Protease inhibitors in chronic obstructive pulmonary disease.
Quantification of the major plasma protease inhibitors and genetic typing of alpha1-antirypsin were done in 107 patients with chronic obstructive pulmonary disease and in 91 control subjects with normal ventilatory function who were similar with respect to age, race, and sex. There was a significant increase in frequency of the PiZ gene and the Pi MZ phenotype of alpha1-antitrypsin among the patients when compared with the control subjects. No evidence for a primary deficiency of any other antiprotease was found; however, the mean concentration of inter-alpha-trypsin inhibitor was significantly lower in the patients than the control subjects, and moderate deficiency of alpha1-antichymotrypsin was noted in a few patients. These data indicate an increased risk of developing chronic obstructive pulmonary disease in persons with the Pi MZ phenotype of alpha1-antirypsin and suggest a possible relationship between these diseases and low serum concentrations of inter-alpha-trypsin inhibitor.


Geographic origin of benthic foraminiferal species.
Museum collections were used to document the worldwide Pliocene and Pleistocene fossil record of 59 species that now occur on the Atlantic continental margin of North America. Tabulation of these data indicates that benthic foraminifera evolve at all latitudes and in all parts of the world ocean rather than from some center or centers of origin. Dispersal in geologic time is very rapid.


[EFFECT OF SYNTHETIC ANTIOXIADNT THIOPHAN AND SCUTELLARIA BAICALENSIS ROOT EXTRACT ON DRUG-INDUCED MUTAGENESIS].
Gene protective properties of synthetic antioxidant thiophane and the extract of in vitro cultivated roots of Scutellaria baicalensis were studied on the model of Dr. melanogaster larvae genetic structure damage by drugs cisplatin and cyclophosphan (cyclophosphamide). It is established that adding thiophane or Scutellaria baicalensis root extract to a nutrient medium leads to a decrease in amount of Dr. melanogaster recombinants (females bearing recessive yellow and/or singed marker mutations).


Somatic mutations and the hierarchy of hematopoiesis.
Clonal disease is often regarded as almost synonymous with cancer. However, it is becoming increasingly clear that our bodies harbor numerous mutant clones that are not tumors, and mostly give rise to no disease at all. Here we discuss three somatic mutations arising within the hematopoietic system: BCR-ABL, characteristic of chronic myeloid leukemia; mutations of the PIG-A gene, characteristic of paroxysmal nocturnal hemoglobinuria; the V617F mutation in the JAK2 gene, characteristic of myeloproliferative diseases. The population frequencies of these three blood disorders fit well with a hierarchical model of hematopoiesis. The fate of any mutant clone will depend on the target cell and on the fitness advantage, if any, that the mutation confers on the cell. In general, we can expect that only a mutation in a hematopoietic stem cell will give long-term disease; the same mutation taking place in a cell located more downstream may produce just a ripple in the hematopoietic ocean.


Differences between alpha-adrenergic and beta-adrenergic inotropic effects in rat heart papillary muscles.
alpha-And beta-adrenergic inotropic effects have been shown to be qualitatively different. In order to further characterize these difference we compared the mechanical response to alpha- and beta-adrenoceptor stimulation, respectively, in electrically driven left ventricular papillary muscles from rat heart. The muscles were stimulated by either isoprenaline (Beta-adrenoceptor stimulation), phenylephrine in the presence of propranolol (alpha-adrenoceptor stimulation) or phenylephrine alone (combined alpha-and Beta-adrenoceptor stimulation). Isometric tension (T), rate of rise and decline of tension (first derivate=T') and rate of transition from tension rise to tension decline (negative part of second derivative=T') were recorded. These recordings disclosed qualitative differences between the alpha-and Beta-inotropic response both in dose-response and time course experiments. Maximal Beta-adrenoceptor stimulation caused a small increase in Tmax (18%), intermediate increases in T'max (45%) and T'min (68%) and considerable increase in T'min (145%) ("Beta-type" effect). Maximal alpha adrenoceptor stimulation increased all qualities by about the same degree (23-24% ("a-type" effect). While Beta-adrenoceptor stimulation gave a dose-dependent and pronounced increase in the ratio T"min/T'max (relaxation-onset index), alpha adrenoceptor stimulation decreased it to subcontrol values and phenylephrine alone gave a small dose-dependent increase at higher dose. The time course of the alpha-adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4-5 min. Beta-Adrenoceptor stimulation gave a monophasic response which reached maximum after 1-2 min. Phenylephrine alone gave mainly an "a-type" effect although T"min increased significantly more in the absence than in the presence of propranolol and T"min/T'max showed a small increase which developed slowly. Thus Beta-adrenoceptor stimulation activated relaxation compared to contraction by a higher degree than did alpha-adrenoceptor stimulation. This probably reflects different mechanisms of action. While the alpha-effect may rely primarily on an increased calcium influx, the Beta-effect probably is the final result of several subcellular effects of cyclic AMP.


Vitamin E modulates cigarette smoke extract-induced cell apoptosis in mouse embryonic cells.
Vitamin E (VE) can effectively prevent occurrence of lung cancer caused by passive smoking in mice. However, whether VE prevents smoking-induced cytotoxicity remains unclear. In this study, a primary culture of embryonic lung cells (ELCs) was used to observe the cytotoxic effects of cigarette smoke extract (CSE), including its influence on cell survival, cell cycle, apoptosis, and DNA damage, and also to examine the effects of VE intervention on CSE-induced cytotoxicity. Our results showed that CSE could significantly inhibit the survival of ELCs with dose- and time-dependent effects. Furthermore, CSE clearly disturbed the cell cycle of ELCs by decreasing the proportion of cells at the S and G₂/M phases and increasing the proportion of cells at the G₀/G₁ phase. CSE promoted cell apoptosis, with the highest apoptosis rate reaching more than 40%. CSE also significantly caused DNA damage of ELCs. VE supplementation could evidently inhibit or reverse the cytotoxic effects of CSE in a dose- and time-dependent manner. The mechanism of CSE effects on ELCs and that of VE intervention might involve the mitochondrial pathway of cytochrome c-mediated caspase activation. Our study validate that VE plays a clearly protective effect against CSE-induced cytotoxicity in mouse embryonic lung cells.


