in ten patients and we detected that the loss of function is more extensive than expected by the operative reduction of the kidney parenchyma only. The causes for this are discussed.


Critical incident stress management in a mid-sized police department: a case illustration.
Pembroke Pines Police Department (PPPD), Pembroke Pines, Florida, collaborated with Nova Southeastern University (NSU), Fort Lauderdale, Florida, and the Federal Bureau of Intelligence (FBI), Miami Field Office, in the fall of 2001 to develop, train, and launch a specialized unit of crisis negotiators (Critical Response Team; CRT). The hallmark feature of the PPPD CRT was the expectation that all team members were trained in accordance with both the FBI's crisis/hostage negotiations model and the ICISF model of Critical Incident Stress Management (CISM). The deliberate result of this collaborative training provided PPPD with an "in-house" crisis response team grounded in standardized CISM principles and prepared to expand with forthcoming current best practices (e.g., peer support and specialized training) most notably Crisis Management Briefings (Malcolm, Seaton, Perera, Sheehan, & Van Hasselt, 2005; Sheehan, Everly, & Langlieb, 2004; Clark & Volkman, 2005). The purpose of this case illustration is to present the development and application of this agency's tactical execution of a police-based approach aimed at addressing the inherent CISM needs of law enforcement. Practical relevance and suggestions for future research are also discussed.


Effect of fluoxetine on the spontaneous electrical activity of fronto-cortical neurons.
The effect of fluoxetine on spontaneous extracellular activity of fronto-cortical neurons of chloral hydrate-anesthetized rats was investigated. Fluoxetine significantly increased the basal firing rate of cortical neurons in a dose-dependent manner (0.1-1000 micrograms kg-1 i.v.), with a maximum excitatory effect of 53% at 1000 micrograms kg-1. Selective destruction of ascending serotoninergic pathways induced by intracerebroventricular injections of 150 micrograms 5,7-dihydroxytryptamine, in desipramine-pretreated rats, antagonized the excitatory effect of fluoxetine. The present results suggest that fluoxetine significantly increases the electrical activity of the fronto-cortical neurons acting on serotoninergic uptake mechanisms localized at the level of raphe nuclei.


Monoclonal immunoglobulins in patients with renal transplants: characterization, evolution and risk factors.
Gammopathies were found to be present in 25 (13%) of 192 HIV-negative renal transplant recipients with more than 30 months follow-up prospectively investigated for monoclonal or oligoclonal immunoglobulins (mIg) by agarose gel electrophoresis and immunofixation. Eleven patients had only one monoclonal band, whereas 14 had two or more bands. Of these bands, 60% were IgG kappa, 29% IgG lambda and 11% IgM lambda or kappa, and 90% did not exceed 2 g/l. Most gammopathies occurred early post-transplant (median 5 months) and they were always transient. Some predisposing factors for mIg emergence could be identified: 1. age, but only in women, 2. duration of dialysis, 3. occurrence of prior cytomegalovirus infection, and 4. immunosuppressive regimen including cyclosporine. Serological evidence for active EBV infection was obtained in ten patients, but in six cases infection occurred subsequent to the finding of mIg. In eight patients, the clinical course was characterised by severe infection or tumours (one Kaposi's sarcoma, one B-cell brain lymphoma). The present findings and experimental studies support the view that the development of mIg in renal transplant patients is associated with a failure of regulatory T-cell function. This T-B-cell imbalance requires a careful follow-up in these patients.


Risk Factors of Chronic Obstructive Pulmonary Disease Exacerbations.
Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease characterized by persistent respiratory symptoms and airflow limitation. COPD has a major impact on public health, mainly due to its increasing prevalence, morbidity and mortality.(1) The natural course of COPD is aggravated by episodes of respiratory symptom worsening termed exacerbations that contribute to disease progression. Acute Exacerbations of COPD (AECOPD) can be triggered by a multitude of different factors, including respiratory tract infections, various exposures, prior exacerbations, non-adherence to treatment, and associated comorbidities. AECOPD are associated with an inexorable decline of lung function, and a significantly worse survival outcome. This review will summarize the most important aspects regarding the impact of different factors that contribute to COPD exacerbations.


