Differential effects of light and alcohol on the electro-oculographic responses of patients with age-related macular disease.
Alcohol (EtOH) affects the electro-oculogram (EOG) in ways very similar to light, although the two agents act on the RPE through different routes. Are the EOGs to light and to alcohol affected similarly in age-related macular degeneration (AMD) and age-related maculopathy (ARM)? Standard eye movements and recording of EOGs were used. After 26 minutes of baseline recording in darkness, subjects were either exposed to 30 cd/m(2) light or drank 226 mg/kg alcohol (7.1% vol/vol) in water. In 17 patients with ARM and AMD (aged 67-86 years; mean, 77), the light-EOG was slowed in comparison to normal, and the voltage changes were somewhat reduced. The mean reduction in the alcohol-EOG (EtOH-EOG) was much greater. The reduction was equal in the two eyes, regardless of uniocular foveal impairment. Some EtOH-EOG loss occurred in patients with minor fundus changes and no loss of acuity, but the loss was greater in patients with "wet" or "dry" ARM and AMD. Grading of RPE changes correlated with the decrease in EtOH-EOG responsiveness, but not with light-EOG responsiveness. EtOH- and light-EOGs are affected differentially. In ARM, even with minor fundus changes, patients appear to have a general abnormality in the RPE. The alcohol response abnormality is correlated to the fundus appearance, but not with age. These results provide further evidence that EtOH acts by a pathway different from that governing the action of light. These results support histologic and other evidence that in ARM there is a functional barrier between the choroid and the RPE-retina.


Identification of mitochondrial respiratory proteins from the green alga Chlamydomonas reinhardtii.
Membrane preparations from the green alga Chlamydomonas reinhardtii contain both thylakoid and mitochondrial membranes [1]. These preparations have been intensely used to study the structure, function and biogenesis of protein complexes involved in the photosynthetic pathway. We show here that these preparations are also suitable for studying protein complexes of the mitochondrial respiratory chain of the alga. The respiratory complexes, fractionated on a sucrose gradient in the presence of Triton X-100, were identified by their catalytic properties and their polypeptide content. From the bottom to the top of the sucrose gradient, we identified the NADH: ubiquinone oxidoreductase (complex I), the mitochondrial ATP synthase (F0F1-ATPase), the cytochrome bc1 complex and the cytochrome c oxidase. At the top of the gradient, another enzyme was detected which displayed an NADH: menaquinone oxidoreductase activity.


The discovery of novel β-secretase inhibitors: pharmacophore modeling, virtual screening, and docking studies.
This article describes the identification of two small molecular inhibitors for β-secretase by integrating virtual screening with fluorescence resonance energy transfer bioassay. A ligand-based pharmacophore model was developed, and the sequential virtual screening of ZINC database was performed using the acquired pharmacophore model and molecular docking. Biological evaluation of 10 virtual hits led to the identification of two novel inhibitors with IC(50) values of 4.76 and 0.31 μm, respectively. These two moderate inhibitors could represent new potentials for the development of anti-Alzheimer's disease agents.


Response of CD4+ T cells from myasthenic patients and healthy subjects of biosynthetic and synthetic sequences of the nicotinic acetylcholine receptor.
We investigated the suitability of pools of overlapping synthetic peptides spanning the complete alpha 1 subunit sequence of the human muscle acetylcholine receptor (AChR) (alpha 1 pool) or the extracellular domain (residues 1-218, alpha 11-218 pool), and of biosynthetic alpha 1 constructs from E. coli, as stimulants of human CD4+ cells from myasthenia gravis (MG) patients and healthy subjects. A construct corresponding to residues alpha 11-209 was obtained as solubilized inclusion bodies (ib alpha 11-209), or purified by SDS gel electrophoresis (pur alpha 11-209). A second construct included the extracellular, cytoplasmic and carboxylterminal domains plus histidine residues, and was obtained as inclusion bodies (ib alpha 1NoTrans) or purified by gel permeation and histidine tag affinity chromatography (pur alpha 1NoTrans). A biosynthetic extracellular domain of the neuronal AChR alpha 7 subunit (ib alpha 71-206) isolated from E. coli as inclusion bodies served as control for bacterial contaminants. We used ib alpha 11-209, pur alpha 11-209 and peptide pools to propagate CD4+ lines from two MG patients. The lines obtained using pur alpha 11-209 and the peptide pools recognized the peptide pools and alpha 1 constructs tested well, but ib alpha 71-206 poorly or not at all. These lines recognized peptides known to form CD4+ epitopes in these patients. The ib alpha 11-209 lines recognized ib alpha 11-209 and ib alpha 71-206 strongly, but recognized poorly pur alpha 11-209 and the alpha 11-218 pool. We propagated T-cell lines from a healthy subject using pur alpha 11-209 and ib alpha 11-209. The pur alpha 11-209 line recognized pur alpha 11-209 and the alpha 11-218 pool, but not ib alpha 11-209 or ib alpha 71-206. The ib alpha 11-209 line recognized ib alpha 11-209 and ib alpha 71-206, but not pur alpha 11-209 or the alpha 11-218 pool. We tested blood CD4+ cells from six MG patients and eight healthy subjects with ib alpha 11-209, pur alpha 11-209, the alpha 11-218 pool and--in the healthy subjects--also ib alpha 71-206, ib alpha 1NoTrans and pur alpha 1NoTrans. In both populations, the alpha 11-218 pool elicited low and sporadic responses, while the constructs elicited clear responses that were frequently higher for ib alpha 11-209 than pur alpha 11-209. The responses to ib alpha 71-206 were strong and comparable to those to ib alpha 11-209, ib alpha 1NoTrans, and pur alpha 1NoTrans. These results indicate that even purified constructs from E. coli contain bacterial contaminants recognized by CD4+ cells. They should not be used to test unselected blood CD4+ cells, because they may evoke strong CD4+ responses to the bacterial antigens. Purified recombinant sequences may be suitable for propagation of CD4+ cell lines, if the specificity of the lines can be verified using different antigen preparations. Short synthetic peptide sequences can be safely used for propagation of specific CD4+ cells. Although they are poor stimulants for unselected blood CD4+ cells, the low responses they elicit are probably due to these cells.


[Current concepts of the treatment of cholelithiasis in aged patients].
Biliary lithiasis in elder patients is characterized by the physical defects usually present--therefore surgery is less mandated than endoscopic procedures or extra corporeal lithotripsy. However, if surgery is undertaken, then it should be carried out as completely as possible. In this paper, the authors emphasize the special aspects of its indications and technics--for more than any where else this surgery required perfection.


Humoral nature of the urine response to simulation of atrial receptors.
The diuretic response to stimulation of left atrial receptors by distending small balloons located at the pulmonary vein--left atrial junctions and in the left atrial appendage was studied in anaesthetized dogs in which bretylium tosylate, atenolol and atropine had been administered to effect blockade of renal nerves and to prevent increases in heart rate resulting from stimulation of atrial receptors. In these dogs, distension of the balloons was not associated with significant changes in heart rate, left atrial pressure or arterial blood pressure, and resulted in increases in urine flow, decreases in urinary sodium concentration and no significant changes in urinary sodium excretion. It is concluded that the humoral mechanism is responsible for the diuresis in response to stimulation of atrial receptors and has no significant effect on the response of natriuresis known to involve a decrease in the activity in the renal nerves and haemodynamic changes associated with stimulation of atrial receptors.


Real-time Virtual Sonography for navigation during targeted prostate biopsy using magnetic resonance imaging data.
To evaluate the effectiveness of the medical navigation technique, namely, Real-time Virtual Sonography (RVS), for targeted prostate biopsy. Eighty-five patients with suspected prostate cancer lesions using magnetic resonance imaging (MRI) were included in this study. All selected patients had at least one negative result on the previous transrectal biopsies. The acquired MRI volume data were loaded onto a personal computer installed with RVS software, which registers the volumes between MRI and real-time ultrasound data for real-time display. The registered MRI images were displayed adjacent to the ultrasonographic sagittal image on the same computer monitor. The suspected lesions on T2-weighted images were marked with a red circle. At first suspected lesions were biopsied transperineally under real-time navigation with RVS and then followed by the conventional transrectal and transperineal biopsy under spinal anesthesia. The median age of the patients was 69 years (56-84 years), and the prostate-specific antigen level and prostate volume were 9.9 ng/mL (4.0-34.2) and 37.2 mL (18-141), respectively. Prostate cancer was detected in 52 patients (61%). The biopsy specimens obtained using RVS revealed 45/52 patients (87%) positive for prostate cancer. A total of 192 biopsy cores were obtained using RVS. Sixty-two of these (32%) were positive for prostate cancer, whereas conventional random biopsy revealed cancer only in 75/833 (9%) cores (P < 0.01). Targeted prostate biopsy with RVS is very effective to diagnose lesions detected with MRI. This technique only requires additional computer and RVS software and thus is cost-effective. Therefore, RVS-guided prostate biopsy has great potential for better management of prostate cancer patients.


The immunophenotypic spectrum of meningeal hemangiopericytoma: a comparison with fibrous meningioma and solitary fibrous tumor of meninges.
Despite controversy regarding its histogenesis, meningeal hemangiopericytoma (HPC) is a well-defined clinicopathologic entity exhibiting high rates of recurrence and late extracranial metastasis. It must be distinguished from several benign neoplasms, particularly fibrous meningioma (FM) and solitary fibrous tumor (SFT). To determine the immunoprofile of HPC, we studied 27 meningeal examples, including 13 low-grade and 14 high-grade tumors. For comparison, 20 FMs and eight SFTs of the meninges were also evaluated. The immunotype of HPC included vimentin (85%), factor XIIIa (78%) in individual scattered cells, Leu-7 (70%), and CD34 (33%) in a weak, patchy pattern. Focal desmin and cytokeratin positivity was only occasionally encountered (20% each). The SFT shared a similar immunophenotype, except that CD34 expression (100%) was characteristically strong and diffuse. The FM characteristically expressed epithelial membrane antibody (EMA) (80%) and S-100 protein (80%); CD34 reactivity (60%) was patchy and weak. Both within and among all three tumor types, MIB-1 labeling indices varied widely. Specifically, they were unrelated to tumor grade in HPC. Significant reactivity for p53 protein was detected in 52% of HPCs, 17% of SFTs, and 5% of FMs. Meningeal HPC exhibits a distinct antigenic profile, one enabling the exclusion of other entities in nearly all cases. The rare expression of desmin or cytokeratin in HPC suggests either the occurrence of divergent differentiation or, less likely, the possibility that its distinctive morphology is but a phenotype shared by several types of meningeal sarcoma.