Polytomography in an otologic practice.
The polytome should be used as an adjunct to conventional roentgenograms of the temporal bone and not as a substitute. The purpose of this paper is to demonstrate how the polytome has been used to great advantage in a private otologic practice.


Expression and function of dopamine in odontoblasts.
Dopamine (DA) is produced from tyrosine by tyrosine hydroxylase (TH). A recent study has reported that DA promotes the mineralization of murine preosteoblasts. However, the role of DA in odontoblasts has not been examined. Therefore, in this investigation, we researched the expression of TH and DA in odontoblasts and the effects of DA on the differentiation of preodontoblasts (KN-3 cells). Immunostaining showed that TH and DA were intensely expressed in odontoblasts and preodontoblasts of rat incisors and molars. KN-3 cells expressed D1-like and D2-like receptors for DA. Furthermore, DA promoted odontoblastic differentiation of KN-3 cells, whereas an antagonist of D1-like receptors and a PKA signaling blocker, inhibited such differentiation. However, antagonists of D2-like receptors promoted differentiation. These results suggested that DA in preodontoblasts and odontoblasts might promote odontoblastic differentiation through D1-like receptors, but not D2-like receptors, and PKA signaling in an autocrine or paracrine manner and plays roles in dentinogenesis.


Genetic and functional analysis of the styrene catabolic cluster of Pseudomonas sp. strain Y2.
The chromosomal region of Pseudomonas sp. strain Y2 involved in the conversion of styrene to phenylacetate (upper catabolic pathway) has been cloned and sequenced. Four catabolic genes, styABCD, and two regulatory genes, stySR, were identified. This gene cluster when transferred to Escherichia coli W confers to this phenylacetate-degrading host the ability to grow on styrene as the sole carbon and energy source. Genes styABCD are homologous to those encoding the styrene upper catabolic pathway in Pseudomonas fluorescens ST. Northern blot analyses have confirmed that genes styABCD constitute a transcription unit. The transcription start site of the sty operon was mapped 33 nucleotides upstream of the styA translational start codon. The styS and styR genes, which form an independent transcriptional unit, are located upstream of the styABCD operon, and their gene products show high similarity to members of the superfamily of two-component signal transduction systems. The styS gene product is homologous to histidine kinase proteins, whereas the styR gene product exhibits similarity at its N-terminal domain with cluster 1 of receiver modules and at its C terminus with the LuxR/FixJ family 3 of DNA-binding domains. Expression of the catabolic operon decreased significantly in the absence of the stySR genes and was restored when the stySR genes were provided in trans in the presence of styrene, suggesting that the stySR system behaves as a styrene-inducible positive regulator of the styABCD operon. Finally, a gene encoding a phenylacetyl-coenzyme A ligase that catalyzes the first step in the phenylacetate catabolism (styrene lower catabolic pathway) has been identified upstream of the styS gene. This activity was found to be induced in Pseudomonas sp. strain Y2 cells grown on styrene but not present in cells grown on glycerol. These results strongly suggest that the genes responsible for the complete mineralization of styrene are clustered in the chromosome of Pseudomonas sp. strain Y2.


[Micropsychiatry and the possibilities for correcting mental disorders in infancy].
The investigations of authors concerning infants and their families were generalized on the basis of the observations of infants and their parents with some psychological problems in families. The principles of psychotherapeutic work in above-mentioned groups were formulated. Besides the methods of the diagnosis of psychical deviations development in first year infants as well as peculiarities of alterations in mother-baby system and the main forms of psychic disturbances correction in infants were also described.


C-lobe of lactoferrin: the whole story of the half-molecule.
Lactoferrin is an iron-binding diferric glycoprotein present in most of the exocrine secretions. The major role of lactoferrin, which is found abundantly in colostrum, is antimicrobial action for the defense of mammary gland and the neonates. Lactoferrin consists of two equal halves, designated as N-lobe and C-lobe, each of which contains one iron-binding site. While the N-lobe of lactoferrin has been extensively studied and is known for its enhanced antimicrobial effect, the C-lobe of lactoferrin mediates various therapeutic functions which are still being discovered. The potential of the C-lobe in the treatment of gastropathy, diabetes, and corneal wounds and injuries has been indicated. This review provides the details of the proteolytic preparation of C-lobe, and interspecies comparisons of its sequence and structure, as well as the scope of its therapeutic applications.


Mortality Rate and Ten Years Survival of Elderly Patients Treated with Total Hip Arthroplasty for Femoral Neck Fractures.
Mortality following traumatic femoral neck fractures in the elderly (age >60 years) is influenced by many factors. Addressing some of them may reduce the mortality rate thus improving patient survival and quality of life. This study was a retrospective research using data collected from Hospital Sultanah Bahiyah, Kedah between the years 2008-2018. We measured outcomes such as age, gender, hospital stay, default rate, ambulation post-surgery, American Society of Anaesthesiologists score (ASA) and surgical timing in correlation with mortality rate and 10-year survival of elderly patients treated with Total Hip Arthroplasty for femoral neck fractures in this centre. A total of 291 traumatic femoral neck fractures aged above 60 years post total hip arthroplasty performed were included. There was higher number of female (n =233) compared to male (n=53) Estimated 10 years survival from Kaplan Meier was 42.88% (95% CI: 33.15, 52.54). One year mortality rate in our study was found to be 18.9%. The average time to event was 7.1 years (95% CI:33.15, 52.24) with a mean age group of 75. Total hip arthroplasty patients not ambulating after surgery had a 4.2 times higher hazard ratio compared to ambulators. Those with pre-existing systemic disease (ASA III and IV) were found to have the highest hazard ratio, almost five times that of healthy patients, after adjusting for confounding factors. Delay of more than seven days to surgery was found to be a significant factor in 10-year survival with a hazard ratio of 3.8, compared to surgery performed earlier. Delay of more than 7 days to surgery in 10 years survival was significant with high hazard ratio. It is a predictor factor for survival in 10 years. A larger sample size with a prospective design is required to confirm our findings regarding "unacceptable surgical timing" for femoral neck fractures in patients above 60 years of age.


Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography.
Neuroendocrine tumors (NETs) can be small and situated almost anywhere throughout the body. Our objective was to investigate whether whole-body (WB) positron emission tomography (PET) with (11)C-5-hydroxytryptophan (5-HTP) can be used as a universal imaging technique for NETs and to compare this technique with established imaging methods. Forty-two consecutive patients with evidence of NET and a detected lesion on any conventional imaging (six bronchial, two foregut, 16 midgut, and two thymic carcinoids; one ectopic Cushing's syndrome; four gastrinomas; one insulinoma; six nonfunctioning endocrine pancreatic tumors; one gastric carcinoid, one paraganglioma; and two endocrine-differentiated pancreatic carcinomas) were studied. The WB-(11)C-5-HTP-PET examinations were compared with WB-computed tomography (CT) and somatostatin receptor scintigraphy (SRS). Tumor lesions were imaged with PET in 95% of the patients. In 58% of the patients, PET could detect more lesions than SRS and CT and equal numbers in 34%, whereas in three cases, SRS or CT showed more lesions. In 84% (16 of 19 patients), PET could visualize the primary tumor compared with 47 and 42% for SRS and CT, respectively. The surgically removed PET-positive primary tumor sizes were 6-30 mm. To conclude, this study indicates that WB-(11)C-5-HTP-PET can be used as a universal imaging method for detection of NETs. This study also shows that WB-(11)C-HTP-PET is sensitive in imaging small NET lesions, such as primary tumors, and can in a majority of cases image significantly more tumor lesions than SRS and CT.


Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network.
Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.


Differential role of pre- and postsynaptic neurons in the activity-dependent control of synaptic strengths across dendrites.
Neurons receive a large number of active synaptic inputs from their many presynaptic partners across their dendritic tree. However, little is known about how the strengths of individual synapses are controlled in balance with other synapses to effectively encode information while maintaining network homeostasis. This is in part due to the difficulty in assessing the activity of individual synapses with identified afferent and efferent connections for a synapse population in the brain. Here, to gain insights into the basic cellular rules that drive the activity-dependent spatial distribution of pre- and postsynaptic strengths across incoming axons and dendrites, we combine patch-clamp recordings with live-cell imaging of hippocampal pyramidal neurons in dissociated cultures and organotypic slices. Under basal conditions, both pre- and postsynaptic strengths cluster on single dendritic branches according to the identity of the presynaptic neurons, thus highlighting the ability of single dendritic branches to exhibit input specificity. Stimulating a single presynaptic neuron induces input-specific and dendritic branchwise spatial clustering of presynaptic strengths, which accompanies a widespread multiplicative scaling of postsynaptic strengths in dissociated cultures and heterosynaptic plasticity at distant synapses in organotypic slices. Our study provides evidence for a potential homeostatic mechanism by which the rapid changes in global or distant postsynaptic strengths compensate for input-specific presynaptic plasticity.


Secretion of Recombinant Interleukin-22 by Engineered Lactobacillus reuteri Reduces Fatty Liver Disease in a Mouse Model of Diet-Induced Obesity.
The incidence of metabolic syndrome continues to rise globally. In mice, intravenous administration of interleukin-22 (IL-22) ameliorates various disease phenotypes associated with diet-induced metabolic syndrome. In patients, oral treatment is favored over intravenous treatment, but methodologies to deliver IL-22 via the oral route are nonexistent. The goal of this study was to assess to what extent engineered Lactobacillus reuteri secreting IL-22 could ameliorate nonalcoholic fatty liver disease. We used a mouse model of diet-induced obesity and assessed various markers of metabolic syndrome following treatment with L. reuteri and a recombinant derivative. Mice that received an 8-week treatment of wild-type probiotic gained less weight and had a smaller fat pad than the control group, but these phenotypes were not further enhanced by recombinant L. reuteri However, L. reuteri secreting IL-22 significantly reduced liver weight and triglycerides at levels that exceeded those of the probiotic wild-type treatment group. Our findings are interesting in light of the observed phenotypes associated with reduced nonalcoholic liver disease, in humans the most prevalent chronic liver disease, following treatment of a next-generation probiotic that is administered orally. Once biological and environmental containment strategies are in place, therapeutic applications of recombinant Lactobacillus reuteri are on the horizon.IMPORTANCE In humans, nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease due to the increased prevalence of obesity. While treatment of NAFLD is often geared toward lifestyle changes, such as diet and exercise, the use of dietary supplements such as probiotics is underinvestigated. Here, we report that probiotic Lactobacillus reuteri reduces fatty liver in a mouse model of diet-induced obesity. This phenotype was further enhanced upon delivery of recombinant interleukin-22 by engineered Lactobacillus reuteri These observations pave the road to a better understanding of probiotic mechanisms driving the reduction of diet-induced steatosis and to development of next-generation probiotics for use in the clinic. Ultimately, these studies may lead to rational selection of (engineered) probiotics to ameliorate fatty liver disease.


The relation between paracetamol use and asthma: a GA2LEN European case-control study.
Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking. As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (20-45 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma. These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.