[Treatment of severe hepatic insufficiency by perfusion of patients' blood through a suspension of cryopreserved hepatocytes].
The results of hemoperfusion through a suspension of cryoconserved hepatocytes in 21 patients with severe hepatic insufficiency are analysed. It is shown that the manipulation had a beneficial effect on the clinical and biochemical indices, which was manifested by diminished jaundice and skin pruritus, increased physical activity, improved appetite; reduced levels of bilirubin, transaminase, alkaline phosphatase, bile acids, and cholesterol. The information gained is evidence that the method can be included in the complex treatment of patients with severe hepatic insufficiency.


Apoptosis of PC12 cells by 4-hydroxy-2-nonenal is mediated through selective activation of the c-Jun N-terminal protein kinase pathway.
Cytotoxic lipid peroxides such as 4-hydroxy-2-nonenal (HNE) are produced when cells are exposed to toxic chemicals. However, the mechanism by which HNE induces cell death has been poorly understood. In this study, we investigated the molecular mechanism of HNE-induced apoptosis in PC12 cells by measuring the activities of the mitogen-activated protein (MAP) kinases involved in early signal transduction pathways. Within 15-30 min after HNE treatment, c-Jun N-terminal protein kinase (JNK) was maximally activated, before returning to control level after 1 h post-treatment. In contrast, activities of extracellular signal regulated kinase (ERK) and p38 MAP kinase remained unchanged from their basal levels. SEK1, an upstream kinase of JNK, was also activated (phosphorylated) within 5 min after HNE treatment and remained activated for up to 60 min. Marked activation of the JNK pathway through SEK1 was demonstrated by the transient transfection of cDNA for wild type SEK1 and JNK into COS-7 cells. Furthermore, significant reductions in JNK activation and HNE-induced cell death were observed when the dominant negative mutant of SEK1 was co-transfected with JNK. Pretreatment of PC12 cells with a survival promoting agent, 8-(4-chlorophenylthio)-cAMP, prevented both the HNE-induced JNK activation and apoptosis. Nonaldehyde, a nontoxic aldehyde, caused neither apoptosis nor JNK activation. Pretreatment of PC12 cells with SB203580, a specific inhibitor of p38 MAP kinase, had no effect on HNE-induced apoptosis. All these data suggest that the HNE-mediated apoptosis of PC12 cells is likely to be mediated through the selective activation of the SEK1-JNK pathway without activation of ERK or p38 MAP kinase.


Modulatory effects of serotonin on excitatory amino acid responses and sensory synaptic transmission in the ventrobasal thalamus.
Excitatory amino acid receptors are thought to mediate sensory input to the ventrobasal thalamus. There is evidence for a brainstem serotonergic projection to the ventrobasal thalamus which may have a modulatory role. The possibility that serotonin may selectively modulate responses to excitatory amino acid receptor agonists, and its effects on sensory synaptic transmission has been examined in the rat ventrobasal thalamus in vivo. Iontophoretic ejection of serotonin at low currents produced a marked facilitation of responses to excitatory amino acids. In contrast, excitatory responses to cholinomimetic agonists were attenuated. Synaptic transmission was concomitantly enhanced or unchanged in these circumstances. Higher serotonin ejection currents reversed the facilitation, or inhibited excitatory amino acid responses and synaptic transmission. It is concluded that serotonin can modulate responses to excitatory amino acids relatively selectively and that synaptic transmission of somatosensory information through the ventrobasal thalamus may be susceptible to brainstem serotonergic modulation.


[The Library of the Franciscan pharmacy in Jerusalem].
The inventory of the pharmacy of Franciscan monks in Jerusalem contained the description of the eighty books they kept in their Library. Most of them could be identified. A great number were of Italian origin, 45 were redacted in Latin, and 32 in an Italian language. 27 dealt with pharmacy, 18 with medicine and 17 were encyclopaedias or hygiene books.


