Is it time to reposition vasopressors and inotropes in sepsis?
To review the literature on the current use of vasopressors and inotropes in patients with sepsis and sepsis syndrome with respect to the choice of agent, therapeutic end points, and safe and effective doses to be used. To examine the available evidence that supports or refutes goal-directed therapy toward supranormal oxygen transport in optimizing the outcome of critically ill sepsis syndrome patients. All pertinent English and French articles dealing with hemodynamic support with selected vasopressors and inotropic agents in human sepsis and sepsis syndrome retrieved from a computerized MEDLINE search from 1985 to 1994. Clinical studies with norepinephrine, epinephrine, phenylephrine, dopamine, and dobutamine in sepsis syndrome were considered if goal-directed therapy with oxygen transport variables was utilized. Emphasis was placed on prospective, randomized, controlled comparative trials. However, open-label, observational, and comparative studies, or case series, were also evaluated when limited data were available. From the selected studies, information was obtained regarding patient population, dosing regimen, type of therapeutic goals or end points (hemodynamic, or normal vs. supranormal oxygen transport variables) and outcome data (e.g., achievement of goals, resolution of the episode, mortality rate, and development of end-organ dysfunction). When used in larger than usual doses, epinephrine, norepinephrine, and phenylephrine uniformly increased hemodynamic values. Epinephrine may increase oxygen transport values more reliably than norepinephrine. Dobutamine doses in the range of 2.5 to 6 microgram/kg/min increase oxygen transport variables and hemodynamics to predetermined goals in only 30% to 70% of patients. Larger infusion rates offer no further benefits. Insufficient evidence exists to support goal-directed therapy with vasopressors and inotropes in the treatment of sepsis syndrome. No definitive recommendations can be made about the superiority of a vasopressor or inotropic agent due to the lack of data. However, it may be that evaluation of vasopressors earlier in sepsis syndrome will yield more promising results. Large, comparative, controlled trials assessing mortality rate and development of multiple organ system dysfunction are needed.


Tunable transition metal complexes as hole transport materials for stable perovskite solar cells.
Transition metal complexes offer cost-effective alternatives as hole-transport materials (HTMs) in perovskite solar cells. However, the devices suffer from low performance. We boost the power conversion efficiency of devices with transition metal complex HTMs from 2% to above 10% through energy level tuning. We further demonstrate the excellent photostability of the device based on the additive-free HTM.


Congenital heart defects and coronary anatomy.
Coronary artery anomalies are a well recognized feature of many cardiac malformations and have been catalogued in a number of reviews. This overview concentrates on 1) the interplay between congenital heart defects and coronary morphogenesis, examining how some of the embryology fits with the experiments of nature encountered in clinical practice; and 2) the influence of coronary anatomy on patient management. This overview uses, as examples, pulmonary atresia with intact ventricular septum, complete and congenitally corrected transpositions of the great arteries, and tetralogy of Fallot.


How to obtain uniformity of occlusal detail.
At a recent Primary Dental Care Editorial Board meeting it was suggested that a series of short articles providing practical advice on clinical procedures might well be appreciated by our readers. This, then, is an invitation to our readers to submit material of this type, for publication. The text may be kept brief by the use of illustrations. The following example is the type of communication that we have in mind, but any information of a practical nature about the use of dental products would be carefully considered. We are grateful to the publishers of Fenestra (3M Dental Products) and the authors for permission to republish this piece first published in 1999.


Investigating Nurses' Views on Care of Mentally Ill Patients with Skin Injuries.
Individuals with mental illness are at increased risk of skin injuries. The role of nurses in skin injury prevention and management is crucial and therefore their views on wound care may provide useful information for improving the quality of the care provided. To investigate nurses' views on care of mentally ill patients with skin injuries. A qualitative research design based on the principles of grounded theory approach was followed. Unstructured interviews were conducted with seven nurses working in psychiatric wards with frequent skin injuries. Data were analyzed using the constant comparative method of analysis. Two main themes were emerged from data analysis. The first main theme, namely factors affecting the care of patients with skin injuries, included seven categories: (a) shortage of hospital supplies, equipment and services (b) staff shortages, (c) lack of knowledge, (d) nurses' resistance to change, (e) difficulty in collaborating with patients, (f) patients' physical conditions and (g) nurses' attitudes as an obstacle to care. The second main theme, namely nurses' suggestions for optimizing care, included five categories: (a) need for additional staff, (b) need for increasing hospital supplies and equipment availability, (c) need for training (d) need of changing nurses' attitudes towards care and (e) need of changing the patients' approach to collaboration. The care of mentally ill patients with skin injuries is affected by multidimensional factors that have a direct impact on the quality of nurses' work and patients' hospitalization. Specific efforts are needed to overcome the obstacles that hinder the care provided and to improve clinical practice.


[Progress in application of microbeam X-ray fluorescence spectroscopy in forensic science].
Microbeam X-ray fluorescence (micro-XRF) spectrometry has been raised as an analytical technique of microbeam during the recent years. With its advantages of high sensitivity, small sample requirement, high testing accuracy and non-destruction, the technique is widely utilized in forensic science. This review bases on recent researches at home and abroad, describes its applications including identification of gunshot residue, visualization of fingerprints, discrimination of drug source, production process, and other material evidences of analysis in crime scene. Thanks to the advances in technology, intelligent and portable micro-XRF equipment has appeared to be applied. It is believed that it may be more popular and frequent in administration of forensic science in the near future.


Successfully achieving target weight loss influences subsequent maintenance of lower weight and dropout from treatment.
The influence of the amount and rate of weight loss on subsequently regaining weight and dropout from treatment in severely obese patients targeting 5% weight loss was investigated. A total of 120 consecutive hospital patients with severe obesity (BMI: 42 ± 9 kg/m(2) ) participated in an inpatient program targeting 5% weight loss that involved goal setting, charting weight four times daily, and diet and exercise. They were followed after discharge to assess subsequent regaining of weight and dropout. Mean weight loss was 4.9 ± 2.4% after a mean of 19 days in the hospital, and 43% of the patients achieved the target weight loss (>5%). Over the median 2-year follow-up period, greater than 5% in-hospital weight loss was associated with a significantly lower risk of regaining weight after adjustment for various factors (>5% to ≤7% loss: hazard ratio 0.30 [0.11-0.85] for regaining all of the lost weight and 0.32 [0.13-0.78] for regaining half of the lost weight). No significant relation between the amount or rate of weight loss and dropout from subsequent outpatient treatment was seen. Successfully achieving the target weight loss in a comprehensive program predicts subsequent maintenance of lower weight without increasing the risk of dropout. Successful in-hospital weight loss might increase the motivation of obese patients.


Validity of criteria-based content analysis (CBCA) at trial in free-narrative interviews.
The reliability of child witness testimony in sexual abuse cases is often controversial, and few tools are available. Criteria-Based Content Analysis (CBCA) is a widely used instrument for evaluating psychological credibility in cases of suspected child sexual abuse. Only few studies have evaluated CBCA scores in children suspected of being sexually abused. We designed this study to investigate the reliability of CBCA in discriminating allegations of child sexual abuse during court hearings, by comparing CBCA results with the court's final, unappealable sentence. We then investigated whether CBCA scores correlated with age, and whether some criteria were better than others in distinguishing cases of confirmed and unconfirmed abuse. From a pool of 487 child sexual abuse cases, confirmed and unconfirmed cases were selected using various criteria including child IQ≥70, agreement between the final trial outcome and the opinion of 3 experts, presence of at least 1 independent validating informative component in cases of confirmed abuse, and absence of suggestive questions during the child's testimonies. This screening yielded a study sample of 60 confirmed and 49 unconfirmed cases. The 14 item version of CBCA was applied to child witness testimony by 2 expert raters. Of the 14 criteria tested, 12 achieved satisfactory inter-rater agreement (Maxwell's Random Error). Analyses of covariance, with case group (confirmed vs. unconfirmed) and gender as independent variables and age as a covariate, showed no main effect of gender. Analyses of the interaction showed that the simple effects of abuse were significant in both sex. Nine CBCA criteria were satisfied more often among confirmed than unconfirmed cases; seven criteria increased with age. CBCA scores distinguish between confirmed and unconfirmed cases. The criteria that distinguish best between the 2 groups are Quantity of Details, Interactions, and Subjective Experience. CBCA scores correlate positively with age, and independently from abuse; all the criteria test except 2 (Unusual Details and Misunderstood Details) increase with age. The agreement rate could be increased by merging criteria Unusual and Superfluous details that achieve a low inter-rater agreement when investigated separately. Given its ability to distinguish between confirmed and unconfirmed cases of suspected child abuse, the CBCA could be a useful tool for expert opinion. Because our strict selection criteria make it difficult to generalize our results, further studies should investigate whether the CBCA is equally useful in the cases we excluded from our study (for example mental retardation).


SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.
Polymorphisms in the gene encoding sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) associate with hypertension susceptibility in humans. SPAK interacts with WNK kinases to regulate the Na(+)-K(+)-2Cl(-) and Na(+)-Cl(-) co-transporters [collectively, N(K)CC]. Mutations in WNK1/4 and N(K)CC can cause changes in BP and dyskalemia in humans, but the physiologic role of SPAK in vivo is unknown. We generated and analyzed SPAK-null mice by targeting disruption of exons 9 and 10 of SPAK. Compared with SPAK(+/+) littermates, SPAK(+/-) mice exhibited hypotension without significant electrolyte abnormalities, and SPAK(-/-) mice not only exhibited hypotension but also recapitulated Gitelman syndrome with hypokalemia, hypomagnesemia, and hypocalciuria. In the kidney tissues of SPAK(-/-) mice, the expression of total and phosphorylated (p-)NCC was markedly decreased, but that of p-OSR1, total NKCC2, and p-NKCC2 was significantly increased. We observed a blunted response to thiazide but normal response to furosemide in SPAK(-/-) mice. In aortic tissues, total NKCC1 expression was increased but p-NKCC1 was decreased in SPAK-deficient mice. Both SPAK(+/-) and SPAK(-/-) mice had impaired responses to the selective α(1)-adrenergic agonist phenylephrine and the NKCC1 inhibitor bumetanide, suggesting that impaired aortic contractility may contribute to the hypotension of SPAK-null mice. In summary, SPAK-null mice have defects of NCC in the kidneys and NKCC1 in the blood vessels, leading to hypotension through renal salt wasting and vasodilation. SPAK may be a promising target for antihypertensive therapy.