Did the expansion of free GP care impact demand for Emergency Department attendances? A difference-in-differences analysis.
The removal of co-payments for General Practitioner (GP) services has been shown to increase utilisation of GP care. The introduction of free GP care may also have spillover effects on utilisation of other healthcare such as Emergency Department (ED) services, which often serve as substitutes for primary care, and where co-payments to attend exist for many. In Ireland, out-of-pocket payments are paid by the majority of the population to access GP care, and these costs are amongst the highest in Europe. However, in July 2015 all children in Ireland aged under 6 became eligible for free GP care. Using a large administrative dataset on 413,562 ED attendances between January 2015 and June 2016 we apply a difference-in-differences method, with treatment and control groups differentiated by age, to examine whether ED utilisation changed amongst younger children following the introduction of universal free GP care. In particular, we examine ED attendances following a GP referral, as referrals from GPs also afford access to the ED free of charge. We find that the expansion of free GP care did not reduce overall ED utilisation for under 6s. Additionally, we find that the proportion of ED attendances occurring through GP referrals increased by over 2 percentage points. This latter finding may be indicative of increased pressure placed on GPs from increased demand. Overall, this study finds that expanding free GP care to all young children did not reduce their ED utilisation.


WIDESPREAD MACULAR NEUROSENSORY DETACHMENT AFTER OCRIPLASMIN INTRAVITREAL INJECTION.
To present the case of a patient with vitreomacular traction who experienced immediate severe acute complications after ocriplasmin intravitreal injection. Case report. A 61-year-old woman with vitreomacular traction underwent ocriplasmin treatment. Within 24 hours after injection, she noticed severe reduction in visual acuity. Spectral domain optical coherence tomography revealed release of vitreous traction, together with widespread subretinal fluid and decreased reflectivity in the outer retina. Ten weeks after treatment, visual acuity improved, although below pretreatment levels, with partial reduction in subretinal fluid. Intravitreal ocriplasmin can produce acute visual acuity changes with widespread subretinal fluid and outer retinal ellipsoid zone hyporeflectivity on spectral domain optical coherence tomography. The overall acute and long-term safety profile of ocriplasmin remains unknown.


Decreased plasma soluble RAGE in patients with hypercholesterolemia: effects of statins.
The receptor for advanced glycation endproducts (RAGE) is overexpressed at sites of vascular pathology. A soluble RAGE isoform (sRAGE) neutralizes the ligand-mediated damage by acting as a decoy. We hypothesized that in hypercholesterolemia up-regulation of the ligand-RAGE axis may bridge impairment of nitric oxide biosynthesis with oxidative stress. We measured in 60 hypercholesterolemic patients and 20 controls plasma total sRAGE levels, urinary 8-iso-prostaglandin (PG) F(2alpha) excretion, and plasma levels of asymmetric dimethylarginine (ADMA). The effects of two structurally different statins (pravastatin and atorvastatin) on these parameters were analyzed in 20 hypercholesterolemic subjects free of vascular disease. Plasma sRAGE was significantly lower, ADMA and urinary 8-iso-PGF(2alpha) were higher, in hypercholesterolemic versus normocholesterolemic patients. Patients on statin treatment with previous myocardial infarction had lower 8-iso-PGF(2alpha), higher sRAGE, and unchanged ADMA levels compared to subjects free of vascular disease. On multivariate regression analysis only 8-iso-PGF(2alpha) and ADMA predicted sRAGE levels. An 8-week treatment with either statin was associated with a significant reduction in urinary 8-iso-PGF(2alpha), whereas only atorvastatin raised sRAGE levels near to normal values, with no change in ADMA levels. sRAGE might serve as an endogenous protecting factor for accelerated atherosclerosis mediated by oxidative stress and endothelial dysfunction in hypercholesterolemia.


Cysteine proteases and acid phosphatases contribute to Tetrahymena spp. pathogenicity in guppies, Poecilia reticulata.
Systemic tetrahymenosis caused by the protozoan parasite Tetrahymena spp. is a serious problem in guppy (Poecilia reticulata) farms worldwide. There is no therapeutic solution for the systemic form of this disease. Guppies severely infected with Tetrahymena spp. were imported by a commercial ornamental fish farm and brought to our laboratory. Tetrahymena sp. (Tet-NI) was isolated and in vitro cultured. Isolates maintained in culture for different time periods (as reflected by different numbers of passages in culture) were analyzed-Tet-NI 1, 4, 5 and 6, with Tet-NI 1 being cultured for the longest period (about 15 months, 54 passages) and Tet-NI 6 for the shortest (2.5 months, 10 passages). Controlled internal infection was successfully achieved by IP injection with most isolates, except for Tet-NI 1 which produced no infection. The isolate Tet-NI 6 induced the highest infection rates in internal organs (80% vs. 50% and 64% for Tet-NI 4 and 5, respectively) and mortality rates (67% vs. 20% and 27% for Tet-NI 4 and 5, respectively, and 6.7% for Tet-NI 1). The correlation between pathogenicity and Tetrahymena enzymatic activity was studied. Electrophoretic analyses revealed at least two bands of gelanolytic activity in Tet-NI 4 and 5, three bands in Tet-NI 6, and no activity in Tet-NI 1. Total inhibition of gelanolytic activity was observed after pretreatment of Tet-NI 6 with E-64, a highly selective cysteine protease inhibitor. Using hemoglobin as a substrate, Tet-NI 6 had two bands of proteolytic activity and no bands were observed in Tet-NI 1. A correlation was observed between pathogenicity and acid phosphatase activities (analyzed by commercial fluorescence kit) for Tet-NI 1 and Tet-NI 6.


The effect of midazolam premedication on patient satisfaction during fiberoptic bronchoscopy under patient-controlled sedation.
Patient-controlled sedation (PCS) with propofol is a safe and effective method of attenuating discomfort during fiberoptic bronchoscopy. The purpose was to evaluate the usefulness of midazolam in addition to PCS for fiberoptic bronchoscopy. We randomly assigned 155 patients undergoing diagnostic bronchoscopy to two groups. Group M (n = 79) received 0.03 mg/kg of midazolam for premedication while group P (n = 76) received a loading dose (0.05 ml/kg) of PCS solution composed of 200 mg (20 ml) of propofol and 1 mg (2 ml) of alfentanil. Both groups received the PCS solution 0.2 ml/kg/hr with a bolus of 1 ml and a lockout time of 1 min. Vital signs, pulmonologist satisfaction, patient satisfaction and amnesia were evaluated. After the insertion of the bronchoscope, there was a slight decrease of SpO2 and an increase of blood pressure and heart rate in both groups with no significant differences between the two groups. The group P required more bolus injections (1.6 +/- 1.7 in the group M vs 2.5 +/- 2.2 in group P; P < 0.05). There was no difference in the satisfaction of pulmonologists, but the satisfaction of patients was higher in the group M (P < 0.05). More patients in the group P (93%) remembered the procedure than in the group M (70%) (P < 0.05). PCS is an effective method for sedating patients undergoing fiberoptic bronchoscopy and midazolam provides more patient satisfaction and amnesia.


Sex differences in behavioral and PKA cascade responses to repeated cocaine administration.
Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point. Our results showed that females exhibited higher cocaine-induced behavioral responses and developed behavioral sensitization and tolerance faster than males. Whereas females developed behavioral sensitization to cocaine after 2 days and tolerance after 14 days, male rats developed sensitization after 5 days. In addition, cocaine induced a sexual dimorphic pattern in the progression of neuronal adaptations on the PKA cascade signaling in region (NAc vs. CPu) and time (days of cocaine administration)-dependent manners. In general, more PKA signaling cascade changes were found in the NAc of males on day 5 and in the CPu of females with repeated cocaine injection. In addition, in females, behavioral activities positively correlated with FosB levels in the NAc and CPu and negatively correlated with Cdk5 and p35 in the CPu, while no correlation was observed in males. Our studies suggest that repeated cocaine administration induced different patterns of behavioral and molecular responses in the PKA cascade in male and female rats.


Oxytocin reduces the activity of N-methyl-D-aspartate receptors in cultured neurons.
N-Methyl-D-Aspartate(NMDA)-sensitive glutamate receptors, are critically involved in the induction of the learning process. Activation of NMDA receptors by glutamate lead to massive influx of extracellular Ca2+, with ensuing activation of a variety of Ca(2+)-dependent enzymes, including protein kinase C. This triggers a cascade of intracellular reactions which is essential for memory formation. In culture neurons, high concentrations of oxytocin (> 1 microM) attenuate the stimulation of 45Ca2+ influx promoted by glutamate through the activation NMDA receptors. In addition, the hormone reduces glutamate-stimulated [3H]4-beta-phorbol 12,13-dibutyrate (PdBu) binding in intact cells, a parameter that reflects the translocation of protein kinase C from the cytosol to the cell membrane. Taken collectively, these results indicate that oxytocin reduces the activity of NMDA receptors, thus impairing one of the major substrates for the induction of learning and memory.


[Bacterial ecology on burn wound and antibacterial agent therapy].
The main factors influencing the bacterial ecology on burn wound are the selection of antibacterial agents and systemic antibiotic. Some antibacterial agents more active against P. aeruginosa were developed in 1960s, and the detection rate of P. aeruginosa on burn wound has been declined, and the detection rate of Enterobacteriaceae species and Acinetobacter SPP. has been raised since then. In 1990s, the third generation Cephalosporin was widely used in burn unit and the detection rate of staphylococcus aureus showed an increased trend. Especially, the positive rate of MRSA was increased significantly. Under the selection pressure of antibacterial agent, the resistant strains are rapidly increased and the antibiotics against opportunistic pathogen on burn wound should be selected continuously. Finally, the bacterial ecology pattern on burn wound is changing incessantly. The result is that the prevalence of infection of multi-drug resistance strains and opportunistic pathogen appears on burn wound. In order to optimize the antibiotic therapy, the bacterial ecology pattern on burn wound has to be investigated, and the dominant pathogen including invasive and currently prevailing strains in the burn unit also should always be surveyed. In addition, we also should know the mechanisms of bacterial resistance. The regular surveillance of antibiotic resistance in the clinical isolates is the most important and valuable for understanding the trend of bacterial resistance. The antibiotic therapy should be decided according to the result of susceptibility tests.