Switching between "On" and "Off" states of persistent activity in lateral entorhinal layer III neurons.
Persistent neural spiking maintains information during a working memory task when a stimulus is no longer present. During retention, this activity needs to be stable to distractors. More importantly, when retention is no longer relevant, cessation of the activity is necessary to enable processing and retention of subsequent information. Here, by means of intracellular recording with sharp microelectrode in in vitro rat brain slices, we demonstrate that single principal layer III neurons of the lateral entorhinal cortex (EC) generate persistent spiking activity with a novel ability to reliably toggle between spiking activity and a silent state. Our data indicates that in the presence of muscarinic receptor activation, persistent activity following an excitatory input may be induced and that a subsequent excitatory input can terminate this activity and cause the neuron to return to a silent state. Moreover, application of inhibitory hyperpolarizing stimuli is neither able to decrease the frequency of the persistent activity nor terminate it. The persistent activity can also be initiated and terminated by synchronized synaptic stimuli of layer II/III of the perirhinal cortex. The neuronal ability to switch "On" and "Off" persistent activity may facilitate the concurrent representation of temporally segregated information arriving in the EC and being directed toward the hippocampus.


Increased cyclic AMP levels enhance IL-1 alpha and IL-1 beta mRNA expression and protein production in human myelomonocytic cell lines and monocytes.
The effects of increasing intracellular cAMP levels on IL-1 alpha and IL-1 beta mRNA expression and IL-1 production in human monocytes and nonlymphoid hematopoietic cell lines were examined. Peripheral monocytes and myelomonocytic cell lines could be stimulated by LPS or phorbol myristate acetate (PMA) to express IL-1 mRNA. Dibutyryl cAMP, 8-bromo-cAMP, forskolin, cholera toxin, PGE1, and PGE2 synergized with PMA or LPS to increase the accumulation in cell lines of IL-1 alpha mRNA by up to 50-fold and that of IL-1 beta mRNA by 10- to 20-fold compared to LPS or PMA alone. This increase in IL-1 alpha and IL-1 beta mRNA accumulation was more modest in monocytes. The synergistic stimulation was due to enhanced IL-1 gene transcription rate rather than increased IL-1 mRNA stability. Despite this marked increase in IL-1 mRNA accumulation, IL-1 protein synthesis in these cells was increased by only twofold. Thus, IL-1 synthesis in monocytes and myelomonocytic cell lines is under stringent translational control.


The Implication of Chemotypic Variation on the Anti-Oxidant and Anti-Cancer Activities of Sutherlandia frutescens (L.) R.Br. (Fabaceae) from Different Geographic Locations.
Extracts of Sutherlandia frutescens (cancer bush) exhibit considerable qualitative and quantitative chemical variability depending on their natural wild origins. The purpose of this study was thus to determine bioactivity of extracts from different regions using in vitro antioxidant and anti-cancer assays. Extracts of the species are complex and are predominantly composed of a species-specific set of triterpene saponins (cycloartanol glycosides), the sutherlandiosides, and flavonoids (quercetin and kaempferol glycosides), the sutherlandins. For the Folin-Ciocalteu phenolics test values of 93.311 to 125.330 mg GAE/g DE were obtained. The flavonoids ranged from 54.831 to 66.073 mg CE/g DE using the aluminum chloride assay. Extracts from different sites were also assayed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging method and ferric reducing anti-oxidant power (FRAP) methods. This was followed by an in vitro Cell Titer-Glo viability assay of various ecotypes using the DLD-1 colon cancer cell line. All test extracts displayed anti-oxidant activity through the DPPH• radical scavenging mechanism, with IC50 values ranging from 3.171 to 7.707 µg·mL-1. However, the degree of anti-oxidant effects differed on a chemotypic basis with coastal plants from Gansbaai and Pearly Beach (Western Cape) exhibiting superior activity whereas the Victoria West inland group from the Northern Cape, consistently showed the weakest anti-oxidant activity for both the DPPH• and FRAP methods. All extracts showed cytotoxicity on DLD-1 colon cancer cells at the test concentration of 200 µg·mL-1 but Sutherlandia plants from Colesburg (Northern Cape) exhibited the highest anti-cancer activity. These findings confirm that S. frutescens specimens display variability in their bioactive capacities based on their natural location, illustrating the importance of choosing relevant ecotypes for medicinal purposes.


The platform for better oral health in Europe--report of a new initiative.
Public health practitioners are required to apply their competencies at a range of levels from governmental to small community groups. A recurring theme at BASCD conferences has been the need to influence policy at the highest level if improvements to oral health and better treatment of oral ill-health are to occur. This paper presents a clear example of such dental public health action at a European level. This report outlines the reasons why it is necessary to try to improve oral health within Europe, in general, and the European Union in particular. It goes on to describe how the newly formed Platform for Better Oral Health in Europe is trying to work at a macro level, and bring interested associations, groups and individuals together. Collectively they can then alert European institutions and national governments to oral health problems and promote policies to improve the current situation. It describes the current problems, their resource implications, the objectives of the Platform, its actions so far and its plans for the immediate future. It suggests that, if the problems are to be addressed, it will be necessary for all interested parties to work together at a European level to raise oral health issues higher on the E.U. agenda.


Personalized Assistance for Patients with Chronic Diseases Through Multi-Level Distributed Healthcare Process Assessment.
The study is aimed towards the assessment and improvement of complex informational, healthcare, and medical processes existing in the distributed environment during monitoring and providing healthcare services to patients with chronic diseases. The study is performed within a framework of a project for development a complex unified medical information system capable to work on large scale (on population-level). The presented experimental studies show that predictive modelling enables unified detection of remote patients' state using self-measuring and distributed electronic health records. In addition, an experimental mobile application is presented as a tool for data collection and user-system interaction during chronic disease monitoring and treatment.