[Tumor seeding of the abdominal wall after fine needle cytologic puncture of the liver. Apropos of a case].
Tumor seeding of the abdominal wall during fine needle puncture-aspiration of the liver is a very rare complication. The authors report a case of this complication affecting a 50-year-old Senegalese woman. She underwent echo-guided fine needle cyto-puncture of a hepatocellular carcinoma arising from the left lobe, followed by left lobectomy. The subcutaneous nodule was discovered 42 months after cyto-puncture. Histology following its excision revealed infiltration of carcinomatous hepatocytes between the fibers of rectus abdominis. There was no recurrence and the patient was well 10 months after excision of the subcutaneous nodule. With a review of 10 others cases reported in the literature, the authors feel that, although rare, this complication must be avoided and suggest a system for the protection of structures through which the needle passes.


Prevalence, predictors, and consequences of long-term refusal of antipsychotic treatment in first-episode psychosis.
Studies investigating medication adherence in psychosis are limited by the need of a certain degree of medication adherence and the inclusion of mostly multiple-episode patients. By contrast, noninformed consent, epidemiological studies in first-episode psychosis (FEP) allow the assessment of an important subgroup of patients who persistently refuse antipsychotic medication and thereby never receive an adequate antipsychotic trial. The present study aims to assess the prevalence and predictors of such a "medication refusal" subgroup and its association with illness outcome. The present file audit study assessed medication adherence in an epidemiological cohort of 605 FEP patients who were treated within the Early Psychosis Prevention and Intervention Centre for up to 18 months. Medication adherence was categorized into full adherence, nonadherence, and persistent medication refusal. Predictors were analyzed using logistic regression models. During the 18-month treatment period, 204 patients (33.7%) were fully adherent, 287 (47.4%) displayed at least 1 phase of nonadherence, and 114 patients (18.8%) were persistent medication refusers. Poor premorbid functioning, comorbid substance use, and poor insight predicted both medication refusal and nonadherence; a forensic history and no previous contact to psychiatric care were specifically predictive of medication refusal. With respect to illness outcome, nonadherent patients were worse off when compared with fully adherent patients, and medication refusers were even worse off compared with nonadherent patients. Within a nonselected epidemiological FEP cohort, almost 20% of patients are persistent medication refusers. The found predictors may help to identify the individual risk of persistent medication refusal and may enable an early (preventive) treatment adaptation.


Mapping the invisible chromatin transactions of prophase chromosome remodeling.
We have used a combination of chemical genetics, chromatin proteomics, and imaging to map the earliest chromatin transactions during vertebrate cell entry into mitosis. Chicken DT40 CDK1as cells undergo synchronous mitotic entry within 15 min following release from a 1NM-PP1-induced arrest in late G2. In addition to changes in chromatin association with nuclear pores and the nuclear envelope, earliest prophase is dominated by changes in the association of ribonucleoproteins with chromatin, particularly in the nucleolus, where pre-rRNA processing factors leave chromatin significantly before RNA polymerase I. Nuclear envelope barrier function is lost early in prophase, and cytoplasmic proteins begin to accumulate on the chromatin. As a result, outer kinetochore assembly appears complete by nuclear envelope breakdown (NEBD). Most interphase chromatin proteins remain associated with chromatin until NEBD, after which their levels drop sharply. An interactive proteomic map of chromatin transactions during mitotic entry is available as a resource at https://mitoChEP.bio.ed.ac.uk.


[Palliation of airway obstruction under a T-tube stent in a patient with thyroid carcinoma invading the trachea: a case report].
Invasion of the neoplasma to the upper airway tract is the life threatening factor. We experienced a 74-year-old female with thyroid carcinoma invading the trachea, for whom radical resection was infeasible. So for the palliation of airway obstruction we inserted the silicone rubber T-tube stent from 0.5 cm above the vocal cord to 2 cm before the carina after endotracheal tumor resection with Nd-YAG laser. As the result, she has led an active life for the last 6 months after the operation. We consider that the T-tube stent is effective tool in the management of airway obstruction for the slow growing neoplasma.


Seed Dormancy Breaking and Germination in Bituminaria basaltica and B. bituminosa (Fabaceae).
Most legumes are well-known for the physical dormancy of their seeds; hence, the implementation of appropriate scarification techniques is essential for introducing new legume crops within agricultural systems. This study investigated morpho-anatomical traits and dormancy-breaking requirements in two taxa of the genus Bituminaria: the widespread B. bituminosa and the point endemic B. basaltica. As the species under investigation show monospermic indehiscent legumes, pods were used in this research. We performed pod trait measurements, light microscopy observations on the seed coat anatomical structure, and germination tests after mechanical, thermal, and chemical scarification treatments for seed dormancy breaking. Moreover, germination performance at different pod maturity stages and storage times was tested. Differences in morpho-anatomical traits were found, with B. basaltica having a thicker palisade cell layer and B. bituminosa showing larger pods. All of the scarification treatments proved to be able to break physical dormancy, with mechanical and chemical scarification being the most effective methods in both species. Nevertheless, dormancy-breaking treatments performed better in B. bituminosa. Seeds at early pod maturity stages showed higher germination capacity in both species. Overall, this research provided background knowledge on seed collection time, storage strategy, and effective pre-sowing treatment, which might contribute to enhance propagation and use of Bituminaria species for multiple purposes. Under this perspective, the future characterization of additional Bituminaria genetic resources from other Mediterranean populations will have remarkable importance.


The cardioprotective actions of leptin are lost in the Zucker obese (fa/fa) rat.
Protection against myocardial ischemia-reperfusion injury, including that induced by leptin, involves activation of the reperfusion injury salvage kinase pathway and inhibition of the mitochondrial permeability transition pore. In the current study, we explored the mechanisms underlying leptin-induced cardioprotection further with reference to the leptin receptor (OB-R) and obesity. We examined hearts from Wistar and Zucker lean rats that express functional OB-R and Zucker obese (fa/fa) rats with nonfunctional OB-R. In Langendorff experiments, leptin (10 nM) caused significant reductions in infarct size in hearts from Wistar (leptin treated, 32.4% +/- 3.9% vs. control, 53.2% +/- 3.2%, P < 0.01) and Zucker lean animals (leptin treated, 25.2% +/- 3.7% vs. control, 53.9% +/- 11.3%, P < 0.01). By contrast, hearts from (fa/fa) did not exhibit significant decreases in infarct size. Leptin increased p44 and p42 phosphorylation in Wistar rat hearts by 103.9% (P < 0.05) and 157.3% (P < 0.001), respectively, and by 97.0% (P < 0.05) and 158.1% (P < 0.05) in hearts from Zucker lean rats. Akt/serine-473 phosphorylation was increased in Wistar hearts by 96.7% (P < 0.05), whereas Akt/threonine-308 phosphorylation was elevated by 43.9% (P < 0.05) in Zucker lean rat hearts. Leptin did not influence Akt or p44/42 phosphorylation in (fa/fa) animals. On leptin treatment, mitochondrial permeability transition pore opening was delayed by 43% (P < 0.01) and 30.9% (P < 0.01), respectively, in cardiomyocytes from Wistar and Zucker lean rat hearts but not in cardiomyocytes from (fa/fa). This study provides the first evidence that myocardial sensitivity to the tissue preserving actions of leptin is influenced by adiposity and OB-R status.


Spin-Delocalization in a Helical Open-Shell Hydrocarbon.
Neutral open-shell molecules, in which spin density is delocalized through a helical conjugated backbone, hold promise as models for investigating phenomena arising from the interplay of magnetism and chirality. Apart from a handful of examples, however, the chemistry of these compounds remains largely unexplored. Here, we examine the prospect of extending spin-delocalization over a helical backbone in a model compound naphtho[3,2,1-no]tetraphene, the first helically chiral open-shell hydrocarbon, in which one benzene ring is fused to [5]helicene, forming a phenalenyl subunit. The unpaired electron in this molecule is delocalized over the entire helical core composed of six rings, albeit in a nonuniform fashion, unlike in phenalenyl. In the case of a monosubstituted derivative, the uneven spin-distribution results in a selective σ-dimer formation in solution, as confirmed by 2D NMR spectroscopy. In contrast, the dimerization process is suppressed entirely when four substituents are installed to sterically hinder all reactive positions. The persistent nature of the tetrasubstituted derivative allowed its characterization by EPR, UV-vis, and CD spectroscopies, validating spin-delocalization through a chiral backbone, in accord with DFT calculations. The nonuniform spin-distribution, which dictates the selectivity of the σ-dimer formation, is rationalized by evaluating the aromaticity of the resonance structures that contribute to spin-delocalization.


Compartmentalization in a water-in-oil emulsion repressed the spontaneous amplification of RNA by Q beta replicase.
During RNA replication mediated by Qbeta replicase, self-replicating RNAs (RQ RNAs) are amplified without the addition of template RNA. This undesired amplification makes the study of target RNA replication difficult, especially for long RNA such as genomic RNA of Qbeta phage. This perhaps is one of the reasons why the precise rate of genomic RNA replication in the presence of host factor Hfq has not been reported in vitro. Here, we report a method to repress RQ RNA amplification by compartmentalization of the reaction using a water-in-oil emulsion but maintaining the activity of Qbeta replicase. This method allowed us to amplify the phage Qbeta genome RNA exponentially without detectable amplification of RQ RNA. Furthermore, we found that the rate constant of genome RNA replication in the exponential phase at the optimum Hfq concentration was approximately 4.6 times larger than that of a previous report, close to in vivo data. This result indicates that the replication rate in vivo is largely explained by the presence of Hfq. This easy method paves the way for the study of genomic RNA replication without special care for the undesired RQ RNA amplification.