Microassay of acetylcholinesterase activity in small portions of single mosquito homogenates.
1. A simple, rapid microassay method is described for measuring acetylcholinesterase (AChE) activity accurately and precisely in small portions of single mosquito homogenates. 2. Up to 30 microassay replicates were possible for individual insects. 3. Microassay data on individual mosquitoes were compared with conventional enzyme assay data acquired using pools of the same homogenates. 4. Under the optimum reaction conditions established, an average Vmax of 7.1 nmol/l/min/mosquito and an average Km of 1.3 x 10(-4) M were observed with acetylthiocholine iodide as substrate. 5. Variability in AChE activity within a sample population of Anopheles albimanus was observed using measurements from individual insects. 6. Such information is fundamental to comparative studies of pesticide physiology (in particular, the resistance phenomenon) in the individual mosquitoes in a population pool; this technique forms the basis for a recently developed resistance microassay.


Telephone Follow-Up for Older Adults Discharged to Home from the Emergency Department: A Pragmatic Randomized Controlled Trial.
Telephone calls after discharge from the emergency department (ED) are increasingly used to reduce 30-day rates of return or readmission, but their effectiveness is not established. The objective was to determine whether a scripted telephone intervention by registered nurses from a hospital-based call center would decrease 30-day rates of return to the ED or hospital or of death. Randomized, controlled trial from 2013 to 2016. Large, academic medical center in the southeast United States. Individuals aged 65 and older discharged from the ED were enrolled and randomized into intervention and control groups (N = 2,000). Intervention included a telephone call from a nurse using a scripted questionnaire to identify obstacles to elements of successful care transitions: medication acquisition, postdischarge instructions, and obtaining physician follow-up. Control subjects received a satisfaction survey only. Primary outcome was return to the ED, hospitalization, or death within 30 days of discharge from the ED. Rate of return to the ED or hospital or death within 30 days was 15.5% (95% confidence interval (CI) = 13.2-17.8%) in the intervention group and 15.2% (95% CI = 12.9-17.5%) in the control group (P = .86). Death was uncommon (intervention group, 0; control group, 5 (0.51%), 95% CI = 0.06-0.96%); 12.2% of intervention subjects (95% CI = 10.1-14.3%) and 12.5% of control subjects (95% CI = 10.4-14.6%) returned to the ED, and 9% of intervention subjects (95% CI = 7.2-10.8%) and 7.4% of control subjects (95% CI = 5.8-9.0%) were hospitalized within 30 days. A scripted telephone call from a trained nurse to an older adult after discharge from the ED did not reduce ED or hospital return rates or death within 30 days. Clinicaltrials.gov identifier: NCT01893931z.


[Mental disorders in severely dysfunctional and in well-functioning families].
The types of mental disorders and their prevalence in severely dysfunctional (SD) and well-functioning (WF) families were compared. SD families were characterized by chronic conflicts, absence of closeness and lack of trust between parents, and bad relations and lack of support between parents and their children. WF families were characterized by high levels of psychological intimacy, warm and satisfying relationships between parents and children, and a warm, affectionate, optimistic family mood. 23 SD families (44 parents and 60 children) and 61 WF families (121 parents and 184 children) were followed for over 4 years by the author of this study. There was a high prevalence of mental disorders in parents of SD families in comparison to the WF families (43.2% vs 6.6%). This excess was significantly less in men (p = 0.05), in whom the risk ratio was 3.3 (p = 0.03), while for women it was 10.2 (p less than 0.0001). Most prominent was the higher prevalence of chronic anxiety: 25% vs 5% with a risk ratio for men of 2.9 (p = 0.09), and for women 7.1 (p less than 0.0001). Among children as well, there was greater prevalence of psychiatric illness in SD families--56.6% vs 3.8%, risk ratio 14.9 (p less than 0.0001). The prevalence of developmental speech and language disorders in SD families was 33.2 times greater, of hyperkinetic syndrome 12.3 times, and of enuresis 7.2 times. In contrast to the parents, the overall rate of illness was not significantly different between the sexes. We feel that it is important to discover such families because treatment and intervention early in childhood may increase the effectiveness of treatment.


Itopride in functional dyspepsia: results of two phase III multicentre, randomised, double-blind, placebo-controlled trials.
Functional dyspepsia (FD) is a common disorder but there is currently little efficacious drug therapy. Itopride, a prokinetic approved in several countries, showed promising efficacy in FD in a phase IIb trial. The aim of this study was to test the efficacy and safety of this drug in FD. Two similar placebo-controlled clinical trials were conducted (International and North America). Males and females, 18-65 years old, with a diagnosis of FD (Rome II) and the absence (by upper endoscopy) of any relevant structural disease were recruited. All were negative for Helicobacter pylori and, if present, heartburn could not exceed one episode per week. Following screening, patients were randomised to itopride 100 mg three times daily or identical placebo. The co-primary end points were: (1) global patient assessment (GPA) of efficacy; and (2) Leeds Dyspepsia Questionnaire (LDQ). Symptoms were evaluated at weeks 2, 4 and 8. Secondary measures of efficacy included Nepean Dyspepsia Index (NDI) quality of life. The GPA responder rates at week 8 on itopride versus placebo were similar in both trials (45.2% vs 45.6% and 37.8 vs 35.4%, respectively; p = NS). A significant benefit of itopride over placebo was observed for the LDQ responders in the International (62% vs 52.7%, p = 0.04) but not the North American trial (46.9% vs 44.8%). The safety and tolerability profile were comparable with placebo, with the exception of prolactin elevations, which occurred more frequently on itopride (18/579) than placebo (1/591). In this population with FD, itopride did not show a difference in symptom response from placebo.


[Content of carcinogenic substances in the oil-refrigerating technology].
Benz(a)pyrene and nitrosamines serve as bases for oiling refrigerating technologic mediums. Such mediums applied to metals processing lead to higher carcinogens content and their release into the air of working area. Studies demonstrate that employees are exposed to effective doses of carcinogens.


Effect of GABA-T inhibitors on prolactin secretion in vitro.
A study was made of the effect of GABA-transaminase (GABA-T) inhibitors on the in vitro release of prolactin by pituitaries of male and female rats. Aminooxyacetic acid (AOAA) and gamma-acetylenic GABA (GAG) added to the incubation medium decreased prolactin release from both male and female rat pituitaries. Additive effects on prolactin release were only observed when male rat pituitaries were incubated with AOAA plus GABA. Prolactin concentration in the pituitary gland was also decreased by AOAA in both sexes. The present results lend support to the idea of an inhibitory action of GABA on prolactin release by the pituitary gland.


Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.
E26 transformation-specific (ETS) gene family contains a common DNA-binding domain, the ETS domain, responsible for sequence-specific DNA recognition on target promoters. The Fli-1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline-like compounds including 4'-demethoxy-3',4'-methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli-1 transactivation ability. These compounds altered expression of Fli-1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline-like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli-1-driven mouse model. Mechanistically, the compounds blocked c-Raf-MEK-MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli-1 protein synthesis. Consistent with its high expression in myelomas, B-cell lymphoma, and B chronic lymphocytic leukemia (B-CLL), pharmacological inhibition of Fli-1 by the flavagline-like compounds or genetic knock-down via shRNA significantly hindered proliferation of corresponding cell lines and patients' samples. These results uncover a critical role of Fli-1 in growth and survival of various hematological malignancies and point to flavagline-like agents as lead compounds for the development of anti-Fli-1 drugs to treat leukemias/lymphomas overexpressing Fli-1.


Domain wall propagation and nucleation in a metastable two-level system.
We present a dynamical description and analysis of nonequilibrium transitions in the noisy one-dimensional Ginzburg-Landau equation for an extensive system based on a weak noise canonical phase space formulation of the Freidlin-Wentzel or Martin-Siggia-Rose methods. We derive propagating nonlinear domain wall or soliton solutions of the resulting canonical field equations with superimposed diffusive modes. The transition pathways are characterized by the nucleation and subsequent propagation of domain walls. We discuss the general switching scenario in terms of a dilute gas of propagating domain walls and evaluate the Arrhenius factor in terms of the associated action. We find excellent agreement with recent numerical optimization studies.


Case 271.
History An 11-year-old boy taking oral antibiotics for Fusobacterium meningitis diagnosed 3 months earlier presented to the emergency department with a 1-week history of intermittent emesis, dizziness, and vertigo and a 1-day history of wobbly gait and bilateral lower extremity paresthesia without confusion. His metabolic profile was normal. Contrast material-enhanced MRI of the brain was performed, and selected images are shown ( Fig 1 - 4 ). Figure 1a: (a) Axial fluid-attenuated inversion recovery (repetition time msec/echo time msec, 11 000/125) MRI and (b) axial turbo spin-echo T2-weighted (3000/80) MRI of the brain through the cerebellum at presentation. (c) Axial fluid-attenuated inversion recovery (6000/120) MRI and (d) axial turbo spin-echo T2-weighted (5545/100) MRI through the same level of the cerebellum obtained 6 weeks earlier. Figure 1b: (a) Axial fluid-attenuated inversion recovery (repetition time msec/echo time msec, 11 000/125) MRI and (b) axial turbo spin-echo T2-weighted (3000/80) MRI of the brain through the cerebellum at presentation. (c) Axial fluid-attenuated inversion recovery (6000/120) MRI and (d) axial turbo spin-echo T2-weighted (5545/100) MRI through the same level of the cerebellum obtained 6 weeks earlier. Figure 1c: (a) Axial fluid-attenuated inversion recovery (repetition time msec/echo time msec, 11 000/125) MRI and (b) axial turbo spin-echo T2-weighted (3000/80) MRI of the brain through the cerebellum at presentation. (c) Axial fluid-attenuated inversion recovery (6000/120) MRI and (d) axial turbo spin-echo T2-weighted (5545/100) MRI through the same level of the cerebellum obtained 6 weeks earlier. Figure 1d: (a) Axial fluid-attenuated inversion recovery (repetition time msec/echo time msec, 11 000/125) MRI and (b) axial turbo spin-echo T2-weighted (3000/80) MRI of the brain through the cerebellum at presentation. (c) Axial fluid-attenuated inversion recovery (6000/120) MRI and (d) axial turbo spin-echo T2-weighted (5545/100) MRI through the same level of the cerebellum obtained 6 weeks earlier. Figure 2a: (a) Axial fast spin-echo T1-weighted MRI (496/8) and (b) axial reconstruction of three-dimensional fast field-echo T1-weighted contrast-enhanced (7 mL of gadobutrol, Gadavist; Bayer Healthcare Pharmaceuticals, Berlin, Germany) MRI (7.98/3.72) of regions similar to those in Figure 1 . Figure 2b: (a) Axial fast spin-echo T1-weighted MRI (496/8) and (b) axial reconstruction of three-dimensional fast field-echo T1-weighted contrast-enhanced (7 mL of gadobutrol, Gadavist; Bayer Healthcare Pharmaceuticals, Berlin, Germany) MRI (7.98/3.72) of regions similar to those in Figure 1 . Figure 3a: (a) Axial diffusion-weighted MRI (3090/71) and (b) axial apparent diffusion coefficient map (3090/71) of regions similar to those in Figure 1 . Figure 3b: (a) Axial diffusion-weighted MRI (3090/71) and (b) axial apparent diffusion coefficient map (3090/71) of regions similar to those in Figure 1 . Figure 4: Three-dimensional maximum intensity projection image (25/3.45) of the posterior cerebral circulation obtained with MR angiography of the head.