Cohort study examining long-term respiratory health, career duration and racing performance in racehorses that undergo left-sided prosthetic laryngoplasty and ventriculocordectomy surgery for treatment of left-sided laryngeal hemiplegia.
The risk of respiratory conditions, such as inflammatory airway disease (IAD) and exercise-induced pulmonary haemorrhage (EIPH), are thought to be higher in racehorses that undergo prosthetic laryngoplasty with ventriculocordectomy (PLVC) surgery to treat left-sided laryngeal hemiplegia (LLH) than in racehorses with normal laryngeal function. However, this has not been investigated formally owing to the difficulty of obtaining reliable follow-up data. To determine the incidence of respiratory conditions (IAD and EIPH), duration of racing career, number of starts and number of starts for which stakes money was earned in racehorses that had undergone PLVC surgery to treat LLH, compared with racehorses that did not have LLH or undergo any laryngeal surgery. A retrospective cohort study design was used, with surgical, clinical and race data of Thoroughbred racehorses obtained from the time of importation until retirement. The surgical cohort consisted of racehorses that had undergone PLVC for LLH and met specific inclusion criteria. Every surgical case was matched, according to trainer, year of import into Hong Kong and pre-import international handicap rating, to 2 unexposed racehorses. Respiratory conditions, such as excessive tracheal mucus and epistaxis due to severe EIPH, were significantly increased in the surgical cohort, compared with the matched unexposed cohort (P values <0.001 and <0.004, respectively). Racing career duration in the surgical cohort was significantly shorter than in the unexposed cohort, which was primarily due to retirement because of epistaxis. The number of race starts was fewer in the surgical than in the unexposed cohort after surgery/matching, but the number of starts for which stakes money was earned was not significantly different. Owners and trainers should be advised that racehorses with LLH that undergo PLVC surgery are at an increased risk of respiratory conditions (IAD and severe EIPH), which is likely to shorten their racing career compared to racehorses with normal laryngeal function. Racing performance in terms of race starts was significantly less in racehorses that had undergone PLVC surgery; however, the number of starts for which stakes money was earned was similar to those racehorses that were unexposed.


Herpes simplex virus type 1 glycoprotein K is not essential for infectious virus production in actively replicating cells but is required for efficient envelopment and translocation of infectious virions from the cytoplasm to the extracellular space.
We characterized the glycoprotein K (gK)-null herpes simplex virus type 1 [HSV-1] (KOS) delta gK and compared it to the gK-null virus HSV-1 F-gKbeta (L. Hutchinson et al., J. Virol. 69:5401-5413, 1995). delta gK and F-gKbeta mutant viruses produced small plaques on Vero cell monolayers at 48 h postinfection. F-gKbeta caused extensive fusion of 143TK cells that was sensitive to melittin, a specific inhibitor of gK-induced cell fusion, while delta gK virus did not fuse 143TK cells. A recombinant plasmid containing the truncated gK gene specified by F-gKbeta failed to rescue the ICP27-null virus KOS (d27-1), while a plasmid with the delta gK deletion rescued the d27-1 virus efficiently. delta gK virus yield was approximately 100,000-fold lower in stationary cells than in actively replicating Vero cells. The plaquing efficiencies of delta gK and F-gKbeta virus stocks on VK302 cells were similar, while the plaquing efficiency of F-gKbeta virus stocks on Vero cells was reduced nearly 10,000-fold in comparison to that of delta gK virus. Mutant delta gK and F-gKbeta infectious virions accumulated within Vero and HEp-2 cells but failed to translocate to extracellular spaces. delta gK capsids accumulated in the nuclei of Vero but not HEp-2 cells. Enveloped delta gK virions were visualized in the cytoplasms of both Vero and HEp-2 cells, and viral capsids were found in the cytoplasm of HEp-2 cells within vesicles. Glycoproteins B, C, D, and H were expressed on the surface of delta gK-infected Vero cells in amounts similar to those for KOS-infected Vero cells. These results indicate that gK is involved in nucleocapsid envelopment, and more importantly in the translocation of infectious virions from the cytoplasm to the extracellular spaces, and that actively replicating cells can partially compensate for the envelopment but not for the cellular egress deficiency of the delta gK virus. Comparison of delta gK and F-gKbeta viruses suggests that the inefficient viral replication and plaquing efficiency of F-gKbeta virus in Vero cells and its syncytial phenotype in 143TK- cells are most likely due to expression of a truncated gK.


Effects of nucleotide changes on the ability of hepatitis delta virus to transcribe, process, and accumulate unit-length, circular RNA.
The circular RNA genome of hepatitis delta virus (HDV) can fold into an unbranched rodlike structure. We mutagenized the two ends of this structure and assayed the effects on the ability of the genomes to replicate and accumulate processed RNA transcripts in transfected cells. The top end, defined as that nearest to the 5' end of the putative mRNA for delta antigen, was much more sensitive than the other end, defined as the bottom. Most of the 22 mutants made at the bottom were able to accumulate RNA as well as the wild type. For deletions extending as close as 2 nucleotides (nt) from the predicted domains needed for the two ribozymes, the accumulation levels dropped to <0.1%. In one mutant, 13 nt of HDV was replaced with 57 nt of non-HDV sequences, and accumulation was at 20% of the wild-type level, consistent with the potential of HDV to act as a vector. However, after replacement with a second sequence, accumulation dropped to 1%. For most of the 14 mutants made at the top of the rod, we observed dramatic inhibitory effects. For example, after removal of 3 bp from the stem adjacent to the terminal loop, accumulation dropped to <0.06% of the wild-type genome level. The top region that we considered was adjacent to both the 5' end of the putative mRNA and the domain that has been proposed to contain a promoter for RNA-directed RNA synthesis. The RNA accumulation abilities of certain mutants were tested under additional different experimental conditions. It was found that after longer times, some mutants began to catch up with the wild type. Also, it was found that certain top mutants gave much greater levels of accumulation when transfected into cells containing the small delta antigen. One interpretation of these data is that certain features at the top of the rod are needed for the accumulation of essential delta antigen mRNA species.