Relationship between genetic and environmental factors and hypercholesterolemia in children.
Pediatric hypercholesterolemia has increased over the past decades. Knowing the environmental and genetic factors that have an impact on it would allow establishing more adequate screening guidelines. To determine if there is an association between genetic and environmental factors and hypercholesterolemia in children. To assess the predictive qualities of outcome measures associated with hypercholesterolemia. Observational, analytical, cross-sectional study. students from all schools located in Jovita. Age: >> 6 and < 12 years old. The total cholesterol level was measured. A survey was administered to parents to assess their family medical history (FMH) and socioeconomic level (SEL). Weight and height were recorded to establish nutritional status. A survey was administered to children to identify their level of physical activity and their eating habits. The association was assessed by estimating the OR value (p < 0.05). Diagnostic tests were done to establish outcome measures that predict hypercholesterolemia. Three hundred and eighty-two students were included. Their mean cholesterol level was 168 mg/dL, and 13.4% had hypercholesterolemia. A sedentary lifestyle was observed in 22.8%, and obesity, in 10.5%. A positive FMH, a high/ middle SEL, and obesity were associated with hypercholesterolemia (OR: 2.10, 2.10 and 2.05, respectively). No association was found between physical activity and fat/cholesterol intake and hypercholesterolemia. A positive FMH and a high/middle SEL were sensitive enough (75% and 88%) to predict hypercholesterolemia. The presence of hypercholesterolemia inboth parents in relation to hypercholesterolemia in their child showed an OR of 9.59, a sensitivity of 73%, a specificity of 71%, a positive predictive value of 57%, and a negative predictive value of 83%. A positive FMH, a high/ middle SEL, and obesity were associated with hypercholesterolemia in children. The presence of hypercholesterolemia in both parents was associated with hypercholesterolemia in their child and showed itself to be a great potential predictor and screening criterion.


Prins cyclizations: labeling studies and application to natural product synthesis.
The first syntheses of two natural products, catechols 1 and 2, isolated from Plectranthus sylvestris (labiatae), are reported. Oxygen-18 labeling studies support the proposed intermediacy of a stabilized benzylic cation in the acid-promoted cyclization of an aldehyde and benzylic homoallylic alcohol possessing an electron-rich aromatic ring. In contrast, with an electron-deficient aromatic ring the pathway via a benzylic cation is only minor. [reaction: see text]


The P2X7 Receptor: Central Hub of Brain Diseases.
The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP). Upon long-term activation, it complexes with membrane proteins forming a wide pore that leads to cell death and increased release of ATP into the extracellular milieu. The P2X7 receptor is widely expressed in the CNS, such as frontal cortex, hippocampus, amygdala and striatum, regions involved in neurodegenerative diseases and psychiatric disorders. Despite P2X7 receptor functions in glial cells have been extensively studied, the existence and roles of this receptor in neurons are still controversially discussed. Regardless, P2X7 receptors mediate several processes observed in neuropsychiatric disorders and brain tumors, such as activation of neuroinflammatory response, stimulation of glutamate release and neuroplasticity impairment. Moreover, P2X7 receptor gene polymorphisms have been associated to depression, and isoforms of P2X7 receptors are implicated in neuropsychiatric diseases. In view of that, the P2X7 receptor has been proposed to be a potential target for therapeutic intervention in brain diseases. This review discusses the molecular mechanisms underlying P2X7 receptor-mediated signaling in neurodegenerative diseases, psychiatric disorders, and brain tumors. In addition, it highlights the recent advances in the development of P2X7 receptor antagonists that are able of penetrating the central nervous system.


A prospective study to assess the effect of ambulatory teaching on patient satisfaction.
To assess the effect of ambulatory teaching on patients' satisfaction. In 1996, 103 adult patients presenting to the Walter Reed General Medicine Walk-in Clinic completed a patient-satisfaction questionnaire immediately following their visits, during which they were initially seen by a trainee (third-year medical student or intern) and then seen by a faculty preceptor. The questionnaire included five items from the validated Medical Outcomes Study (MOS)-9 questionnaire as well as two open-ended questions. Fourteen staff physicians, 13 students (49% of the visits), and 11 interns (51% of the visits) participated in the study. Satisfaction was analyzed by level of training, and the responses from the study patients were compared with the responses from 372 usual-care (i.e., non-teaching) patients from the same clinic, using the chi-squared test. The study patients were typically pleased with their encounters, rating their overall satisfaction as excellent (61%), very good (29%), or good (9%). Nearly two thirds of the patients rated their satisfaction with waiting time to be very good or excellent. Compared with the usual-care patients, the study patients reported equal or greater satisfaction for all five MOS-9 items. Ninety-five percent of the study patients said they would be willing to be seen by a trainee-staff team on future visits. There was no difference in patient satisfaction by trainee level. The study patients cited enhanced interaction (45%), enhanced education (34%), and improved care (26%) as benefits of trainee-involved care, and increased waiting time (18%) and worse care (5%) as drawbacks. The results of this study suggest that ambulatory teaching does not adversely affect patient satisfaction, regardless of trainee level, and that patients who have been seen by trainee-staff teams are willing to experience such encounters again.


Protocol for north of England and Scotland study of tonsillectomy and adeno-tonsillectomy in children (NESSTAC). A pragmatic randomised controlled trial comparing surgical intervention with conventional medical treatment in children with recurrent sore throats.
Uncertainties surrounding the effectiveness and cost-effectiveness of childhood tonsillectomy for recurrent sore throat led the NHS Health Technology Assessment Programme to commission this research to evaluate the effectiveness and cost-effectiveness of tonsillectomy and adeno-tonsillectomy in comparison with standard non-surgical management in children aged under 16 with recurrent throat infections. The aim is to evaluate if tonsillectomy and adeno-tonsillectomy reduces the number of episodes of sore throats among children to a clinically significant extent. A simple prospective pragmatic randomised controlled trial with economic analysis and prospective cohort study of non-trial participants comparing surgical intervention with conventional medical treatment. The treatment arm will receive tonsillectomy and adeno-tonsillectomy while in the control arm non-surgical conventional medical treatment only will be used. The primary outcome measure will be reported number of episodes of sore throat over two years with secondary outcomes measures of reported number of episodes of sore throat, otitis media and upper respiratory tract infection which invoke a GP consultation; reported number of symptom-free days; reported severity of sore throats and surgical and anaesthetic morbidity. The study will take place in five hospitals in the UK. The trial population will be 406 children aged 4-15 on their last birthday with recurrent sore throat referred by primary care to the 5 otolaryngology departments. The duration of the study is seven years (July 2001-July 2008). As with all pragmatic randomised controlled trials it is impossible to control the external environment in which the research is taking place. Since this trial began a number of factors have arisen which could affect the outcome including; a reduction in the incidence of respiratory tract infections, marked socio-economic differences in consultation rates, the results from the National Prospective Tonsillectomy Audit and the Government's waiting list initiatives.


[An ultrastructural analysis of the peritubular dentin and of the tubular lumen in healthy teeth].
In this study the authors examined some specimens of fractured dentine of embedded healthy teeth, of people aged between 20 and 30. Connecting the scanning electron microscopy to a system of computerised analysis of spectrometry (EDS) allowed the analysis of the qualitative composition of the specimens. Therefore, the authors described the tubular structure of the sound, the peri- and the intertubular dentine, the winding course of the dentinal tubules and in some specimens, the presence of cylindrical structures inside the tubules. The EDS analysis demonstrated that these tubular structures have the same composition as the intertubular dentine. Former studies described hollow cylindrical structures having a similar morphology solely as a response of the odontoblasts to white spots. On the contrary, in this study it was demonstrated that it is possible to find cylindrical structures which are definitely mineralized in sound teeth without caries. However, the presence of such formations is not concomitant with the disappearance of peritubular dentine which is a typical structural modification of the pathological advancement of the carious lesion.


Dynamic equilibrium between the two conformational states of spin-labeled tropomyosin.
Tropomyosin was labeled with a maleimide nitroxide spin-label attached to cysteine-190 via a succinimido ring which was subsequently opened by incubation at alkaline pH. Electron spin resonance (ESR) spectra showed a temperature-dependent equilibrium, below the main unfolding transition of tropomyosin, between labels which were restricted in their motion (strongly immobilized), predominating at low temperatures, and those which were highly mobile (weakly immobilized), predominating at higher temperatures. These label states were associated with two protein states from a comparison of the ESR spectral changes with the thermal unfolding profile of tropomyosin. The strongly immobilized labels were associated with the completely folded molded and the weakly immobilized labels with a partially unfolded (in the cysteine-190 region) state which is an intermediate in the thermal unfolding of tropomyosin. A spectral subtraction technique was used to measure the concentration ratio of strongly and weakly immobilized labels from which an equilibrium constant, K, was determined at different temperatures. A linear van't Hoff plot was obtained, indicating that the spin-labeled protein is in thermal equilibrium between these two conformational states with delta H = 17 kcal/mol, delta S = 56 cal/(deg X mol), and K = 1.0 at 34 degrees C. An upper limit of 10(7) s-1 for the conformational fluctuation was estimated from the shapes and separation of the two ESR spectral components. In contrast to the label with the opened succinimido ring, the spin-label with an intact succinimido ring remained strongly immobilized on the protein, indicating that in the partially unfolded state the molecule retains structure in the cysteine-190 region.


A reliable technique of nuclear transplantation for immature mammalian oocytes.
Transplanting a germinal vesicle (GV) to another enucleated oocyte provides a possible way to avoid age-related aneuploidy in metaphase II (MII) oocytes from older women. This study was conducted to examine the efficiency of each step of nuclear transplantation as reflected in the survival and maturation capacity of immature mouse oocytes subjected to this procedure. GV stage oocytes were retrieved from unstimulated ovaries. A GV removed with a small amount of cytoplasm (karyoplast) was transferred subzonally into a previously enucleated oocyte, which was then exposed to direct current to promote fusion. Such reconstituted oocytes were placed in culture to allow maturation, and some that had extruded a first polar body were fixed and processed for chromosome analysis. Each step of nuclear transplantation - survival, enucleation, grafting, and reconstitution - was successful in >90%, with the overall efficiency of reconstitution being 80%. The observation of normal karyotypes confirmed that the procedure did not increase chromosomal aneuploidy. An electrolytic medium, revealed to be superior for the reconstitution procedure, also allowed haploidization of the transplanted nucleus. These findings suggest that this technique can be applied to study the effects of a 'younger' woman's ooplasm on the disjunction of an 'older' woman's chromosomes during meiosis I.