Galactocele in a male infant: case report and review of literature.
An 11-month-old male developed painless enlargement of the left breast over 1 month. The lesion was mobile, fluctuant, and nontender. Surgical excision was performed and histological examination revealed a galactocele. A galactocele is a very rare cause of breast enlargement in male infants and children.


Vagus nerve stimulation paired with tactile training improved sensory function in a chronic stroke patient.
Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitation can enhance neural plasticity in the primary sensory and motor cortices, improve forelimb function after stroke in animal models and improve motor function in patients with arm weakness after stroke. To gain "first-in-man" experience of VNS paired with tactile training in a patient with severe sensory impairment after stroke. During the long-term follow-up phase of a clinical trial of VNS paired with motor rehabilitation, a 71-year-old man who had made good motor recovery had ongoing severe sensory loss in his left hand and arm. He received VNS paired with tactile therapy in an attempt to improve his sensory function. During twenty 2-hour sessions, each passive and active tactile event was paired with a 0.5 second burst of 0.8 mA VNS. Sensory function was measured before, halfway through, and after this therapy. The patient did not report any side effects during or following VNS+Tactile therapy. Quantitative measures revealed lasting and clinically meaningful improvements in tactile threshold, proprioception, and stereognosis. After VNS+Tactile therapy, the patient was able to detect tactile stimulation to his affected hand that was eight times less intense, identify the joint position of his fingers in the affected hand three times more often, and identify everyday objects using his affected hand seven times more often, compared to baseline. Sensory function significantly improved in this man following VNS paired with tactile stimulation. This approach merits further study in controlled clinical trials.


The growth of rats and mice vibrissae under normal and some abnormal conditions.
The growth of hair from the mystacial vibrissal follicles of C3H mice and Wistar rats has been measured for up to seven cycles. Normally growth in length and thickness was regular and little affected by age or sex. Plucking vibrissae at any stage during the growing period was followed by the appearance of a new vibrissa 8-11 days later. Plucking when growth had ceased had no effect on the time of appearance of the subsequent cycle. New whiskers emerging after plucking grew at the normal rate. Withholding food slowed the growth of vibrissae within 1 day. Normal growth was re-established 3 days after return to full diet.


Multimodal treatment for t1-2 supraglottic cancer: the impact of tumor location.
To examine the outcome and prognostic factors after multimodal treatment of T1-2 supraglottic cancer. We analyzed 49 patients with T1-2 supraglottic cancer who received multimodal treatment between 1990 and 2011. Their age range was 43-86 years (median=66 years). Fifteen patients had a T1 tumor and 34 had a T2 tumor (40 N0, 3 N1, 4 N2, and 2 N3). Debulking using transoral laser excision was employed in 25 patients. Neck dissection was performed in four patients. Chemotherapy was administered to 29 patients: intra-arterial infusion in four and systemic infusion in 25. Radiotherapy was administered at a median dose of 64.8 Gy (range=30-70 Gy) with once- or twice-daily fractionation. Median follow-up time was 60 months (range=12-153 months). Two patients interrupted radiotherapy because of a poor response at 30 Gy (T2N2) and 49.9 Gy (T2N0). They underwent total laryngectomy and were still alive without any evidence of cancer 48 and 28 months after treatment, respectively. The other 47 patients (96%) had a complete local response to treatment. Locoregional failure was observed in six tumor sites, and one patient had simultaneous locoregional recurrence. The 5-year local control, disease-free, overall survival, and laryngeal preservation rates were 82%, 74%, 82%, and 90%, respectively. The location of a primary tumor within the supraglottis (epilarynx or elsewhere) was identified as the only factor predictive of progression-free survival by univariate and multivariate analyses (p=0.04). Acute adverse reactions of grade 3 or more were: one grade 3 laryngeal edema, one grade 3 dyspnea, and one grade 5 hematological toxicity (disseminated intravascular coagulation). Among late adverse events, one grade 1, one grade 2 hoarseness, and grade 3 laryngeal necrosis were observed. Multimodal radiotherapy produced a good outcome. Localization of the tumor in the epilarynx was associated with a better progression-free survival rate than that in the other parts of the supraglottis.


'It's all in the message': the utility of personalised short message service (SMS) texts to remind patients at higher risk of STIs and HIV to reattend for testing-a repeat before and after study.
Patients at increased risk of sexually transmitted infections (STIs)/HIV acquisition are advised to reattend for retesting. A previous study showed that 'generic' text reminders did not improve reattendance. To assess if a personalised text message with increased contact information would increase reattendance rates of at-risk patients. Patients who are at risk of future STIs, defined by having a current acute STI, attending for emergency contraception, commercial sex workers (CSWs) or men who have sex with men (MSM), were sent a text reminder to reattend for retesting 6 weeks after initial visit. Reattendance rates were measured for September to December 2012 (control group who received a generic text message) and February to May 2014 (intervention 'personalised message' group who received a text message containing their first name and ways to contact the clinic). Reattendance was counted within 4 months of the end of the initial episode of care. The reattendance rate was significantly higher for the intervention group: 149/266 (56%) than the control group: 90/273 (33%) (p=0.0001) and was also significantly higher in the intervention group than the control group in patients with the following risks: recent chlamydia (64/123 (52%) vs 43/121 (36%)) (p=0.03), recent gonorrhoea (41/64 (64%) vs 4/21 (19%)) (p=0.0003) and MSM (26/45 (58%) vs 3/18 (16%)) (p=0.006). New STI rates in the reattending intervention group and controls were 26/ 149 (17%) and 13/90 (14%) (n.s), respectively. Sending a personalised text message with increased contact information as a reminder for retesting increased reattendance rates by 23% in patients who are at higher risk of STIs.


The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets.
Vascular endothelial growth factor (VEGF) and endostatin are key protein modulators of angiogenesis found within platelets. The platelet activation pathways that control angiogenic protein release are incompletely elucidated. The differential release of pro-angiogenic and anti-angiogenic proteins from the platelet has been demonstrated for proteinase activated receptors (PARs). Given the ability of tumors to secrete ADP and the availability of ADP receptor antagonists clinically, we determined the influence of adenosine diphosphate (ADP) and the ADP receptors, P2Y(1) and P2Y(12), on platelet release of the angiogenic stimulator protein, VEGF, and the angiogenic inhibitor protein, endostatin. Minimally altered whole blood (WB) and platelet rich plasma (PRP) from healthy volunteers was stimulated with ADP alone (12.5 uM), in combination with a P2Y(1) antagonist (MRS2179) or a P2Y(12) antagonist (cangrelor). VEGF and endostatin protein concentrations were assessed by an ELISA assay. We report that maximally stimulating concentrations of ADP significantly increased VEGF release from platelets in both PRP and WB by 36+/-12% 36+/-12% 54+/-18% 36 +/- 12% (p < 0.05) respectively as compared to control. Both P2Y(1) and P2Y(12) receptor antagonism inhibited this release. Conversely, endostatin levels did not change following ADP stimulation in PRP, while a 4.7% (p = 0.03) increase was observed in WB. As compared to thrombin receptor activation, ADP activation was a weaker stimulus for VEGF release. We found that activation of platelets by ADP results in an increase in soluble VEGF concentrations with minimal effects on endostatin concentrations, suggesting ADP release in the tumor microenvironment may be, on balance, proangiogenic. P2Y receptor antagonism abrogates ADP mediated proangiogenic protein release and thus may represent a potential pharmacologic strategy for regulating platelet mediated angiogenesis.


Ventricular remodeling in heart failure and the effect of beta-blockade.
Left ventricular (LV) remodeling has an important role in the progression of cardiovascular disease. An understanding of the process of LV remodeling has led to greater knowledge of the pathophysiology of heart failure. Drug therapies that slow or reverse the remodeling process seem to have favorable natural history effects in short-term and long-term therapy. Angiotensin-converting enzyme (ACE) inhibitors have been associated with a significant reduction in mortality, and the effect of beta-blockers on the remodeling process has now been studied across much of the spectrum of severity in patients with heart failure. beta-Blockade seems to add favorable and independent effects on the post-myocardial infarction remodeling process over and above those of ACE inhibitors. A combination of both drugs shows the greatest reduction in mortality (ie, the most favorable reverse remodeling). Differences in their effect on remodeling have been recently shown among the beta-blockers. Several studies and a meta-analysis suggest that carvedilol may be more favorable to outcome, having the most effect on LV remodeling.


Tropomyosins regulate the impact of actin binding proteins on actin filaments.
The state of actin depends intimately on its interaction partners in eukaryotic cells. Classically, the cooperative force-generating acto-myosin couple is turned off and on by the calcium-dependent binding and release of tropomyosin molecules. The situation with nonmuscle cells appears to be much more complicated, with tropomyosin isoforms regulating the kinds of tension-producing and stress-bearing structures formed of actin filaments. The polymerization of even the shortest gelsolin-capped filaments is efficiently promoted by the binding of tropomyosin, for example, a process that might occur all the way out to the leading edges of advancing cells. Recently, multimers of tropomyosin have been discovered that appear to be assembly intermediates, formed from identical tropomyosin molecules, which act as ready pools of tropomyosin during the catalytic formation of lamellipodia and filopodia. Remarkably, these multimers apparently reform during the disassembly of cellular actin-containing structures. The existence of these recyclable, tropomyosin isoform-specific structures suggests how cells prevent nonproductive association of non-identical, but closely similar, tropomyosin isoforms.


Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate.
To compare the efficacy and safety of ibandronate and pamidronate in patients with hypercalcemia of malignancy (HCM). Seventy-two patients with HCM [albumin-corrected serum calcium (CSC) >2.7 mmol/l] were treated with a single infusion of ibandronate (2 or 4 mg) or pamidronate (15, 30, 60, or 90 mg) on day 0. The dose was dependent on the severity of hypercalcemia (baseline CSC level). CSC was assessed daily until day 4, then at intervals until day 28. The primary endpoint was lowering of CSC at day 4. Secondary endpoints included the number of patients responding and time to re-increase following response. Using the CSC baseline approach, the most frequently administered doses were 4 mg ibandronate (78.4%) and 60 mg pamidronate (50.0%). Mean lowering of CSC at day 4 was 0.6 mmol/l for ibandronate and 0.41 mmol/l for pamidronate. The 95% confidence interval for the difference ibandronate pamidronate had a lower limit of 0.05 mmol/l, indicating that ibandronate was as effective as pamidronate. The number of patients responding to the two agents was also similar; 76.5% of ibandronate patients and 75.8% of pamidronate patients were rated as responders after the first dose of study medication. The median time to re-increase after response was longer for ibandronate (14 days) than pamidronate (4 days) ( P=0.0303). In the subgroup of 17 patients with high baseline CSC (>3.5 mmol/l), ibandronate appeared to be more effective than pamidronate. The safety profile of both agents was similar. Ibandronate is at least as effective as pamidronate in the treatment of HCM. Furthermore, in patients with higher baseline CSC ibandronate appears to be more effective than pamidronate. The duration of response is significantly longer with ibandronate than pamidronate.


[Serological diagnosis of Staphylococcus aureus infections using anti-A beta teichoic acid antibodies assay (author's transl)].
225 control subjects, 12 hospitalized Staphylococcus free (34 sera) and 16 S. aureus infected patients (79 sera) were tested for anti-A beta teichoic acid antibodies, using counter-immunoelectrophoresis. Anti-alpha and gamma haemolysins antibodies were dosed in parallel in 164 sera. Less than 5 per cent of control sera (3,11 per cent) have an antibody tire higher than 1/8: this tire is therefore selected as threshold level of positivity. Ten of the 12 hospitalized patients without staphylococcal infections are below this level. 31,6 per cent of staphylococcus infected patients have higher serum titers; only 3,7 per cent have no antibodies. In the others, a significant rise in titres is observed. There is no correlation between anti-alpha and gamma staphylolysin and anti-teichoic acid antibodies titres. The method suggested, both easy and rapid, could be used in association with anti-staphylolysin dosage for serological diagnosis of staphylococcal infections.


May glutamine addiction drive the delivery of antitumor cisplatin-based Pt(IV) prodrugs?
A small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion. On the contrary, when the Gln concentration in cell medium is near or lower to the physiological value, complex 4 acts as a Trojan horse: it enters SLC1A5-overexpressing cells, where, upon reduction, it releases the active metabolite cisplatin and the Gln-containing ligand, thus preventing any possible extrusion by the L-type amino acid transporter LAT1. This selective mechanism could decrease off-target accumulation of 4 and, consequently, Pt-associated side-effects.


The role of cost effectiveness analysis in health care evaluation.
This paper provides an overview of the key elements of cost effectiveness analysis (CEA). CEA is a method for evaluating the relative costs and benefits of treatments and procedures. Typically, CEA compares a proposed intervention with (at least) one alternative intervention, yielding an incremental cost effectiveness ratio. This ratio reflects both the longevity and health status of the differing interventions and permits the researcher to more completely compare and evaluate the "payoff" of the interventions. This paper discusses different perspectives CEA studies might adopt, and reviews the major methods for measuring both outcomes and costs.


Characterisation of fluorine containing glasses by 19F, 27Al, 29Si and 31P MAS-NMR spectroscopy.
The aim of this study is to characterise a range of model and commercially available glasses used to form glass (ionomer) polyalkenoate cements. A range of model fluoro-alumino-silicate glasses that form the basis of glass (ionomer) polyalkenoate cements and five commercial glasses have been characterised by 29Si, 27Al, 31P and 19F Magic Angle Spinning Nuclear Magnetic Resonance (MAS-NMR). The 29Si spectra indicate a predominantly Q33Al and Q44Al structure where the Q33Al species represents a silicon with one non-bridging oxygen and three Si-O-Al linkages and the Q44Al species a silicon with four Si-O-Al bonds. Aluminium was found in predominantly four coordinate sites, but glasses with high fluorine contents showed an increasing proportion of five and six coordinate aluminium. In phosphate containing glasses the phosphorus was present as Al-O-PO3(2-) type species indicating local charge compensation of Al3+ and P5+ in the glass structure. 19F MAS-NMR indicated the presence of F-Ca(n), Al-F-Ca(n), F-Sr(n), Al-F-Sr(n) and Al-F-Na(n) species where F-M(n) indicates a fluorine surrounded by n next nearest neighbour cations and Al-F-M(n) represents a fluorine bonded to aluminium with the metal, M in close proximity charge balancing the tetrahedral AlO3F species. The proportion of Al-F-M(n) species increased with increasing fluorine content of the glass and lower non-bridging oxygen contents. There was no evidence of Si-F bonds in any of the glasses. The local structure of the phosphate containing glasses with regard to fluorine, calcium, strontium and phosphate is similar to that of fluorapatite the mineral phase of tooth. This may explain the ease with which these glasses crystallize to fluorapatites and the recently observed mineralization of glass polyalkenoate cements found in vivo.


Oral, osmotic minipump, and intramuscular administration to sheep of the Veratrum alkaloid cyclopamine.
Logistic and biologic aspects of three separate means of administration of cyclopamine for experimental induction of terata or embryonic death in sheep were examined. Oral capsule administration of crystalline cyclopamine is logistically simple and biologically effective, but costly in terms of amount of compound required. Embryos were affected in five of seven ewes dosed cyclopamine orally at higher levels (four nonpregnant and one with cyclopia). Intramuscular administration of cyclopamine dissolved in ethanol was logistically simple but without biologic effect at levels tested. Three of three treated ewes had normal offspring. Osmotic minipump administration of powdered cyclopamine suspended in propylene glycol was logistically unsatisfactory with serious delivery complications. Osmotic minipump administration of cyclopamine dissolved in ethanol was logistically very satisfactory, and one ewe among three treated animals was nonpregnant at term. There were no nonpregnant ewes nor deformed offspring in 17 controls.


[The role of middle-molecule peptides in the pathogenesis of traumatic disease].
On the basis of study of mass-spectrum of blood plasma ultrafiltrate in 21 injures with severe associated trauma during first four posttraumatic days and in healthy persons one can suggest that combinations with molecular weights of 300-1050 Da are to be one of the important regulatory mechanisms of posttraumatic adaptative processes. With increasing of the injury gravity reorientation of the levels of adaptative reactions management and level enhancing of mediomolecular regulators are found to be occurred.


Quantitative assessment of early liver fibrosis in rats using 13N-NH3·H2O PET/CT.
To investigate the value of N-NH3·H2O PET/computed tomography (CT) and the inhibitor, acetazolamide (ACZ), in the quantitative diagnosis of early liver fibrosis and the assessment of liver fibrosis stage. Twenty-four male Wistar rats (293.54±37.99 g) were used in this study and grouped by pathology after biopsy. Using N-NH3·H2O as an imaging agent and ACZ as an aquaporin 1 inhibitor, the rats were subjected to a dynamic PET/CT scan for 45 min. According to data reconstruction and imaging analysis, we calculated the mean standard uptake value (SUVmean) of the liver at the time points of 20, 90 s, 5, 10, 15, 20, and 25 min. From the results of N-NH3·H2O, the liver SUVmean in the control group and the liver fibrosis model group at different time points were compared. In addition, blood perfusion, interstitial diffusion, and N-NH3·H2O metabolism of the two groups were compared. Single-factor analysis of variance was used to analyze the differences between the SUVs in the groups at any time point and the paired-sample t-test was used to compare the SUVs before and after addition of the inhibitor. We included four rats in the control group (S0) and 20 rats in the liver fibrosis group (which included early-stage S1: 11 rats, progressive-stage S2+S3+S4: nine rats). Three rats in S0, seven rats in S1, and six rats in S2+S3+S4 were paired. The SUVmean at 90 s was statistically different (P<0.05); however, the other groups showed statistical difference at all time points (P>0.05). After the addition of the inhibitor, ACZ, the SUVmean of S0 and S2+S3+S4 at 10, 15, 20, and 25 min was statistically different (P<0.05). N-NH3·H2O PET/CT may aid the diagnosis of liver fibrosis. N-NH3·H2O PET/CT combined with ACZ may help distinguish between the early stage and the progressive stage of liver fibrosis.


The role of mast cell degranulation in ischaemia-reperfusion-induced mucosal injury in the small intestine.
The role of the intestinal mast cell system in the pathophysiology of postischaemic mucosal lesions is not understood. The present goals were to investigate the contributions of mast cells and mast cell-derived vasoactive mediators to mucosal injury caused by arterial occlusion. We evaluated the intestinal ischaemia-reperfusion-induced local morphological changes in mast cell-depleted anesthetized dogs. Animals subjected to complete segmental intestinal ischaemia and reperfusion served as controls. The selective mucosal-type mast cell degranulator Cremophor-El and the nonselective mast cell depleter Compound 48/80 were used to investigate the involvement of mast cells in reperfusion-induced tissue reactions. Ileal biopsies taken at the end of 120 min of ischaemia and after 120 min of reperfusion were evaluated histologically. The number of mast cells was determined and the degree of mucosal damage was evaluated according to the 0 to 5-grade Chiu scale. Mucosal histidine decarboxylase activity was measured in tissue biopsies and the rate of release of histamine was determined from the venous effluent of the segment. In the control group, 120 min reperfusion induced a severe tissue injury. In the Compound 48/80 and Cremophor-El-pretreated groups, the reduction in the baseline number of mast cells was 37% and 53%, respectively, and the basal mucosal histidine decarboxylase activity was significantly increased. In these groups, the ischaemia-reperfusion-induced release of histamine was significantly decreased, and the degree of damage of the intestinal mucosa was significantly reduced. Mucosal mast cell degranulation plays an important role in the initiation of tissue injury after intestinal ischaemia-reperfusion. Depletion of mast cells prior to ischaemia decreases the severity of mucosal damage, probably in consequence of the stimulation of mucosal histidine decarboxylase activity.