Kinetics and dynamics of cyclosporine A in three hepatic cell culture systems.
In vitro experiments have a high potential to improve current chemical safety assessment and reduce the number of animals used. However, most studies conduct hazard assessment alone, largely ignoring exposure and kinetic parameters. Therefore, in this study the kinetics of cyclosporine A (CsA) and the dynamics of CsA-induced cyclophilin B (Cyp-B) secretion were investigated in three widely used hepatic in vitro models: primary rat hepatocytes (PRH), primary human hepatocytes (PHH) and HepaRG cells. Cells were exposed daily to CsA for up to 14 days. CsA in cells and culture media was quantified by LC-MS/MS and used for pharmacokinetic modeling. Cyp-B was quantified by western blot analysis in cells and media. All cell systems took up CsA rapidly from the medium after initial exposure and all showed a time- and concentration-dependent Cyp-B cellular depletion and extracellular secretion. Only in PRH an accumulation of CsA over 14 days repeated exposure was observed. Donor-specific effects in CsA clearance were observed in the PHH model and both PHH and HepaRG cells significantly metabolized CsA, with no bioaccumulation being observed after repeated exposure. The developed kinetic models are described in detail and show that all models under-predict the in vivo hepatic clearance of CsA, but to different extents with 27-, 24- and 2-fold for PRH, PHH and HepaRG cells, respectively. This study highlights the need for more attention to kinetics in in vitro studies.


Not a walk in the park: the ECVAM whole embryo culture model challenged with pharmaceuticals and attempted improvements with random forest design.
The European Committee for the Validation of Alternative Methods (ECVAM) supported the development of a linear discriminant embryotoxicity prediction model founded on rat whole embryo culture (Piersma et al. (2004). Altern Lab Anim 32:275–307). Our goals were to (1) assess the accuracy of this model with pharmaceuticals, and (2) to use the data to develop a more accurate prediction model. Sixty-one chemicals of known in vivo activity were tested. They were part of the ECVAM validation set (N513), commercially available pharmaceuticals (N531), and Pfizer chemicals that did not reach the market, but for which developmental toxicity data were available (N517). They were tested according to the ECVAM procedures. Fifty-seven of these chemicals were used for Random Forest modeling to develop an alternate model with the goal of using surrogate endpoints for simplified assessments and to improve the predictivity of the model. Using part of the ECVAM chemical test set, the ECVAM prediction model was 77% accurate. This approximated what was reported in the validation study (80%; Piersma et al. (2004). Altern Lab Anim 32:275–307). However, when confronted with novel chemicals, the accuracy of the linear discriminant model dropped to 56%. In an attempt to improve this performance, we used a Random Forest model that provided rankings and confidence estimates. Although the model used simpler endpoints, its performance was no better than the ECVAM linear discriminant model. This study confirms previous concerns about the applicability of the ECVAM prediction model to a more diverse chemical set, and underscores the challenges associated with developing embryotoxicity prediction models.


[The endoscopic diagnosis and differential treatment of the complications of shunting operations in children].
The authors present their experience with endoscopic diagnosis and differential treatment of children with complications after bypass surgery. They show the present-day potentialities, spectrum of surgical interventions and role of video-assisted neuroendoscopic surgery in determining a treatment policy and choosing its method. A principle of multiportality was defined and substantiated, a diagnosis and treatment algorithm for children with this pathology was proposed by using the new minimum invasive technique video-assisted surgery.


What Can Quantitative Gait Analysis Tell Us about Dementia and Its Subtypes? A Structured Review.
Distinguishing dementia subtypes can be difficult due to similarities in clinical presentation. There is increasing interest in discrete gait characteristics as markers to aid diagnostic algorithms in dementia. This structured review explores the differences in quantitative gait characteristics between dementia and healthy controls, and between four dementia subtypes under single-task conditions: Alzheimer's disease (AD), dementia with Lewy bodies and Parkinson's disease dementia, and vascular dementia. Twenty-six papers out of an initial 5,211 were reviewed and interpreted using a validated model of gait. Dementia was associated with gait characteristics grouped by slower pace, impaired rhythm, and increased variability compared to normal aging. Only four studies compared two or more dementia subtypes. People with AD are less impaired in pace, rhythm, and variability domains of gait compared to non-AD dementias. Results demonstrate the potential of gait as a clinical marker to discriminate between dementia subtypes. Larger studies using a more comprehensive battery of gait characteristics and better characterized dementia sub-types are required.


The structure and expression of the mercury-resistance transposon Tn501.
The nucleotide sequence of the mercury-resistance transposon Tn501 has been determined and the functional regions have been identified by a variety of techniques. The transposition gene products are structurally and functionally homologous to those of other transposons in the Tn3 family and of other recombination systems. The expression of the transposition genes may be regulated coordinately with that of the mercury-resistance genes. Comparison of related transposons suggests mechanisms for their evolution.


[Age characteristics of acid-base equilibrium and the blood coagulation system in starvation].
The state of the acid-base balance and of the blood coagulation system was studied in starvation of young (5-6-month-old) and old (24-26-month-old) male rats during starvation. The periods of the maximal changes coincided in both systems; in the young animals the onset of the acidotic crisis and hypercoagulation development occurred earliear and were more pronounced. Old animals proved to be more resistant to the conditions of starvation and died later than the young ones.


A Self-Sacrificing N-Methyltransferase Is the Precursor of the Fungal Natural Product Omphalotin.
Research on ribosomally synthesized and posttranslationally modified peptides (RiPPs) has led to an increasing understanding of biosynthetic mechanisms, mostly drawn from bacterial examples. In contrast, reports on RiPPs from fungal producers, apart from the amanitins and phalloidins, are still scarce. The fungal cyclopeptide omphalotin A carries multiple N-methylations on the peptide backbone, a modification previously known only from nonribosomal peptides. Mining the genome of the omphalotin-producing fungus for a precursor peptide led to the identification of two biosynthesis genes, one encoding a methyltransferase OphMA that catalyzes the automethylation of its C-terminus, which is then released and cyclized by the protease OphP. Our findings suggest a novel biosynthesis mechanism for a RiPP in which a modifying enzyme bears its own precursor peptide.