[Advance of second-line chemotherapy in advanced non-small cell lung cancer.].
There is a temporal disease-free period after 1st line chemotherapy in advanced non-small cell lung cancer (NSCLC), most of patients need 2nd line chemotherapy. The recommended drugs in the 2nd line were docetaxel, pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Single docetaxel is the established therapy for second-line treatment of NSCLC.Pemetexem was validated its indication in the 2nd line in advanced NSCLC through a phase III randomised clinical trial which was compared with docetaxel. Although there were little toxicity, the further research can't find the survival benefit in high dose pemetrexed. EGFR-TKIs target therapy is a hot spot now. Gefitinib and erlotinib monotherapy have a good efficacy in the 2nd line. The research of gefitinib versus traditional chemotherapy manifested that its efficacy was no less than docetaxel, and was less toxicitity . The comparison of erlotinib with chemotherapy is going on. There are more and more other drugs proved their effect in the 2nd line, such as the efficacy of oral toptecan and vinflunine were similar to docetaxel.


Atmospheric pollen count in Monterrey, Mexico.
There are few reports of pollen count and identification in Mexico; therefore, it is important to generate more information on the subject. This study was designed to describe the prevalence of pollen in the city of Monterrey, Mexico, during the year 2004. Atmospheric pollen was collected with a Hirst air sampler, with an airflow of 10 L/minute during 2004. Pollen was identified with light microscopy; the average monthly pollen count as well as total was calculated from January 2004 to January 2005. The months with the highest concentration of pollen were February and March (289 and 142 grains/m(3) per day, respectively), and July and November had the lowest concentration (20 and 11 grains/m(3) per day, respectively). Most of the pollen recollected corresponded to tree pollen (72%). Fraxinus spp had the highest concentration during the year (19 grains/m(3) per day; 27.5% of the total concentration of pollen). Tree pollen predominated from January through March; with Fraxinus spp, Morus spp, Celtis spp, Cupressus spp, and Pinus spp as the most important. Weed pollen predominated in May, June, and December and the most frequently identified, were Amaranthaceae/Chenopodiaceae, Ambrosia spp, and Parietaria spp. The highest concentration of grass pollen was reported during the months of May, June, September, October, and December with Gramineae/Poaceae predominating. Tree pollen was the most abundant during the year, with the ash tree having the highest concentration. Weed and grass pollen were perennial with peaks during the year.


miR-146a suppresses invasion of pancreatic cancer cells.
The aggressive course of pancreatic cancer is believed to reflect its unusually invasive and metastatic nature, which is associated with epidermal growth factor receptor (EGFR) overexpression and NF-kappaB activation. MicroRNAs (miRNA) have been implicated in the regulation of various pathobiological processes in cancer, including metastasis in pancreatic cancer and in other human malignancies. In this study, we report lower expression of miR-146a in pancreatic cancer cells compared with normal human pancreatic duct epithelial cells. Reexpression of miR-146a inhibited the invasive capacity of pancreatic cancer cells with concomitant downregulation of EGFR and the NF-kappaB regulatory kinase interleukin 1 receptor-associated kinase 1 (IRAK-1). Cellular mechanism studies revealed crosstalk between EGFR, IRAK-1, IkappaBalpha, NF-kappaB, and MTA-2, a transcription factor that regulates metastasis. Treatment of pancreatic cancer cells with the natural products 3,3'-diinodolylmethane (DIM) or isoflavone, which increased miR-146a expression, caused a downregulation of EGFR, MTA-2, IRAK-1, and NF-kappaB, resulting in an inhibition of pancreatic cancer cell invasion. Our findings reveal DIM and isoflavone as nontoxic activators of a miRNA that can block pancreatic cancer cell invasion and metastasis, offering starting points to design novel anticancer agents.


FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis.
FOXO transcription factors are central regulators of longevity from worms to humans. FOXO3, the FOXO isoform associated with exceptional human longevity, preserves adult neural stem cell pools. Here, we identify FOXO3 direct targets genome-wide in primary cultures of adult neural progenitor cells (NPCs). Interestingly, FOXO3-bound sites are enriched for motifs for bHLH transcription factors, and FOXO3 shares common targets with the proneuronal bHLH transcription factor ASCL1/MASH1 in NPCs. Analysis of the chromatin landscape reveals that FOXO3 and ASCL1 are particularly enriched at the enhancers of genes involved in neurogenic pathways. Intriguingly, FOXO3 inhibits ASCL1-dependent neurogenesis in NPCs and direct neuronal conversion in fibroblasts. FOXO3 also restrains neurogenesis in vivo. Our study identifies a genome-wide interaction between the prolongevity transcription factor FOXO3 and the cell-fate determinant ASCL1 and raises the possibility that FOXO3's ability to restrain ASCL1-dependent neurogenesis may help preserve the neural stem cell pool.


Uterine sarcoma Part II-Uterine endometrial stromal sarcoma: The TAG systematic review.
Endometrial stromal tumors are rare uterine tumors (<1%). Four main categories include endometrial stromal nodule, low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and uterine undifferentiated sarcoma (UUS). This review is a series of articles discussing the uterine sarcomas. LG-ESS, a hormone-dependent tumor harboring chromosomal rearrangement, is an indolent tumor with a favorable prognosis, but characterized by late recurrences even in patients with Stage I disease, suggesting the requirement of a long-term follow-up. Patients with HG-ESS, based on the identification of YWHAE-NUTM2A/B (YWHAE-FAM22A/B) gene fusion, typically present with advanced stage diseases and frequently have recurrences, usually within a few years after initial surgery. UUS is, a high-grade sarcoma, extremely rare, lacking a specific line of differentiation, which is a diagnosis of exclusion (the wastebasket category, which fails to fulfill the morphological and immunohistochemical criteria of translocation-positive ESS). Surgery is the main strategy in the management of uterine sarcoma. Due to rarity, complex biological characteristics, and unknown etiology and risk factors of uterine sarcomas, the role of adjuvant therapy is not clear. Only LG-ESS might respond to progestins or aromatase inhibitors.


Stem Cells of the Aging Brain.
The adult central nervous system (CNS) contains resident stem cells within specific niches that maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. Physiological aging is associated with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS stem cells. Also, the biggest risk factor for neurodegenerative diseases is age, and current in vivo and in vitro models of neurodegenerative diseases rarely consider this. Therefore, combining both aging research and appropriate interrogation of animal disease models towards the understanding of the disease and age-related stem cell failure is imperative to the discovery of new therapies. This review article will highlight the main intrinsic and extrinsic regulators of neural stem cell (NSC) aging and discuss how these factors impact normal homeostatic functions within the adult brain. We will consider established in vivo animal and in vitro human disease model systems, and then discuss the current and future trajectories of novel senotherapeutics that target aging NSCs to ameliorate brain disease.


[Nocturnal oxymetry in patients with amyotrophic lateral sclerosis: role in predicting survival].
Death is the most important end point along the course of amyotrophic lateral sclerosis (ALS). It is commonly attributed to a respiratory failure in relation with a restrictive respiratory disorder. However, in clinical practice, it is frequent to observe that death has not direct relation with the values of the respiratory function, at least measured with vital capacity. It is also frequent that relatives report sudden death during nocturnal sleep. All these features raised the question of the possible relation between death and nocturnal oxymetry in ALS patients. In a prospective study, we studied 69 ALS patients. We recorded demographic data, clinical parameters as manual muscle testing and functional scales, various parameters of oxymetry measured by pulse oxymetry recorded during night, slow vital capacity and survival time. There is a strong correlation between survival time measured by Kaplan Meier curves and log rank and the mean nocturnal saturation. We determined 93 mmHg as a threshold value. Below this threshold, mean survival time was 7.5+/-1.6 months and above it was equal to 18.5+/-1.5; relative risk was 3.31. These data confirm the importance of nocturnal oxymetry on survival in ALS patients both in clinical practice and in view of therapeutic trials.


Regulation of Apoptosis by HER2 in Breast Cancer.
HER2 is a trans-membrane receptor tyrosine kinase that activates multiple growth-promoting signaling pathways including PI3K-AKT and Ras-MAPK. Dysregulation of HER2 is a frequent occurrence in breast cancer that is associated with poor patient outcomes. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There has been much investigation into the mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical targets for HER2-positive breast cancers as these cancers often become resistant to therapies that directly target HER2. Several apoptotic mechanisms have been shown to be deregulated in HER2-overexpressing cells with examples in both the intrinsic and extrinsic apoptotic pathways. HER2-mediated activation of PI3K-AKT signaling is required for many of the mechanisms HER2 uses to suppress apoptosis. HER2 overexpression is correlated with increases in anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-xL, and Mcl-1. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. In addition, survivin expression is often increased with HER2 overexpression leading to inhibition of caspase activation. There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome c release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis. Elucidation of the mechanisms of apoptotic suppression by HER2 suggest that clinical treatment will likely need to target multiple components of these pathways as there is redundancy in HER2-mediated cell survival. Several therapies have attempted to target Bcl-2 proteins that have promising pre-clinical results. Next-generation HER2 targeting therapies include irreversible pan-ERBB inhibitors and antibody-drug conjugates, such as T-DM1 that has very promising clinical results thus far. Further investigation should include elucidating mechanisms of resistance to HER2-targeted therapies and targeting of multiple components of HER2-mediated cell survival.