Possible intermediates in the biosynthesis of mycoside B by Mycobacterium microti.
Two lipids were isolated from Mycobacterium microti which became labelled when the cells were grown in the presence of [2-14C]propionate. They were purified by thin-layer chromatography and studied by chemical degradation and mass spectrometry. The lipids were identified as phenolphthiocerol dimycocerosate and phenolphthiodiolone dimycocerosate, the aglycosyl derivatives of mycoside B, the phenolic glycolipid produced by M. microti. Cell-free extracts of the organism were able to glycosylate the lipids to form mycoside B in vitro. It is probable that the lipids are intermediates in the biosynthesis of phenolic glycolipids by mycobacteria.


Reducing methylglyoxal as a therapeutic target for diabetic heart disease.
Diabetes is a well-known risk factor for the development of cardiovascular diseases. Diabetes affects cardiac tissue through several different, yet interconnected, pathways. Damage to endothelial cells from direct exposure to high blood glucose is a primary cause of deregulated heart function. Toxic by-products of non-enzymatic glycolysis, mainly methylglyoxal, have been shown to contribute to the endothelial cell damage. Methylglyoxal is a precursor for advanced glycation end-products, and, although it is detoxified by the glyoxalase system, this protection mechanism fails in diabetes. Recent work has identified methylglyoxal as a therapeutic target for the prevention of cardiovascular complications in diabetes. A better understanding of the glyoxalase system and the effects of methylglyoxal may lead to more advanced strategies for treating cardiovascular complications associated with diabetes.


Glycyrrhizic Acid Prevents Oxidative Stress Mediated DNA Damage Response through Modulation of Autophagy in Ultraviolet-B-Irradiated Human Primary Dermal Fibroblasts.
Excessive exposure to UV radiation negatively affects the human skin, characterized by photo-damage (premature aging & carcinogenesis). UV-B radiation causes about 90% of non-melanoma skin cancers by damaging de-oxy ribonucleic acids (DNA). We have previously reported that UV-B radiation induces skin photodamage through oxidative & Endoplasmic Reticulum (ER) stresses and Glycyrrhizic acid (GA), a natural triterpene, protects skin cells against such stresses. UV-B radiation elicits signalling cascade by activation of proteins involved in sensing, signalling, and repair process of DNA damage. In this study, we explored the effects & mechanisms of Glycyrrhizic acid (GA) against UV-B -induced photodamage using a well established cellular model. We used primary human dermal fibroblasts as a cellular model. The cells were cultured in the presence or absence of GA for 3,6, & 24 h. Effect of UV-B was assessed by examining cell viability, cell morphology, oxidative stress, ER stress, DNA damage & cellular autophagy levels through biochemical assays, microscopy & protein expression studies. In this study, we have determined the effect of GA on autophagy mediated DNA damage response system as the main mechanism in preventing photodamage due to UV-B -irradiation to primary human dermal fibroblasts (HDFs). GA treatment to UV-B exposed HDFs, significantly inhibited cell death, oxidative & ER stress responses, prevented Cyclobutane Pyrimidine dimer (CPD) DNA adduct formation, and DNA fragmentation via modulation of UV-B induced autophagic flux. Present results showed that GA treatment quenched reactive oxygen species (ROS), relieved ER stress response, improved autophagy (6 hr's post-UV-B -irradiation) and prevented UV-B induced DNA damage. The present study links autophagy induction by GA as the main mechanism in the prevention of DNA damage and provides a mechanistic basis for the photoprotective effect of GA and suggests that GA can be potentially developed as a promising agent against UV-B induced skin photo-damage.


Detection of type D retrovirus in a human amnion cell line (FL).
This paper describes the detection of viral particles in a human amnion cell line (FL). These particles belong to the group of type D retroviruses, because of their characteristic morphology, their major antigenic determinants, and the presence of particle-associated Mg++-preferring RNA-dependent DNA polymerase. In addition to budding and mature type D virus particles, intracytoplasmic type A structures have also been found. Immunological analysis provided evidence of cross-reactivity between the particles described and the Mason-Pfizer monkey virus as well as type D retroviruses from other human cell lines (PMF, HEp-2). Particles isolated from FL cell medium were shown to infect type D virus-susceptible human TU 197 cells.


Assessing the microbiological risk to stored sixteenth century parchment manuscripts: a holistic approach based on molecular and environmental studies.
The microbial risk for the conservation of seven sixteenth century parchment manuscripts, which showed brown discolouration putatively caused by microorganisms, was evaluated using non-invasive sampling techniques, microscopy, studies of surface-associated and airborne microflora with culture-independent molecular methods, and by measuring repository thermo-hygrometric values. Microscopic observations and ATP assays demonstrated a low level of contamination, indicating that the discolouration was not related to currently active microbial colonisation. Nevertheless, a culture-independent molecular approach was adopted to fully characterise surface-associated communities searching for biodeteriogens that could grow under appropriate thermo-hygrometric conditions. Indeed, potential biodeteriogens and microorganisms that are ecologically related to humans were found, suggesting the need to control the conservation environment and improve handling procedures. Microbial loads of air and thermo-hygrometric measurements showed that the repository was not suitable for preventing the microbial deterioration of parchment. A holistic approach to the assessment of risk of microbial deterioration of documents and heritage preservation is proposed for the first time.


Characterization of production and enzyme properties of an endo-beta-1,4- glucanase from Bacillus subtilis CK-2 isolated from compost soil.
Bacillus subtilis CK-2, isolated from garden organic waste compost, was found to have high hydrolytic activity against carboxymethylcellulose (CMC) due to the secretion of an endo-beta-1,4- glucanase. Enzyme production was related to the sporulation process, and was regulated by the concentration of readily metabolizable carbohydrate in growth medium. Enzyme production did not require CMC or other cellulose containing materials. The endo-beta-1,4-glucanase activity was optimal at pH 5.6-5.8 and at 65 degrees C, and achieved thermal stability up to 55 degrees C. The activity was inhibited by Hg2+. The purified enzyme gave a single band corresponding to a MW of 35.5 kDa on SDS-PAGE, while the Sephadex G-75 chromatography revealed a molecular weight of the active enzyme around 70 kDa, indicating a dimeric form of the active enzyme. The enzyme activity was irreversibly inhibited by SDS. Native PAGE and IEF revealed three different isoelectric forms of the enzyme, all with an identical N-terminal amino-acid sequence.


Microglial activation is not prevented by tacrolimus but dopamine neuron damage is reduced in a rat model of Parkinson's disease progression.
A progressive model of Parkinson's disease has been recently developed in the rat where a unilateral excitotoxic injection into the globus pallidus leads to a gradual loss of dopaminergic neurons in the ipsilateral substantia nigra over a period of at least 6 weeks. In this model microglial activation is observed in the ipsilateral substantia nigra 3 weeks after the lesion and could contribute to neuronal death at this time. The immunosuppressant drug tacrolimus (FK506) reduces dopamine cell death at 3 weeks following a globus pallidus lesion, but not thereafter. Tacrolimus-mediated neuroprotection could result from suppression of microglial activation but the microglial activation at three weeks post-lesion was not much reduced. Microglial activation was observed even in the apparent absence of neuronal death, prompting the suggestion that tacrolimus may prevent, or at least delay, the release of toxic cytokines from activated microglia. By 6 weeks after the GP lesion, even this mechanism fails to protect the dopamine cells from damage.


Nitric oxide-dependent and -independent components of cerebrovasodilation elicited by hypercapnia.
We studied the effect of nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on the increases in cerebral blood flow (CBF) elicited by stepwise elevations in arterial partial pressure of CO2 (PaCO2) from normocapnia up to 204 mmHg. Rats were anesthetized with halothane and ventilated. CBF was monitored over the parietal cortex using a laser-Doppler flowmeter. Increasing levels of hypercapnia elicited graded elevations in CBF that reached a plateau at PaCO2 = 82 +/- 1 mmHg (CBF +215 +/- 25%; n = 8; P < 0.05, analysis of variance). L-NAME (40 mg/kg i.v.; n = 8), but not nitro-D-arginine methyl ester (n = 8), reduced resting CBF (-42 +/- 4%) and attenuated the increase in CBF elicited by hypercapnia. The attenuation occurred only at PaCO2 40-80 mmHg and was maximal (-75 +/- 8%; P < 0.05) at 54 +/- 2 mmHg. At PaCO2 > or = 100 mmHg, L-NAME (40-80 mg/kg) did not attenuate the response (P > 0.05). Reduction of resting CBF (-50 +/- 4%; n = 6) by administration of chloralose (20-40 mg/kg i.v.) did not attenuate the CBF response to hypercapnia (P > 0.05). We also found that the attenuation by L-NAME of resting CBF (n = 5) and of the cerebrovasodilation elicited by hypercapnia (n = 6) has a relatively slow time course, the effects reaching a maximum 45-60 min after intravenous administration of the drug. We conclude that L-NAME does not attenuate the CBF response to CO2 uniformly at all levels of hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)


[Analysis of the inappropriate utilization of the emergency service of a third-level hospital].
a) To find the reasons for inadequate use of Hospital Casualty Departments (HCDs); b) to discover the general population's levels of information concerning non-hospital Emergency Services (NESs); c) to analyse the relationship between the type of Primary Care Centre (PCC), i.e. whether reformed or not, and inadequate use of HCDs. A crossover study. The Germans Trias i Pujol Hospital Casualty Department, Badalona. A random sample of 321 patients over 14 years old, who were attended for pathologies considered emergencies not requiring hospital treatment. The variables gathered were: age, gender, where the patient came from, reason for hospital use, knowledge of NESs and subsequent referral. 83.2% of patients attended on their own initiative. The main reasons given were "advantages of a hospital" and "the persistence of symptoms." 49% of the patients stated they knew of the NESs. 80% of the patients proceeded from PCCs which had not been reformed. There were no statistically significant differences (p > 0.05) when the variables "reason for use" and "knowledge of NESs" were compared in relation to where the patient came from (i.e. reformed or non-reformed PCC). General practitioners in reformed PCCs are less likely to refer to HCDs. Knowledge and use of NESs should be actively supported.