Transcript profiling of functionally related groups of genes during conditional differentiation of a mammalian cochlear hair cell line.
We have used Affymetrix high-density gene arrays to generate a temporal profile of gene expression during differentiation of UB/OC-1, a conditionally immortal cell line derived from the mouse cochlea. Gene expression was assessed daily for 14 days under differentiating conditions. The experiment was replicated in two separate populations of cells. Profiles for selected genes were correlated with those obtained by RT-PCR, TaqMan analysis, immunoblotting, and immunofluorescence. The results suggest that UB/OC-1 is derived from a population of nonsensory epithelial cells in the greater epithelial ridge that have the potential to differentiate into a hair-cell-like phenotype, without the intervention of Math1. Elements of the Notch signaling cascade were identified, including the receptor Notch3, with a transient up-regulation that suggests a role in hair cell differentiation. Several genes showed a profile similar to Notch3, including the transcriptional co-repressor Groucho1. UB/OC-1 also expressed Me1, a putative partner of Math1 that may confer competence to differentiate into hair cells. Cluster analysis revealed expression profiles for neural guidance genes associated with Gata3. The temporal dimension of this analysis provides a powerful tool to study genetic mechanisms that underlie the conversion of nonsensory epithelial cells into hair cells.


Sarcopenia is associated with reduced survival in patients with advanced hepatocellular carcinoma undergoing sorafenib treatment.
Sarcopenia has been associated with poor outcomes in patients with cirrhosis and solid tumours. Analyse the influence of sarcopenia on survival and treatment duration in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. We conducted a multicentre, retrospective study on 96 patients with advanced HCC treated with sorafenib, all with available abdominal computed tomography (CT) scan within 30 days from treatment start. Anthropometric, laboratory, treatment and follow-up data were collected. Sarcopenia was defined by reduced skeletal muscle index calculated from an L3 section CT image. Sarcopenia was present in 49% of patients. Patients were divided into two groups according to sarcopenia: age was significantly higher in the sarcopenic group (SG) (66 years (31-87) versus 72 years (30-84), p = 0.04], with no difference in other baseline characteristics. The SG showed shorter overall survival (OS) (39 (95% confidence interval (CI) 26-50) versus 61 (95% CI 47-77) weeks (p = 0,01)) and shorter time on treatment (12.3 (95% CI 8-19) versus 25.9 (95% CI 15-33) weeks (p = 0.0044)). At multivariate analysis, sarcopenia was independently associated to reduced OS (p = 0.03) and reduced time on treatment (p = 0.001). Sarcopenia is present in almost half of patients with advanced HCC, and is associated with reduced survival and reduced duration of oral chemotherapy.


TGFBI and CHST6 gene analysis in Chinese stromal corneal dystrophies.
To investigate whether mutations in TGFBI gene or CHST6 gene correlated with stromal corneal dystrophies (CD) in 8 Chinese probands. Eight unrelated patients with stromal corneal dystrophies were recruited in this study; all affected members were assessed by completely ophthalmologic examinations. Genomic DNA was extracted from peripheral leukocytes, 17 exons of TGFBI gene and the exon of CHST6 gene were amplified by polymerase chain reaction (PCR), sequenced directly and compared with the reference database. Three heterozygous mutations in TGFBI gene were identified in six patients: c. 370C>T (p.Arg124Cys) was found in exon 4 of TGFBI gene in three members, c. 371G>A (p.Arg124His) was found in one patient; c. 1663C>T (p.Arg555Trp) was found in exon 12 in other two members. In addition, four polymorphisms with the nucleotide changes rs1442, rs1054124, rs4669, and rs35151677 were found in TGFBI gene. Mutations were not identified in the rest of 2 affected individuals in TGFBI gene or CHST6 gene. Within these patients, R124C, R124H and R555W mutations were co-segregated with the disease phenotypes and were specific mutations for lattice corneal dystrophy type I (LCD I), Avellino corneal dystrophy (ACD, GCD II), granular corneal dystrophy type I (GCD I), respectively. Our study highlights the prevalence of codon 124 and codon 555 mutations in the TGFBI gene among the Chinese stromal corneal dystrophies patients.


Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium.
The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.


The Challenge of Treating Myelodysplastic Syndromes/Myeloproliferative Neoplasms.
Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) comprise a spectrum of myeloid disorders with both dysplastic and proliferative features, arising from hematopoietic stem cells. MDS/MPN are neither MDS nor MPN but a distinct World Health Organization-defined subclassification of diseases that, by definition, do not arise from a pre-existing MDS or MPN, inherently creating diagnostic and therapeutic challenges. Appropriately recognizing and classifying MDS/MPN is paramount for appropriately formulating treatment strategies and accurate prognostication. Highlighting the unique molecular, morphologic, and clinical characteristics among the subclassifications of MDS/MPN can assist in the appropriate diagnosis and aid in choice of therapeutic strategies. We describe the challenges of the appropriate diagnosis and treatment of MDS/MPN.