Dimethylarsinic acid: results of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice.
Dimethylarsinic acid (DMA(V), cacodylic acid), a foliar herbicide, was administered in the diet to B6C3F1 mice (at dose levels of 0, 8, 40, 200, and 500 ppm) and to F344 rats (at dose levels of 0, 2, 10, 40, and 100 ppm) for 2 years, according to US EPA guidelines. In mice, there were no treatment-related tumors observed at any site. Treatment-related progressive glomerulonephropathy and nephrocalcinosis were observed in the kidneys in both sexes. The incidence of vacuolation of the epithelium in the urinary bladder was increased in both sexes, but was not associated with cytotoxicity, necrosis or hyperplasia. Based on non-neoplastic lesions found in the urinary bladder, the NOEL for mice was assessed to be 40 ppm in males and 8 ppm in females. In rats, treatment-related mortality occurred early in the study in five males in the 100 ppm group and in one male in the 40 ppm group. Papillomas and carcinomas with degeneration of the urothelium, necrosis and urothelial cell hyperplasia, were found in the urinary bladders of both sexes. In male rats, one papilloma was found in each of the 10 and 40 ppm groups; one urothelial cell carcinoma was found in the 2 ppm group and two in the 100 ppm group. Four papillomas and six urothelial cell carcinomas were found in the female 100 ppm group. Non-neoplastic treatment-related kidney lesions were confined to the 40 and 100 ppm levels and included necrosis, pyelonephritis, medullary nephrocalcinosis and tubular cystic dilation, hyperplasia of the epithelial lining of the papilla, and pelvic urothelial cell hyperplasia. All of these kidney changes appear to be related to an increase in the aging nephropathy of the rat. Dose-related increases in the height of the thyroid follicular epithelium were also noted in males and females, however, such changes reflect an adaptive response of the thyroid to decreased levels of circulating thyroid hormone, rather than an adverse effect. Based on the kidney and bladder lesions, the NOEL for non-neoplastic and neoplastic lesions was considered to be 10 ppm in males and females. Based on these studies, DMA(V) is carcinogenic only in rats and only at relatively high doses, with the urinary bladder as the target organ. Female rats appear to be more sensitive to the effects of DMA(V) than male rats. DMA(V) is not carcinogenic in mice.


Optical resonator using anisotropic metal film for mode selection.
The method of mode selection in optical resonators using a linear polarizer with the help of an anisotropic metal film is proposed. The film thickness is much less than a wavelength. The losses introduced by such a film into undesired oscillation modes are composed of ohmic losses and losses due to the change in radiation polarization caused by the film. The principle of operation has been investigated at 0.63 microm.


Cost control, primary care initiatives challenge teaching hospitals.
Pressures currently affecting medical schools and teaching hospitals are detailed. Although cost containment poses special problems for teaching hospitals, physicians can help hold down cost. Primary care initiatives and specialty redistribution, as well as the classification of "staff" and "private" patients, and planning agencies also are exerting pressures.


RANTES expression induced by Toll-like receptor 4 ligand in rat airway smooth muscle cells.
Airway smooth muscle cells (ASMCs) have been reported to express Toll-like receptors (TLRs) and take part in the pathogenesis of asthma exacerbation. Though TLRs were found to activate epidermal growth factor receptor (EGFR) in airway epithelial cells, little is known about the association of TLR ligands with EGFR signaling pathways in ASMCs. Using primary cultured ASMCs from Brown Norway rats, TLR4, eotaxin, and RANTES mRNA were examined by real-time quantitative RT-PCR after stimulation with the TLR4 ligand, lipopolysaccharides (LPS). The concentration of RANTES protein in culture supernatant was measured by ELISA. The effect of EGFR signaling inhibitors on RANTES expression was examined as well. Phosphorylation of EGFR after stimulation was examined by Western Blotting. Rat ASMCs expressed TLR4 and eotaxin, and LPS upregulated RANTES production. The EGFR tyrosine kinase inhibitor AG1478, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the matrix metalloproteinase (MMP) inhibitor GM6001 inhibited RANTES expression induced by LPS. LPS phosphorylated EGFR. TLR4 activation can induce RANTES expression via EGFR transactivation and PI3K/Akt pathway in rat ASMCs. MMP-induced EGFR proligand cleavage and ligand binding to EGFR seem to be involved in this pathway. These findings may be critical in the pathogenesis of asthma exacerbation by airway infection.


Aggregation in insect communities colonizing cattle-dung.
Ruminant dung is a highly ephemeral, patchily distributed resource, which is used by a diverse community of invertebrate species. In such environments, high levels of insect aggregation may be important in facilitating stability and coexistence across patchily distributed populations. The aim of the present work was to quantify the aggregation of the insects colonising cow-dung in cattle pasture in southwest England and to test the hypothesis that the dung-pat community assemblage observed was the result of stochastic colonization. This was examined using batches of ten standardised, 1.5 kg, artificial cow pats placed out in cattle pastures in each of 24 weeks between May and October in 2001. Pats were left exposed in the field for seven days before being brought back to the laboratory, where any insect colonizers were collected and identified. Individual pats contained, on average, only half the number of insect taxa present in an entire batch put out at any one time. All larval coleopteran taxa, 20 of the 22 adult coleopteran taxa and 22 of the 23 dipteran taxa, showed significant aggregation, with the abundance of most taxa within pats approximating a negative binomial distribution. A simulation analysis was used to show that the observed relative frequency of taxa within pats did not differ from that expected by chance if colonisation is a random binomial event in which each species colonises a pat independently of all other species. Aggregated populations, of even highly abundant insects, may be more susceptible to the deleterious effects of insecticidal contaminants in dung than if they were evenly distributed, if by chance they colonize a pat containing insecticidal residues from a recently treated animal.


Retrograde intussusception following Roux-en-Y gastric bypass.
A case of retrograde intussusception is presented occurring >1 year following a Roux-en-Y gastric bypass (RYGBP). Presentation may be confusing and lead to a serious delay in diagnosis. Review of the literature shows most intussusceptions following RYGBP are retrograde, and most, if not all, appear to originate in the proximal common channel, as ours clearly did. The average excess body weight loss in these patients is much higher than expected, adding evidence that a dysmotility disorder is involved. A hypothesis is presented regarding the mechanism involved in these retrograde intussusceptions.


Structure and expression of an ovine endometrial oxytocin receptor cDNA.
A sheep endometrial oxytocin receptor (OTR) cDNA (1.5 kb) was isolated from a lambda-ZAP library using a reverse transcription-PCR product probe generated from oestrous endometrial mRNA. The sheep OTR cDNA shared an overall similarity of 82% with human OTR cDNA, 85% with pig OTR cDNA and 76% with rat OTR cDNA. The encoded receptor was a 391 amino acid polypeptide 94% similar to human OTR, 94% similar to pig OTR and 93% similar to rat OTR. The sheep OTR contained two additional amino acids compared with human OTR which were located in the highly GC-rich third intracytoplasmic loop. This region is thought to be associated with G protein coupling and signal transduction. Expression of the cDNA in Cos-7 cells and measurement of oxytocin-induced phosphoinositide turnover confirmed that it coded for a functional product. The affinity of the expressed receptor was comparable with that observed for the in vivo receptor.


[Transcheter aortic valve implantation as a method of treatment of chronic heart failure in elderly and old patients: Literature review (part 1).]
Aortic valve (AV) stenosis is the most common acquired valvular disease with an increasing prevalence due to an aging population, requiring surgical or endovascular intervention. Transcatheter Aortic Valve Implantation (TAVI) represents a real revolution in the field of interventional cardiology for the treatment of elderly or high-risk patients with severe symptomatic AV stenosis. TAVI allows for the correction of aortic defect in the most severe group of patients with chronic heart failure (CHF) with severe comorbidity, who are contraindicated for open surgery to replace AV, in order to interrupt the vicious circle in the progression of CHF, stimulate reverse myocardial remodeling, alleviate symptoms, improve the quality of life, and prognosis of patients, and also as a «bridge» to heart transplantation. With the development of next-generation devices, TAVI has evolved from a complex and dangerous procedure to an effective and safe technique. Currently, the greatest scientific interest is the study of valve durability and the possibility of expanding the indications for performing TAVI in categories of patients with low surgical risk, as well as in younger age groups.


The Importance of the Interaction Between Ocular Motor Function and Vision During Human Infancy.
Numerous studies have demonstrated the impact of imposed abnormal visual experience on the postnatal development of the visual system. These studies have provided fundamental insights into the mechanisms underlying neuroplasticity and its role in clinical care. However, the ocular motor responses of postnatal human infants largely define their visual experience in dynamic three-dimensional environments. Thus, the immature visual system needs to control its own visual experience. This review explores the interaction between the developing motor and sensory/perceptual visual systems, together with its importance in both typical development and the development of forms of strabismus and amblyopia.


Rheumatoid meningitis.
An 80-year-old woman with rheumatoid arthritis had gait difficulties and frequent falls. MRI of the brain showed an extra-axial enhancing lesion overlying the right frontal-parietal cortex, that progressively extended to the contralateral side. This was accompanied by further decline in her functional status. We discuss the diagnostic and therapeutic approach of a pachy-leptomeningeal process in a rheumatoid patient.


[Tinnitus. II.--treatment].
Because of varying origin different therapy of tinnitus methods are applied (surgical, pharmacological, psychotherapy). Treatment of objective tinnitus of vascular origin is usually surgical. It is similar as in the case of tinnitus of mechanical origin. The procedure of operating. Treatment of subjective tinnitus is much more complicated because of difficulties with determining of its occurence. We can separate morbus Ménière, otosclerosis, which require precise treatment. Apart from these disease treatment of subjective tinnitus is multidirectional. It may include pharmacological treatment, psychotherapy, surgical treatment and other methods.


LCVM infection generates tumor antigen-specific immunity and inhibits growth of nonviral tumors.
Antibodies and T cells specific for tumor-associated antigens (TAA) are found in individuals without cancer but with a history of infections and are associated with lowered cancer risk. We hypothesized that those immune responses were generated to transiently abnormally expressed self-antigens on infected cells (disease-associated antigens, DAA) and later on tumor cells as TAA. We tested this hypothesis in mice with a history of infection with lymphocytic choriomeningitis virus (LCMV) Armstrong strain (Arm) that causes acute infection when injected intraperitoneally or CL-13 strain that establishes chronic infection when injected intravenously. Both elicited antibodies and T cells that recognized DAA/TAA on infected cells and on mouse tumors. When challenged with those tumors, Arm-experienced mice controlled tumors better than CL-13-experienced mice or infection-naïve mice. We characterized 7 DAA/TAA that were targets of LCMV-elicited antitumor immunity. We then vaccinated mice with tumor-derived gp96, a heat shock protein that binds a variety of TAA peptides, including those expressed on virus-infected cells as DAA. Tumor-gp96 vaccine induced DAA/TAA-specific immunity. When challenged with Cl-13, the mice showed lower viral copy numbers both early (day 7) and late (day 70) in infection. DAA/TAA may be immunogenic and safe candidates to develop vaccines to control both infections and cancer.