Effects of level of feed intake and Fusarium toxin-contaminated wheat on rumen fermentation as well as on blood and milk parameters in cows.
The aims of this study were to examine the effects of and possible interactions between dry matter (DM) intake and feeding Fusarium toxin-contaminated wheat on ruminal fermentation, serum chemical parameters and milk yield of dairy cows. Fourteen dairy cows equipped with ruminal and duodenal cannulas were analysed. All animals were fed the same ration, the daily feed amounts being adjusted to current performance. On DM basis, the ration consisted of 60% concentrate including 55% wheat [Fusarium-contaminated wheat (mycotoxin period) or control wheat (control period)] and was completed with 40% maize and grass silage. Each cow was fed the contaminated wheat [deoxynivalenol (DON), 8.21 mg/kg DM and zearalenone (ZON), 0.09 mg/kg DM] and the control wheat (0.25 mg DON/kg DM and 51 microg ZON/kg DM). As expected, a higher organic matter (OM) intake decreased the amounts of fermented crude nutrients related to the respective intakes. An increased amount of crude protein degraded (p < 0.05) and a lower molar percentage of propionate in the rumen fluid were observed when feeding the Fusarium toxin-contaminated wheat at increased OM intakes in comparison with the control wheat. The activities of serum aspartate aminotransferase (ASAT; p < 0.001), glutamate dehydrogenase (GLDH; p < 0.01) and gamma glutamyl transferase (gamma-GT; p < 0.01) increased with increasing OM intake and were not related to the mycotoxin contamination of the wheat.


Absence of interaction between ramipril, a new ACE-inhibitor, and phenprocoumon, an anticoagulant agent.
In a double-blind, placebo-controlled crossover trial, the effects of ramipril, a long-acting non-sulphydryl angiotensin I converting enzyme inhibitor, on phenprocoumon steady-state pharmacodynamics were investigated in 8 healthy male volunteers taking individually fixed doses of phenprocoumon. The results showed that 5 mg ramipril or placebo once daily for 7 days did not alter the anticoagulant response (Quick values) to phenprocoumon after a stabilization phase of 2 weeks. Mean Quick values during the steady-state phase with ramipril and placebo were 67.5% and 69.3%, respectively. The clotting factors II, VII, IX and X as well as protein C decreased in the run-in phase and remained stable both during ramipril and placebo treatment. There were no differences between ramipril or placebo treatments. As the phenprocoumon dosage was kept unchanged during the double-blind phase, the results indicate that ramipril does not interfere with the vitamin K-dependent cascade.


[Influence of floor surface and access to pasture on claw characteristics in dairy cows kept in cubicle housing systems].
This study aimed at investigating the effect of the floor type used in the walking area of cubicle housing systems and of access to pasture on claw dimensions and claw shape in dairy cows. Data were collected on 36 farms, 12 farms each fitted with mastic asphalt, slatted concrete or solid rubber flooring. With each floor type, cows on half of the farms had access to pasture in summer. The farms were visited three times at intervals of about 6 months and data were collected from 10 cows during each visit. Net growth of the claw horn was highest on rubber flooring and lowest on mastic asphalt. On all floor types, claw angles were larger after the winter period and smaller after the summer period. With regard to claw shape, floor type had an effect on the occurrence of flat, concave and overgrown claw soles. In conclusion, none of the investigated floor types was clearly superior to the others with regard to claw dimensions and claw shape, and access to pasture during summer (median 4 h per day) had only little influence on the investigated claw characteristics.


Biosynthesis and metabolism of retinoic acid: roles of CRBP and CRABP in retinoic acid: roles of CRBP and CRABP in retinoic acid homeostasis.
The enzymes that constitute the pathway of retinoic acid biosynthesis and metabolism may recognize retinoid binding proteins as effectors and substrates. Apocellular retinol-binding protein (CRBP) stimulates a bile-salt independent membrane-bound retinyl ester hydrolase resulting in the hydrolysis of endogenous retinyl esters and the formation of holoCRBP. HoloCRBP delivers retinol to a microsomal nicotin-amide-adenine dinucleotide phosphate-dependent dehydrogenase, protects it from artifactual oxidation and denies enzymes that cannot recognize the binding protein access to retinol. The retinal synthesized may be transferred from the microsomes to the cytosol by CRBP. A cytosolic retinal dehydrogenase has been purified that produces retinoic acid from retinal generated by microsomes in the presence of CRBP and from the complex CRBP-retinal itself. Thus, CRBP(type I) seems to channel retinoids through the reactions of retinoic acid synthesis via a series of protein-protein interactions. Cellular retinoic acid-binding protein (type I) facilitates retinoic acid metabolism by sequestering it and by acting as a low Km substrate, thereby also modulating the steady-state concentrations of retinoic acid.


[Effect of sodium hydroxybutyrate on coronary hemodynamics and microcirculation during hypotension caused by blood loss].
Experiments of 34 dogs were made to study alterations in the cardio- and hemodynamics and microcirculation in the mesenterium during hypotension caused by hemorrhage after intravenous injection of sodium hydroxybutyrate and intravenous re-infusion of heparinized blood under a pressure of 80-120 mm Hg. It was established that single injection of sodium hydroxybutyrate in a dose of 180-200 mg/kg after a 60-minute decrease in the arterial pressure to 40 mm Hg increases pump function of the heart, venous blood returns to the heart, and improves microcirculation. This improvement manifests by the rise in the blood flow rate in the microvessels and in the number of functioning capillaries, and by diminution of red cell aggregation. Favourable effect of the drug is seen within the first minutes after injection and remains unchanged for one hour. Intravenous blood pumping under long-term hypotension is an effective approach to making for the lost blood in the presence of the preceding injection of sodium hydroxybutyrate.


The role of spectral modulation cues in virtual sound localization.
Sound localization cues generally include interaural time difference, interaural intensity difference, and spectral cues. The purpose of this study is to investigate the important spectral cues involved in so-called head related transfer functions (HRTFs) using a combination of HRTF analyses and a virtual sound localization (VSL) experiment. Previous psychoacoustical and physiological studies have both suggested the existence of spectral modulation frequency (SMF) channels for analyzing spectral information (e.g., the spectral cues coded in HRTFs). SMFs are in a domain related to the Fourier transform of HRTFs. The relationship between various SMF regions and sound localization was tested here by filtering or enhancing HRTFs in the SMF domain under a series of conditions using a VSL experiment. Present results revealed that azimuth localization was not significantly affected by HRTF manipulation. Applying notch filters between 0.1 and 0.4 cyclesoctave or between 0.35 and 0.65 cyclesoctave resulted in significantly less accurate elevation responses at low elevations, while spectral enhancement in these two SMF regions did not produce a significant change in sound localization. Likewise, low-pass filtering at 2 cyclesoctave did not significantly influence localization accuracy, suggesting that the major cues for sound localization are in the SMF region below 2 cyclesoctave.


[Functional characteristics of the input-output correlation in the frog vestibular nuclei].
Field and intracellular potentials were recorded in the vestibular nuclear complex of the frog perfused brain following stimulation of the anterior branch of the ipsilateral vestibular nerve and spinal cord. Mono- and polysynaptic EPSPs with orthodromic APs were recorded from vestibular neurones following vestibular nerve stimulation. Antidromic activation of neurones sending their axons to the labyrinth was also recorded. Antidromic APs of vestibulo-spinal neurones evoked with mean latency of 1.43 and 2.19 ms to stimulation of cervical and lumbar cords, respectively, were revealed.


Epstein-Barr virus-encoded LMP1 induces ectopic CD137 expression on Hodgkin and Reed-Sternberg cells via the PI3K-AKT-mTOR pathway.
CD137 is a potent co-stimulatory molecule on activated T cells, and its ligand (CD137L) is expressed on antigen presenting cells (APC). Ectopic expression of CD137 has been identified on Hodgkin Reed-Sternberg (HRS) cells, the malignant cells in Hodgkin Lymphoma (HL), and CD137 on HRS cells was found to support growth of HRS cells and escape from immune surveillance. HRS cells are mostly derived from B cells, which poses the question of how B cells acquire ectopic CD137 expression during the transformation process. HL is associated with Epstein-Barr virus (EBV) infection. We show that the EBV latent membrane protein 1 (LMP1) induces expression of CD137 in HRS cell lines. In a HL tissue microarray, 96% of the CD137-positive HL cases stained positive for LMP1. LMP1 utilizes the PI3K-AKT-mTOR pathway for inducing CD137 expression. These findings support the role of EBV in HL pathogenesis.


The fecal hemoglobin concentration, age and sex test score: Development and external validation of a simple prediction tool for colorectal cancer detection in symptomatic patients.
Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f-Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi-square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02-1.05), male sex: 1.6 (95% CI: 1.1-2.3) and f-Hb (0-<20 µg Hb/g feces): 2.0 (95% CI: 0.7-5.5), (20-<200 µg Hb/g): 16.8 (95% CI: 6.6-42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3-164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85-0.90) in the derivation and 0.91 (95% CI: 0.90-093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value-PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients.


Use of a bronchoscopic protected catheter brush for the diagnosis of pulmonary infections.
Fiberoptic bronchoscopy using a protected brush catheter was done in 65 patients with suspected pulmonary infections to obtain uncontaminated specimens for culture. Quantitative aerobic and anaerobic cultures were done on each specimen. Forty-one patients had pneumonia. Ten bacteremic patients had the same organisms recovered from the catheter and blood cultures. Seven patients had received antibiotics before the procedure, and cultures grew no organisms in high concentration. In 23 of 24 remaining patients probable pathogens were recovered in high concentrations, and specific therapy resulted in clinical improvement in all of these patients. Five patients with lung abscesses and seven with necrotizing pneumonia had mixed aerobic and anaerobic organisms recovered. Twelve patients had final diagnoses of nonbacterial lung disease, and cultures were negative or revealed low concentrations of organisms. Quantitative cultures were necessary in distinguishing pathogens from nonpathogens. There were no complications. The results of this study indicate that fiberoptic bronchoscopy using a special protected catheter is an accurate and safe technique for identification of etiologic agents in lower respiratory tract infections.


An easy preparation of 'monolithic type' hydrophilic solid phase: capability for affinity resin to isolate target proteins.
An easy preparation method of monolithic type hydrophilic solid phase was discussed. Newly invented functional monomer with a hydrophilic cross-linking agent was co-polymerized to realize well-controlled monolithic co-continuous structure by use of diethylene glycol as porogenic solvent. We were able to control the content of the functional monomer up to 40 vol% without loss of monolithic structure. Those prepared were utilized as affinity resins after immobilization of FK506, an immunosuppressive drug as a ligand. It was found that the affinity resins prepared were hydrophilic enough to eliminate non-specific adsorption of proteins, while two of the target proteins of FK506 tested were successfully captured.