Youth to adult body mass index trajectories as a predictor of metabolically healthy obesity in adulthood.
Adiposity in childhood and adolescence (youth) has been shown to associate with adult metabolic health. What is not known, is whether youth body mass index (BMI) associates with metabolically healthy obesity (MHO) in adulthood, and if so, the age when the BMI to MHO association emerges. This study aimed to determine if BMI trajectories from youth to adulthood differed between adults with MHO and metabolically unhealthy obesity (MUHO). The Cardiovascular Risk in Young Finns Study had measured weight and height up to eight times in individuals from youth (3-18 years in 1980) to adulthood (24-49 years). Adult MHO was defined as BMI ≥ 30 kg m-2, normal fasting glucose (<5.6 mmol l-1), triglycerides (<1.695 mmol l-1), high density lipoprotein cholesterol (≥1.295 mmol l-1 females, ≥1.036 mmol l-1 males), blood pressure (<130/85 mmHg) and no medications for these conditions. BMI trajectories were compared for adults with MHO and MUHO using multilevel mixed models adjusted for age, sex and follow-up time. Mean (SD) follow-up time was 29 (3) years. Five hundred and twenty-four participants were obese in adulthood, 66 (12.6%) had MHO. BMI was similar through childhood, adolescence and young adulthood. BMI trajectories diverged at age 33, when individuals with MHO had at least 1.0 kg m-2 lower BMI than those with MUHO, significantly lower at 36 (-2.1 kg m-2, P = 0.001) and 42 years (-1.7 kg m-2; P = 0.005). Adult MHO was characterized by lower adult BMI, not youth BMI. Preventing additional weight gain among adults who are obese may be beneficial for metabolic health.


A novel description of FDG excretion in the renal system: application to metformin-treated models.
This paper introduces a novel compartmental model describing the excretion of 18F-fluoro-deoxyglucose (FDG) in the renal system and a numerical method based on the maximum likelihood for its reduction. This approach accounts for variations in FDG concentration due to water re-absorption in renal tubules and the increase of the bladder's volume during the FDG excretion process. From the computational viewpoint, the reconstruction of the tracer kinetic parameters is obtained by solving the maximum likelihood problem iteratively, using a non-stationary, steepest descent approach that explicitly accounts for the Poisson nature of nuclear medicine data. The reliability of the method is validated against two sets of synthetic data realized according to realistic conditions. Finally we applied this model to describe FDG excretion in the case of animal models treated with metformin. In particular we show that our approach allows the quantitative estimation of the reduction of FDG de-phosphorylation induced by metformin.


Fluctuations and correlations in hexagonal optical patterns.
We analyze the influence of noise in transverse hexagonal patterns in nonlinear Kerr cavities. The near-field fluctuations are determined by the neutrally stable Goldstone modes associated to translational invariance and by the weakly damped soft modes. However, these modes do not contribute to the far-field intensity fluctuations that are dominated by damped perturbations with the same wave vectors than the pattern. We find strong correlations between the intensity fluctuations of any arbitrary pair of wave vectors of the pattern. Correlation between pairs forming 120 degrees is larger than between pairs forming 180 degrees, contrary to what a naive interpretation of emission in terms of twin photons would suggest.


Fall in the number of intracardiac neurons in aging rats.
The neurons of whole cardiac atria were stained using a NADH-diaphorase technique in young adult (3 months old) (GI) and aging rats (20 months old) (GII). Light microscopy revealed differences in the appearance of the neurons in the two groups. In GI, most ganglia contained 50-100 neurons while in GII, most ganglia usually contained 20 neurons. The mean total number of neurons in the atria of GII was 245+/-31, i.e. only 23% of the mean value in GI (1086+/-203). The mean size of the ganglionic neurons (area of maximum cell profile) was 702 microm2 in GI and 1065 microm2 in GII. Histological sections of the ganglia revealed that a capsule of collagen fibers sheaths each ganglion in both groups. In GII, the density of collagen fibers increases in the capsule and in the septa within the ganglia; yellow or red, type I collagen fibers predominate in this group. No elastic fibers were present in the cardiac ganglia of either group. It is suggested that in aging rats, structural changes and reorganization of the remnant neurons accompany neuron reduction.