Cerebral inflammation in X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disease that affects approximately 1 in 25 000 males. It is characterized by elevated levels of saturated very long chain fatty acids (VLCFA), i.e., >C22:0, particularly in ganglioside and cholesterol ester fractions of brain white matter and adrenal cortex. Failure of peroxisomal very long chain fatty acyl-CoA synthetase (VLCS) to activate these VLCFA prevents their degradation by peroxisomal beta-oxidation. X-ALD maps to Xq28 and the gene encodes a peroxisomal membrane protein and not the gene for VLCS. The two most common forms of X-ALD are the cerebral (CER) form, with an inflammatory demyelinating reaction that resembles multiple sclerosis (MS), and adrenomyeloneuropathy (AMN), which involves the spinal cord and in which the inflammatory reaction is mild or absent. Investigations into the nature of the cerebral inflammatory demyelinating reaction in X-ALD will be the subject of this review.


Reduction of moiré for coarse integral volumetric imaging.
This paper proposes two moiré reduction methods for coarse integral volumetric displays composed of multilayer display panels. The quality of the image presented by the conventional multilayer integral imaging stays relatively low because of the moiré pattern, which appears due to the layering structure of display panels with limited pixel aperture. The authors propose two methods to solve this problem. The first method is to add another layer of convex lens array with short focal length on the front side of the layered display panels. The second method is to enlarge the pixel pitch of the back-layer panel while fixing that of the front-layer panel.


Beyond child soldiering: the interference of daily living conditions in former child soldiers' longer term psychosocial well-being in northern Uganda.
Given the various developments in former child soldiers' psychosocial well-being over time, the question arises as to which factors are associated with the prevalence of psychological distress. An ongoing debate points to the plausible importance of child soldiering-related and post-child soldiering factors. This study is an exploratory analysis of both types of association with former child soldiers' psychosocial well-being in the longer term. Follow-up data on a convenience sample of 424 northern Ugandan former child soldiers are analysed. Psychological symptoms are assessed by a review of the intake and assessment forms of the Rachele Rehabilitation Centre, which were not validated and did not include a standardised translation into the local language. These psychological symptoms and possible associated factors are analysed using binary logistic regression analysis. Thereby, both child soldiering-related and post-child soldiering variables are accounted for. The outcomes reveal almost no significant main effects of child soldiering-related variables, while a range of post-child soldiering variables (number of meals a day, school attendance, insults and professional support) are clearly associated with the prevalence of the measured psychological symptoms in the longer term. These exploratory conclusions should be further investigated in representative samples of former child soldiers using validated assessment tools.


Production and characterization of monoclonal antibodies against Clostridium perfringens type A enterotoxin.
Hybridomas secreting monoclonal antibodies (MABs) specific for Clostridium perfringens type A enterotoxin were produced by fusion of P3X63Ag8.653 myeloma cells with spleen cells from BALB/c mice immunized with purified enterotoxin. Wells containing hybridomas secreting immunoglobulin G (IgG) antibodies against enterotoxin were specifically identified by an indirect enzyme-linked immunosorbent assay (ELISA), and 10 ELISA-positive hybridomas were selected and cloned twice by limiting dilution. All 10 hybridomas produced MABs containing immunoglobulin G1 heavy chains and kappa (kappa) light chains. These hybridomas were then grown as ascitic tumors in mice, and MABs were purified from the ascites fluids with DEAE Affi-gel blue. The specificity of the MABs for enterotoxin was demonstrated by immunoblotting and ELISA. Competitive radioimmunoassay with 125I-MABs suggests that these MABs recognized at least four epitopes on the enterotoxin molecule. The enterotoxin-neutralizing ability of MABs from both hybridoma culture supernatants and ascites fluids was assessed by using a 3H-nucleotide-release Vero (African green monkey kidney) cell assay. Only 2 of the 10 hybridomas produced MABs which completely (greater than 90%) neutralized the biologic activity of enterotoxin. Preincubation of 125I-enterotoxin with MABs demonstrated that MAB neutralizing ability correlated with MAB-specific inhibition of specific binding of enterotoxin to intestinal brush border membranes.


Low aromatase activity in microsomes from complete hydatidiform mole.
The complete hydatidiform mole (CHM) is characterized by the presence of aberrant placenta, with hyperplasia of cyto- and syncytiotrophoblasts and the absence of maternal genetic information. Steroidogenesis in this condition is, thus, of special interest. In this study we investigated the kinetic parameters of aromatase in microsomes from CHM compared with those in normal early placenta (NEP). The enzyme activity was determined by measuring the conversion of [3H] testosterone to [3H]estradiol plus [3H]estrone. The Km value for testosterone was 33 nmol/L in CHM and 17 nmol/L in NEP of similar gestational ages. Aminoglutethimide, a nonsteroidal inhibitor, decreased in a dose-dependent manner and with the same potency the aromatization of testosterone in both tissues (ID50, 2 vs. 1 mumol/L in CHM and NEP, respectively). These results suggest that the enzymes from the two sources are kinetically similar. However, the enzyme efficiency, expressed as the maximum velocity/Km ratio, was 17-fold lower in CHM than in NEP tissue (1.22/33 vs. 10.68/17 min/mg.mL). These findings suggest that in molar pregnancy the decreased capacity of trophoblast tissue for the formation of estrogen could increase the testosterone concentration inside the molar vesicle, which, in turn, as we previously reported, inhibits progesterone formation. All of these data could provide an explanation for the low circulating level of progesterone, which may directly or indirectly affect the spontaneous expulsion of this aberrant tissue in the second trimester of pregnancy.


Violence and personality in forensic patients: is there a forensic patient-specific personality profile?
Concerning the discussion about the connection of personality traits, personality disorders, and mental illness, this study focused on the personality profiles of male forensic patients, prison inmates, and young men without criminal reports. The main topic centered on group-specific personality profiles and identifying personality facets corresponding with mental illness. The authors therefore used the Rasch model-based Trier Integrated Personality Inventory. They individually tested 141 German forensic patients with different crime backgrounds, 122 prison inmates, and 111 soldiers of the German army. Within group differences they found that the individuals with mental retardation differ from patients with a personality disorder or psychosis. Patients with mental retardation displayed higher neurotic and/or paranoid personality accents and tended to be low organized and self-confident.


V-ATPase inhibition by archazolid leads to lysosomal dysfunction resulting in impaired cathepsin B activation in vivo.
The myxobacterial agent archazolid inhibits the vacuolar proton pump V-ATPase. V-ATPases are ubiquitously expressed ATP-dependent proton pumps, which are known to regulate the pH in endomembrane systems and thus play a crucial role in endo- and exocytotic processes of the cell. As cancer cells depend on a highly active secretion of proteolytic proteins in order to invade tissue and form metastases, inhibition of V-ATPase is proposed to affect the secretion profile of cancer cells and thus potentially abrogate their metastatic properties. Archazolid is a novel V-ATPase inhibitor. Here, we show that the secretion pattern of archazolid treated cancer cells includes various prometastatic lysosomal proteins like cathepsin A, B, C, D and Z. In particular, archazolid induced the secretion of the proforms of cathepsin B and D. Archazolid treatment abrogates the cathepsin B maturation process leading to reduced intracellular mature cathepsin B protein abundance and finally decreased cathepsin B activity, by inhibiting mannose-6-phoshate receptor-dependent trafficking. Importantly, in vivo reduced cathepsin B protein as well as a decreased proteolytic cathepsin B activity was detected in tumor tissue of archazolid-treated mice. Our results show that inhibition of V-ATPase by archazolid reduces the activity of prometastatic proteases like cathepsin B in vitro and in vivo.


Simulating the effect of cochlear-implant electrode insertion depth on speech understanding.
Normally hearing listeners were presented with vowels, consonants, and sentences for identification through an acoustic simulation of a five-channel cochlear implant with electrodes separated by 4 mm (as in the Ineraid implant). The aim of the experiment was to simulate the effect of depth of electrode insertion on identification accuracy. Insertion depth was simulated by outputting sine waves from each channel of the processor at a frequency determined by the cochlear place of electrodes inserted 22-25 mm into the cochlea. The results indicate that simulated insertion depth had a significant effect on performance. Performance at 22- and 23-mm simulated insertion depths was always poorer than normal, and performance at 25 mm simulated insertion depth was, most generally, the same as normal. It is inferred from these results that, if insertion depth could be unconfounded from other coexisting factors in implant patients, then insertion depth would be found to affect speech identification performance significantly.


Fibrinogen and homocysteine levels in coronary artery disease.
Conventional risk factors like high serum cholesterol, smoking and hypertension do not explain all the mortality and morbidity due to coronary artery disease in Indian population. Novel factors like plasma fibrinogen and homocysteine have been currently recognised as independent risk factors for coronary artery disease. A case-control study was carried out to examine the role of plasma fibrinogen, homocysteine, lipid profile and anthropometric parameters in angiographically established coronary artery disease patients. The relationship between the biochemical and anthropometric parameters was also examined. Fifty-eight male patients in the age range of 35-60 years with angiographically established coronary artery disease and equal number of matched-controls were the subjects of this study. Cases with coronary artery disease had significantly higher waist-to-hip ratio, waist-to-thigh ratio, plasma fibrinogen and total cholesterol. Mean plasma total homocysteine levels were not significantly different between cases and controls. In Indian population, elevated plasma fibrinogen and abdominal obesity appear to be significantly associated with coronary artery disease.


Charge-transfer excitons at organic semiconductor surfaces and interfaces.
When a material of low dielectric constant is excited electronically from the absorption of a photon, the Coulomb attraction between the excited electron and the hole gives rise to an atomic H-like quasi-particle called an exciton. The bound electron-hole pair also forms across a material interface, such as the donor/acceptor interface in an organic heterojunction solar cell; the result is a charge-transfer (CT) exciton. On the basis of typical dielectric constants of organic semiconductors and the sizes of conjugated molecules, one can estimate that the binding energy of a CT exciton across a donor/acceptor interface is 1 order of magnitude greater than k(B)T at room temperature (k(B) is the Boltzmann constant and T is the temperature). How can the electron-hole pair escape this Coulomb trap in a successful photovoltaic device? To answer this question, we use a crystalline pentacene thin film as a model system and the ubiquitous image band on the surface as the electron acceptor. We observe, in time-resolved two-photon photoemission, a series of CT excitons with binding energies < or = 0.5 eV below the image band minimum. These CT excitons are essential solutions to the atomic H-like Schrodinger equation with cylindrical symmetry. They are characterized by principal and angular momentum quantum numbers. The binding energy of the lowest lying CT exciton with 1s character is more than 1 order of magnitude higher than k(B)T at room temperature. The CT(1s) exciton is essentially the so-called exciplex and has a very low probability of dissociation. We conclude that hot CT exciton states must be involved in charge separation in organic heterojunction solar cells because (1) in comparison to CT(1s), hot CT excitons are more weakly bound by the Coulomb potential and more easily dissociated, (2) density-of-states of these hot excitons increase with energy in the Coulomb potential, and (3) electronic coupling from a donor exciton to a hot CT exciton across the D/A interface can be higher than that to CT(1s) as expected from energy resonance arguments. We suggest a design principle in organic heterojunction solar cells: there must be strong electronic coupling between molecular excitons in the donor and hot CT excitons across the D/A interface.