The 25.2 MDa tetracycline-resistance plasmid is not derived from the 24.5 MDa conjugative plasmid of Neisseria gonorrhoeae.
High-level tetracycline resistance in strains of Neisseria gonorrhoeae is due to the presence of a 25.2 MDa conjugative plasmid. This plasmid has been shown to carry the streptococcal tetM determinant, and has been thought to have evolved from the 24.5 MDa conjugative plasmid found in N. gonorrhoeae. We have derived a physical map of the 25.2 MDa plasmid pUS100 using seven restriction endonucleases. Comparison of the physical map with the previously published physical map of the conjugative plasmid pLE2451 shows there to be no obvious similarity between the two plasmids. The location of the tetM determinant has been established, by Southern hybridization, confirming the restriction endonuclease map. This has also provided evidence that the transposition functions normally associated with the tetM determinant have been lost.


Short-term preoperative treatment of macroprolactinomas by dopamine agonists.
During a period of 3 years, 25 patients with intra- and extrasellar macroprolactinomas were pretreated with dopamine agonists for a period of 2 to 6 1/2 weeks prior to transsphenoidal microsurgical tumor resection. Dopamine agonists were administered orally to 17 patients, intramuscularly to three patients, and both orally and intramuscularly to five patients. Repeated computerized tomography (CT) examinations revealed that all neoplasms except one cystic tumor were reduced in size during the course of dopamine-agonist administration. No complications attributable to medical pretreatment were observed. Tumor shrinkage increased the efficacy of surgery, especially in cases with considerable extrasellar extension of the adenomas. Within 3 months following adenomectomy, prolactin levels were adjusted to normal levels in 19 patients by additional low-dose treatment with dopamine agonists. Thin-collimation CT assessments performed at least 3 months after surgery showed no evidence of residual tumor tissue in 23 patients. It is concluded that administration of dopamine agonists for some weeks prior to surgery is a useful adjunct to transsphenoidal microsurgery for macroprolactinomas. The new injectable form of bromocriptine is particularly valuable for this purpose.


[Le Quercinois, Guillaume Jacob, physician and surgeon at the Montpellier School, artisan of the reform of medical sciences in Spain the the 18th century].
Guillaume Jacob born in Castelnau-Montratier at the dawn of the XVIIIth century, physician of the School of Medicine of Montpellier was attracted by Spain during the reign of Philip V grand-son of Louis XIV. Nominated Professor of Anatomy at the Royal Society of Medicine of Sevilla, later Royal Academy, he worked during seventeen years to improve Spanish medical science: he informed himself in Paris of the discoveries of French scientists, obtained modern surgical instruments, books to enrich the library, laid the foundations of a botanical garden for medical plants and established links between the Royal Society of Sevilla and various European Royal Academies in order to allow exchanges.


Heparin-binding growth factor(s) derived from head and neck squamous cell carcinomas induce endothelial cell proliferations.
Tumor growth is dependent on the expansion and proliferation of the host vascular system into the primary neoplasm (angiogenesis). The development of an intact vascular system requires migration and proliferation of endothelial cells and assembly into microvessels. Previous studies in our laboratory demonstrated that head and neck squamous cell carcinomas (HNSCC) are angiogenic in vivo. To clarify the mechanism of HNSCC-induced angiogenesis, the present study sought to determine if HNSCCs produced endothelial cell mitogens in vitro. Production of PGE-2, TGF-beta, FGF-2 (basic-FGF [fibroblast growth factor]), and vascular endothelial cell growth factor (VEGF) were quantitated by enzyme-linked immunoabsorbant assay (ELISA) in five HNSCC lines. Cell free supernatants of 5 HNSCC lines were tested in a nonradioactive proliferation assay using human umbilical vein endothelial cells (HUVECs). All lines demonstrated enhanced endothelial cell proliferation in a dose-dependent fashion. Fractionation of these supernatants by heparin column chromatography significantly reduced endothelial cell proliferation in the five lines tested (range, 31.7% to 46.23% reduction; mean, 38.14+/-6.02%). Pretreatment with antibody to VEGF but not transforming growth factor (TGF)-beta inhibited endothelial cell proliferation. These studies indicate HNSCCs produce factor(s) which stimulate endothelial cell proliferation and that VEGF may be involved in HNSCC-induced endothelial cell mitogenesis.


Activation of myocardial protein kinase C by plasmalogenic diglycerides.
Recently, we have demonstrated that myocardial sarcolemma is predominantly comprised of plasmalogen molecular species and that the plasmalogen metabolite 1-O-alk-1'-enyl-2-acyl-sn-glycerol (AAG) accumulates during myocardial ischemia despite substantial decreases in 1,2-diacyl-sn-glycerol (DAG) content. To elucidate the physiological significance of AAG accumulation during myocardial ischemia, rabbit myocardial protein kinase C was partially purified by DE-52 and high-performance hydroxylapatite chromatographies, and the potency of AAG as an activator of myocardial protein kinase C was assessed. Both AAG and 1-O-alkyl-2-acyl-sn-glycerol are potent activators of myocardial protein kinase C with obligatory requirements for physiological increments in free Ca2+ concentration. In contrast, a substantial amount of myocardial protein kinase C activity elicited by DAG was calcium independent. Concentration dependence of ATP for protein kinase C-mediated phosphorylation was identical utilizing either ether-linked diglycerides or DAG as activators, with maximal phosphorylation manifest at ATP concentrations two orders of magnitude less than those found in ischemic myocardium. Thus accumulation of AAG in ischemic myocardium in conjunction with increases in intracellular free Ca2+ concentration may synergistically activate protein kinase C and therefore modulate phosphorylation of proteins in specific subcellular loci.


Vitreoretinal surgery of retinal detachment and macular hole associated with optic nerve pit: an optical coherence tomography study.
To describe the course of a case of macular elevation and a full-thickness macular hole associated with optic nerve pit. A 28-year-old woman who had laser-assisted in situ keratomileusis surgery 2.5 years ago presented with decreased vision, full-thickness macular hole, and macular detachment in association with optic nerve pit. Complete ophthalmic examination was done and optical coherence tomography (OCT) was performed before and after vitreoretinal surgery. OCT showed that the macular elevation consisted of both separation of the inner and outer retinal layers with neurosensory retinal detachment. There was a full-thickness macular hole. After vitreous surgery and intraocular gas tamponade, the macular elevation completely resolved, and OCT showed the flattening of the outer and inner retinal layers but the macular hole was not closed. OCT is a reliable technique to study macular elevation with a hole associated with optic nerve pit before and after vitrectomy and gas tamponade.(Eur J Ophthalmol 2004; 14: 355-7).


[Dantrium in the treatment of increased muscle tonus in patients with multiple sclerosis].
In 19 patients with multiple sclerosis and 1 with subacute sclerosing panencephalitis the mean increase in muscle tonus was found to be 3.1 (range 1--4 according to Burke-Ashwort). In 10 controls with multiple sclerosis the mean spasticity was 2.4. Dantrium was given in doses up to 800 mg for 14--16 days and it caused a greater reduction of spasticity than placebo (p less than 0.05). In 12 patients (60%) varying degrees of muscle tonus reduction was observed. In 11 patients the efect of Dantrium was compared with that of other drugs (Clonazepam, Tetradiazepam, Carisoprodol and Lyoresal). In 6 cases Dantrium was a more effective drug than other muscle relaxants and in 5 cases no difference was observed or other drugs were superior to Dantrium.


An overview of the results of clinical trials with glycoprotein IIb/IIIa inhibitors.
The era of platelet glycoprotein (GP) IIb/IIIa receptor inhibition in cardiology was inaugurated in 1994 with the publication of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial results. EPIC demonstrated that the GP IIb/IIIa blocker abciximab, administered as a bolus and 12-hour infusion, afforded protection against ischemic complications in high-risk patients undergoing angioplasty and atherectomy, including those with unstable angina or evolving myocardial infarction (MI). A significant reduction in the incidence of death, acute MI, or revascularization was apparent at 30 days and also sustained at 6-month and 3-year follow-up. The subsequent Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) study extended these findings to the full spectrum of coronary intervention patients, confirming that abciximab provided similar benefits in low-risk patients as well. The EPILOG trial also proved that any excess bleeding risk associated with potent antiplatelet therapy could be brought down to placebo levels through the use of a low-dose, weight-adjusted heparin regimen, early vascular sheath removal, and elimination of routine postprocedural heparinization. The potential for an advantage of GP IIb/IIIa blockade in patients with refractory unstable angina/non-Q-wave MI was demonstrated in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, which showed that a 24-hour preprocedural abciximab infusion effectively stabilized these patients, thereby enhancing the safety of intervention and reducing the 30-day incidence of ischemic events. A similar pattern of benefit has emerged from clinical trials of such other GP IIb/IIIa inhibitors as eptifibatide, lamifiban, and tirofiban. Trials are currently underway to clarify the benefits of GP IIb/IIIa blockers in patients undergoing stenting and as an adjunct to thrombolytic therapy or primary angioplasty in patients with acute MI (ST-segment elevation).


[Disinfection of the root canal system during endodontic treatment].
In this article an overview is given of the disinfectants used in root canal therapy. The different properties of anti-microbials and their effect on the endodontic microflora are discussed. A clinical guideline for effective disinfection is included.


Reproducibility of contrast-enhanced transrectal ultrasound of the prostate.
Transrectal three-dimensional (3-D) contrast-enhanced power Doppler ultrasound (US) is a novel technique for studying possible prostate malignancy. Before studies can be performed to investigate the clinical validity of the technique, reproducibility of the contrast US studies must be proven. Reproducibility of contrast US was studied in 10 patients with biopsy-proven prostate cancer. The studies performed included static investigations and dynamic investigations of the prostate vasculature. All studies were double performed. The assessment of reproducibility was done objectively using a computer program and, subjectively, by visual assessment. The results indicate high reproducibility of static contrast investigations, for both the objective and subjective assessment. The subjective assessment of the dynamic studies was also highly reproducible. The objective assessment of the dynamic contrast studies, however, was less reproducible, mainly due to motion artefact. We concluded that, especially static 3-D contrast-enhanced, power Doppler investigations of the prostate are highly reproducible.


[Atresia of the larynx, a rare cause of postnatal respiratory distress (author's transl)].
An infraglottic atresia of the larynx with normally developed vocal cords necessitated postnatally an emergency tracheotomy after intubation attempts had failed. Laryngeal atresia is a very rare malformation. As in our example, it is in most cases accompanied by a tracheo-hypopharyngeal fistula which has to be interpreted ontogenetically. The survival chances of the newborn with this malformation are generally very poor.