Ocular findings in Brazilian identical twins with Cohen syndrome: case report.
A case of identical male twins with Cohen syndrome who present multiple ophthalmic findings is reported. The patients were identical 16 year-old twin boys who showed down slanting eyelids, mild ptosis, high-grade myopia, small cortical lens opacities, posterior subcapsular cataracts, myotic and corectopic pupils with poor dilation due to focal iris atrophy and retinochoroidal dystrophy. Ophthalmologists must be aware of the ocular and systemic findings of Cohen syndrome in the evaluation of young patients with mental retardation and visual impairment.


Liver transplantation for hepatocellular carcinoma--is there a risk of recurrence caused by intraoperative blood salvage autotransfusion?
The use of intraoperative blood salvage autotransfusion (IBSA) during surgical approaches may contribute to tumour cell dissemination. Therefore, IBSA should be avoided in cases of malignancy. However, the risks of IBSA might be acceptable in liver transplantation (LT) for selected small hepatocellular carcinoma (HCC). In total, 136 recipients of LT with histologically proven HCC in the explanted liver were included in this analysis. With regard to tumour recurrence, 40 patients receiving IBSA despite HCC (IBSA group) were compared to 96 patients without IBSA (non-IBSA group). Milan criteria as assessed in the explanted liver were fulfilled in 24 of 40 IBSA patients and 58 of 96 non-IBSA patients (p = 0.85). Five of 40 patients in the IBSA group and 18 of 96 patients in the non-IBSA group experienced tumour recurrence (p = 0.29). In spite the theoretical risk of tumour cell dissemination, the recurrence rate was not increased in the IBSA group. Our results indicate that IBSA does not modify the risk of HCC recurrence. Therefore, in highly selected HCC patients undergoing LT, the use of IBSA appears to be justified.


Cellular targets and mechanisms in the cytotoxic action of non-biodegradable engineered nanoparticles.
The use of nanoparticles (NPs) has improved the quality of many industrial, pharmaceutical, and medical products. Increased surface reactivity, a major reason for the positive effects of NPs, may, on the other hand, also cause adverse biological effects. Almost all non-biodegradable NPs cause cytotoxic effects but employ quite different modes of action. The relation of biodegradable or loaded NPs to cytotoxic mechanism is more difficult to identify because effects may by caused by the particles or degradation products thereof. This review introduces problems of NPs in conventional cytotoxicity testing (changes of particle parameters in biological fluids, cellular dose, cell line and assay selection). Generation of reactive oxygen and nitrogen species by NPs and of metal ions due to dissolution of the NPs is discussed as a cause for cytotoxicity. The effects of NPs on plasma membrane, mitochondria, lysosomes, nucleus, and intracellular proteins as cellular targets for cytotoxicity are summarized. The comparison of the numerous studies on the mechanism of cellular effects shows that, although some common targets have been identified, other effects are unique for particular NPs or groups of NPs. While titanium dioxide NPs appear to act mainly by generation of reactive oxygen and nitrogen species, biological effects of silver and iron oxide are caused by both reactive species and free metal ions. NPs lacking heavy metals, such as carbon nanotubes and polystyrene particles, interfere with cell metabolism mainly by binding to macromolecules.


Enhanced expression of Pctk1, Tcf12 and Ccnd1 in hippocampus of rats: Impact on cognitive function, synaptic plasticity and pathology.
We previously identified a set of 50 genes that were differentially transcribed in the hippocampal CA1 region of aged, learning-impaired rats compared to aged, superior learning animals during a Morris water maze paradigm. In the current study, we expressed three of these genes (Pctk1, Tcf12 and Ccnd1), which had shown increased transcription in aged, learning impaired rats, in the hippocampus of young rats using viral gene transfer and tested for learning and memory deficits at age 7-14months. Pctk1 injected animals displayed a modest deficit in acquiring latency in both the Morris water maze and the reverse Morris maze. In the radial arm water maze paradigm, Pctk1, Tcf12 and Ccnd1 expressing animals all showed significant deficits in spatial working memory compared to controls. Rats injected with Ccnd1 and Tcf12, but not Pctk1, also showed a significant deficit in spatial reference memory in the radial arm water maze. Electrophysiological experiments revealed no difference in LTP in Ccnd1 and Pctk1 animals. However, LTD induced by low frequency stimulation was observed in control and Ccnd1 animals, but not in Pctk1 treated animals. In addition, neither Ccnd1 nor Pctk1 expression produced any detectable neuropathology. In contrast Tcf12 expressing animals displayed significant neurodegeneration in both CA1 and dentate gyrus. Several Tcf12 animals also developed tumors that appeared to be glioblastomas, suggesting that aberrant Tcf12 expression in the hippocampus is tumorigenic. Thus, behavioral experiments suggested that overexpression of Pctk1 and Ccnd1 produce a deficit in learning and memory, but electrophysiological experiments do not point to a simple mechanism. In contrast, the learning and memory deficits in Tcf12 animals are likely due to neuropathology associated with Tcf12 gene expression.


Cytologic appearance of retinal cells included in a fine-needle aspirate of a meningioma around the optic nerve of a dog.
A 6-year-old Wirehair Dachshund had a meningioma around the optic nerve that caused exophthalmos. A benign mesenchymal tumor was suspected based on the cytologic pattern of a fine-needle aspirate, and a meningioma was diagnosed by histopathologic examination. In addition to the meningioma cells, the cytologic smears included groups of cells from apparently 4 layers of normal retina. In particular, uniform rod-shaped structures in the cytologic sample could suggest rod-shaped bacteria, but these structures were identified as cylindrical outer segments of photoreceptor rod cells. Other retinal structures recognized included pigmented epithelial layer cells with their uniquely formed pigment granules, the characteristic bi-lobed, cleaved nuclei from the outer nuclear layer, and nerve tissue likely from the outer plexiform layer of the retina.


Phonation thresholds as a function of laryngeal size in a two-mass model of the vocal folds.
This letter analyzes the oscillation onset-offset conditions of the vocal folds as a function of laryngeal size. A version of the two-mass model of the vocal folds is used, coupled to a two-tube approximation of the vocal tract in configuration for the vowel /a/. The standard male configurations of the laryngeal and vocal tract models are used as reference, and their dimensions are scaled using a single factor. Simulations of the vocal fold oscillation and oral output are produced for varying values of the scaling factor. The results show that the oscillation threshold conditions become more restricted for smaller laryngeal sizes, such as those appropriate for females and children.


Cervical Cancer Protection in Japan: Where Are We?
In Japan, government subsidies for human papillomavirus (HPV) vaccination of girls aged 13-16 commenced in 2010. By early 2013, vaccination had become a widely accepted national immunization program. However, in June of 2013, the Ministry of Health, Labor, and Welfare (MHLW), the government's lead agency, suspended its recommendation for vaccination in response to reports of adverse vaccine events. The rate of HPV vaccination quickly dropped from 70% to almost zero, where it has lingered for eight years. In 2020, a new 9-valent HPV vaccine was licensed in Japan. The momentum seemed to be building for the resumption of HPV vaccinations, yet Japanese mothers remain widely hesitant about vaccinating their daughters, despite the well-proven safety and efficacy of the HPV vaccines. The Japanese government and our educational and medical institutions must work harder as a team to inform our parents and their children about the life-saving benefits of the HPV vaccine, and at the same time, we must respond to all their concerns and questions. The vaccine hesitancy of unvaccinated women born in 2000 and thereafter is a natural consequence of the suspension of the government's recommendation. We must also take every possible measure to reduce the significant risk for cervical cancer these women have.


Low mRNA expression and activity of monoacylglycerol lipase in human SH-SY5Y neuroblastoma cells.
Relatively little is known about the endocannabinoid system in human neuroblastoma cell lines. In the present study, we have investigated the expression of the genes coding for the enzymes involved in the synthesis and catabolism of endocannabinoids in the SH-SY5Y cell line. The expression of MGLL, the gene coding for the 2-arachidonoylglycerol hydrolytic enzyme monoacylglycerol lipase (MAGL), was found to be 85 and 340 fold lower than the expression levels for the genes coding for alpha/beta-hydrolase domain containing 6 and 12 (ABHD6, ABHD12), which are alternative hydrolytic enzymes for this endocannabinoid. In comparison, mRNA levels of MGLL were 1.5 fold higher than ABHD6 and 2 fold lower than the levels of ABHD12 in DU-145 human prostate cells. In functional assays, the hydrolysis of the 2-arachidonoylglycerol homologue 2-oleoylglycerol by intact SH-SY5Y cells was partially inhibited by the ABHD6 inhibitor WWL70, but not by the MAGL inhibitor JZL184, whereas the reverse was true in DU-145 cells. The combination of JZL184 + WWL70 did, however produce a significantly greater inhibition of 2-OG hydrolysis than seen with WWL70 alone in the SH-SY5Y cells. The low MGLL expression in the SH-SY5Y cells was not due to epigenetic silencing, since levels were not affected by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine and/or the histone acetylase inhibitor trichostatin A. The low MGLL expression in SH-SY5Y cells should be taken into account when using these cells in experiments investigating the involvement of the endocannabinoid system in models of physiological and pathological processes.


Impact of funding influenza vaccination on coverage among Australian children: a national study using MedicineInsight, a large general practice database.
Influenza contributes to morbidity and mortality worldwide. Children are at a higher risk of influenza-related complications and vaccination promotes direct protection and limits transmission. This study aimed to explore influenza vaccination coverage among children in Australian general practice from 2015 to 2018, and patterns in coverage before and after the implementation of state-funded immunization programs. Data from 196,520 'active' patients (3+ consultations in two consecutive years) aged <5 years from 542 Australian general practices were included (MedicineInsight database). Logistic regression models were used to identify associations between vaccination with patient and practice characteristics. The overall vaccination coverage increased more than five times from 2015 (3.9%) to 2018 (19.6%) and varied among states. Children attending practices located in the wealthiest areas were more likely to receive the vaccine and appeared to benefit most from the funding, as the increase in coverage from 2017 to 2018 was greater among them than those attending practices in the least advantaged areas (17 vs. 11 percentage points, respectively). This relationship was not evident when analyzing the patient's socioeconomic level. In conclusion, free influenza vaccinations increase coverage in at-risk populations. Promotional campaigns may be required to maintain higher coverage and target practices located in low-income areas.


Effect of household air pollutants on the composition of exhaled breath characterized by solid-phase microextraction and needle-trap devices.
Exposure to household air pollutants is becoming a serious environmental health risk. Various methods can be applied to assess humans' exposure status to indoor pollutants, with breath monitoring being among the best options. Breath sampling is fast and non-invasive, and contains compounds that can be used as markers for evaluating exposure length and estimating internal concentrations of pollutants. However, the distribution of compounds between gas and droplets in breath samples represents one of the key challenges associated with this analytical method. In this work, a needle-trap device (NTD) was prepared by packing the needle with a porous filter, divinyl benzene, and Carboxen to enable the exhaustive capture of both droplet-bound and gaseous components. Furthermore, fiber-based solid-phase microextraction (SPME) was also applied to extract compounds from only the gas phase to distinguish this portion of analytes from the total concentration in the sample. Dynamic, real-time breath sampling was enabled via a new sampling tube equipped with 2 one-way valves, which was specially designed for this work. Both methods provided satisfactory reproducibility, repeatability, and sensitivity, with detection limits as low as 0.05 ng mL-1. To investigate the real-world applicability of the proposed devices, breath samples were obtained from volunteers who had been exposed to candle and incense smoke and aerosol sprays, or had smoked cannabis. The results revealed the high concentration of organic air pollutants in inhaled air (maximum of 215 ng mL-1) and exhaled breath (maximum of 14.4 ng mL-1) and a correlation between the components in inhaled air and exhaled breath. Significantly, the findings further revealed that the developed NTD has enhanced breath-sample determinations, especially for polar compounds, which tend to remain trapped in breath droplets.


Angiopoietin-2 promotes extracellular matrix degradation in human degenerative nucleus pulposus cells.
In contrast to healthy intervertebral discs (IVDs), degenerate IVDs become vascularized. Here, we determined the role of an angiogenesis promoter, angiopoietin (Ang)-2, in the pathology of IVD degeneration (IDD). We evaluated degree of IDD using the Pfirrmann grading system. We used quantitative real-time polymerase chain reaction and western blotting to analyze ANG2 gene expression and Ang-2 protein levels, respectively. The involvement of Ang-2 in IVD degradation and regulation of nuclear factor-κB (NF-κB) signaling was examined by immunohistochemistry, western blotting and immunofluorescence. As a result, 10 samples with grades II and III IDD were categorized as the mild IDD group; for comparison, another 10 specimens with grades IV and V constituted the severe IDD group. Ang-2 expression was significantly higher in severe IDD than in mild IDD. Exogenous Ang-2 administration led to increased production of catabolic proteinases and loss of aggrecan and collagen II in degenerative NP cell cultures, which was mediated by the NF-κB signaling pathway. Elevated Ang-2 levels also increased interleukin-1β expression in degenerative NP cells. We conclude that the release of Ang-2 aggravates NP cell degradation and plays an important role in IDD. Ang-2 may thus constitute a novel therapeutic target for the treatment of IVD.


Anal extrusion of a ventriculo peritoneal shunt tube: Endoscopic removal.
We describe the extrusion of a ventriculo peritoneal shunt tube from the anus into a 6-year-old boy following the placement of a ventriculo peritoneal shunt for postoperative periventricular tumor-induced hydrocephalus. He was admitted with a complaint of extrusion of a tube through anus on and off during bowel evacuation. He was evaluated with an X-ray of the abdomen which was showing a coiled tube in descending and sigmoid colon, confirmed by sigmoidoscopy. The proximal end was exposed for external ventricular drainage and distal end was removed endoscopically. The patient was watched for peritonitis and managed conservatively. The proximal end of the tube was removed after 5 days of external ventricular drainage and after ruling out ventriculitis and meningitis. Bowel perforation by a ventriculo peritoneal tube is a rare complication. Diagnosis is often difficult and delayed. Most of the bowel perforation is seen in young patients.


Regulated expression of HCN channels and cAMP levels shape the properties of the h current in developing rat hippocampus.
The hyperpolarization-activated current (I(h)) contributes to intrinsic properties and network responses of neurons. Its biophysical properties depend on the expression profiles of the underlying hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and the presence of cyclic AMP (cAMP) that potently and differentially modulates I(h) conducted by HCN1, HCN2 and/or HCN4. Here, we studied the properties of I(h) in hippocampal CA1 pyramidal cells, the developmental evolution of the HCN-subunit isoforms that contribute to this current, and their interplay with age-dependent free cAMP concentrations, using electrophysiological, molecular and biochemical methods. I(h) amplitude increased progressively during the first four postnatal weeks, consistent with the observed overall increased expression of HCN channels. Activation kinetics of the current accelerated during this period, consonant with the quantitative reduction of mRNA and protein expression of the slow-kinetics HCN4 isoform and increased levels of HCN1. The sensitivity of I(h) to cAMP, and the contribution of the slow component to the overall I(h), decreased with age. These are likely a result of the developmentally regulated transition of the complement of HCN channel isoforms from cAMP sensitive to relatively cAMP insensitive. Thus, although hippocampal cAMP concentrations increased over twofold during the developmental period studied, the coordinated changes in expression of three HCN channel isoforms resulted in reduced effects of this signalling molecule on neuronal h currents.


[A case of protein-losing gastroenteropathy in association with mixed connective tissue disease which was successfully treated with cyclophosphamide pulse therapy].
A 47-year-old man had been given a diagnosis of mixed connective tissue disease (MCTD) on 1987 when he had presented with Raynaud's phenomenon, polyarthralgia, sclerodactyly, and a high titre of anti-RNP antibody. Once his symptoms had improved following the administration of prednisolone orally and the treatment was discontinued since 1995. He noticed dyspnea and chest pain in February 1997. The bilateral pleural effusion was pointed out in the local hospital and he was admitted to our hospital in March 1997 for further examination. In addition to pleural effusion and ascites, laboratory studies revealed hypoalbuminemia and low serum levels of complements. Renal and liver function tests were normal and the urine gave a trace test for protein. The presence of protein loss in the gut was confirmed by an elevated alpha 1-antitrypsin clearance and 99mTc-albumin scintigraphy showing abnormal radioactivity in the gastrointestinal tract. Although endoscopic examination showed no abnormal findings macroscopically and gastrointestinal biopsies revealed nonspecific inflammation only, immunofluorescent studies demonstrated deposits of C 3, C 4 and IgG in the stomach, colon, and pleura. These findings supported the pathogenesis that immune deposits in tissues caused protein-losing gastroenteropathy (PLGE) in MCTD. Intravenous administration of cyclophosphamide started since July 1997, while the high-dose corticosteroid therapy including methylprednisolone pulse therapy were not effective. Hypoalbuminemia and low serum levels of complements improved remarkably and the pleural effusion and ascites disappeared after cyclophosphamide pulse therapy four times monthly. Cyclophosphamide pulse therapy should be considered as a possibly effective treatment for PLGE in association with collagen disease resistant to corticosteroid therapy.


Pharmacologic treatment of agitation associated with dementia.
Pharmacotherapy of aggressive or agitated behaviors in the dementia patient has not been studied extensively, despite the prevalence of this problem. Neuroleptics have the most support for efficacy, with shorter acting benzodiazepines demonstrating benefit on occasion. However, studies done to date indicate that these drugs are effective only for a minority of patients and that side effects frequently make patients worse. Other medications, such as propranolol, carbamazepine, or lithium, may be helpful, but their efficacy in dementia patients has not been demonstrated in placebo-controlled studies. Until such studies are done, their use is most appropriate in special patient groups or in patients who have failed neuroleptic or benzodiazepine treatment. More studies are needed in elderly patients evaluating effectiveness of pharmacologic agents in specific types of dementia, particularly Alzheimer's disease. Most studies done to date have been of relatively short duration, usually two months or less. Because these medications often are given to dementia patients for prolonged periods, studies are needed to define the long-term clinical efficacy of these agents. In the clinical setting, these agents should be reduced periodically or discontinued to determine ongoing need. In addition, environmental, social, or behavioral methods of reducing agitated behaviors need to be explored as an adjunct to any medication trial.


Distribution of AB0 and RH blood group alleles in different populations of southern Punjab, Pakistan.
The analysis of a sample of 1632 individuals from patients of the Nishtar Teaching Hospital, Multan, suggests that different ethnic groups (Araeen, Mughals, Syed, Jat, Rajputs, Baloch and Pathan) are not significantly different from another with regard to the distribution of RH blood group alleles (RH*d around 0.30). The distributions of the AB0 blood group alleles suggest that different ethnic groups are not significantly different from the average alele frequencies (AB0*A = 0.23, AB0*B = 0.33, AB0*0 = 0.47) except for the Pathan ethnic group (AB0*A = 0.35, AB0*B = 0.47, AB0*0 = 0.27). The populations of different geographic areas are not significantly different from the average allele frequencies, except for the southern district of Rahim Yar Khan (AB0*A = 0.12) and the northern district of Sahiwal (AB0*A = 0.19). The populations of Sahiwal (RH*d = 0.35) and Muzaffargarh (RH*d = 0.36) yield significantly different allele frequencies at the RH locus. The interpopulation differences can be explained by the geographic distance. There is a significant difference in the frequencies of the AB0 alleles between rural and urban populations, suggesting that rural populations maintain their isolation from urban populations. Rural and urban populations are not significantly different from one another concerning the allele frequencies at the RH locus.