Neutral desorption sampling of biological surfaces for rapid chemical characterization by extractive electrospray ionization mass spectrometry.
Extractive electrospray ionization mass spectrometry (EESI-MS) allows the real-time, direct analysis of complex gaseous and liquid samples without any sample pretreatment under ambient conditions. By using a neutral desorption (ND) sampling gas beam to gently impact a surface, the analyte present on a surface can be efficiently sampled and then transported to the EESI source for soft ionization without any previous work-up. By separating the sampling process and the ionization process in both space and time, ion suppression effects are significantly decreased in ND-EESI-MS. Therefore, virtually any surface can be gently sampled in real time, allowing in vivo analysis of living objects while maintaining the native conditions of the sample. This greatly simplifies the procedure for the characterization of complex surfaces (e.g., plants, food, skin) and prevents potential chemical contamination, providing a unique platform for wide applications in multiple disciplines such as chemistry, biology and the life sciences. Here we present a complete description of a protocol for ND-EESI-MS for in vivo analysis of living objects, including equipment setup, reagent preparation, data acquisition and analysis steps. The data collection can be completed within a few minutes even though the time required for the entire analytical process, which largely depends on the preparation of samples and materials, takes slightly longer.


Bovine pretransfer endometrium and embryo transcriptome fingerprints as predictors of pregnancy success after embryo transfer.
Aberrant gene expression in the uterine endometrium and embryo has been the major causes of pregnancy failure in cattle. However, selecting cows having adequate endometrial receptivity and embryos of better developmental competence based on the gene expression pattern has been a greater challenge. To investigate whether pretransfer endometrial and embryo gene expression pattern has a direct relation with upcoming pregnancy success, we performed a global endometrial and embryo transcriptome analysis using endometrial and embryo biopsy technology and the pregnancy outcome information. For this, endometrial samples were collected from Simmental heifers at day 7 and 14 of the estrous cycle, one cycle prior to embryo transfer. In the next cycle, blastocyst stage embryos were transferred to recipients at day 7 of the estrous cycle after taking 30-40% of the blastocyst as a biopsy for transcriptome analysis. The results revealed that at day 7 of the estrous cycle, the endometrial gene expression pattern of heifers whose pregnancy resulting in calf delivery was significantly different compared with those resulting in no pregnancy. These differences were accompanied by qualitative and quantitative alteration of major biological process and molecular pathways. However, the transcriptome difference was minimal between the two groups of animals at day 14 of the estrous cycle. Similarly, the transcriptome analysis between embryos biopsies that resulted in calf delivery and those resulted in no pregnancy revealed a total of 70 differentially expressed genes. Among these, the transcript levels of 32 genes including SPAG17, PF6, UBE2D3P, DFNB31, AMD1, DTNBP1, and ARL8B were higher in embryo biopsies resulting in calf delivery. Therefore, the present study highlights the potential of pretransfer endometrial and embryo gene expression patterns as predictors of pregnancy success in cattle.


Expression pattern of olfactory receptor genes in human cumulus cells as an indicator for competent oocyte selection.
Odorant or olfactory receptors are mainly localized in the olfactory epithelium for the perception of different odors. Interestingly, many ectopic olfactory receptors with low expression levels have recently been found in nonolfactory tissues to involve in local functions. Therefore, we investigated the probable role of the olfactory signaling pathway in the surrounding microenvironment of oocyte. This study included 22 women in intracytoplasmic sperm injection cycle. The expression of olfactory target molecules in cumulus cells surrounding the growing and mature oocytes was evaluated by Western blotting and real-time polymerase chain reaction. Additionally, integrated bioinformatics analyses were carried out and 6 ectopic olfactory receptors were selected for further evaluation. The initiation of olfactory transduction cascade in cumulus cells of competent oocytes was confirmed by analyzing the expression of adenylyl cyclase type 3 and olfactory market protein. Moreover, the expression pattern of the selected olfactory receptors was evaluated and OR10H2 was selected due to a high level of expression in mature fertile oocytes. We suggested that OR10H2 could be considered as a reliable biomarker for oocyte selection in assisted reproduction technique programs. However, further studies are required to elucidate the role of olfactory transduction cascade in embryo quality and implantation.


Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis.
Angiogenin is an angiogenic protein that undergoes nuclear translocation in endothelial cells where it accumulates in the nucleolus and stimulates rRNA transcription, a rate-limiting step in ribosome biogenesis, protein translation, and cell growth. Here, we report that angiogenin is required for cell proliferation induced by various other angiogenic proteins including acidic and basic fibroblast growth factors (aFGF and bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). Downregulation of angiogenin in endothelial cells by small interfering RNA (siRNA) and antisense results in a decrease in rRNA transcription, ribosome biogenesis, and cell proliferation induced by these angiogenic factors. Inhibitors of the nuclear translocation of angiogenin abolish the angiogenic activities of these factors. Stable angiogenin antisense transfection in HeLa cells reduces tumor angiogenesis in athymic mice despite the elevated expression level of bFGF and VEGF. Thus, nuclear angiogenin assumes an essential role in endothelial cell proliferation and is necessary for angiogenesis induced by other angiogenic factors. Angiogenin-stimulated rRNA transcription in endothelial cells may thus serve as a crossroad in the process of angiogenesis induced by various angiogenic factors.


Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma.
Aldosterone-producing adenoma (APA) cause primary aldosteronism-the most frequent form of secondary hypertension. Somatic mutations in genes coding for ion channels and ATPases are found in APA and in aldosterone-producing cell clusters. We investigated the genetic, cellular, and molecular heterogeneity of different aldosterone-producing structures in adrenals with APA, to get insight into the mechanisms driving their development and to investigate their clinical and biochemical correlates. Genetic analysis of APA, aldosterone-producing cell clusters, and secondary nodules was performed in adrenal tissues from 49 patients by next-generation sequencing following CYP11B2 immunohistochemistry. Results were correlated with clinical and biochemical characteristics of patients, steroid profiles, and histological features of the tumor and adjacent adrenal cortex. Somatic mutations were identified in 93.75% of APAs. Adenoma carrying KCNJ5 mutations had more clear cells and cells expressing CYP11B1, and fewer cells expressing CYP11B2 or activated β-catenin, compared with other mutational groups. 18-hydroxycortisol and 18-oxocortisol were higher in patients carrying KCNJ5 mutations and correlated with histological features of adenoma; however, mutational status could not be predicted using steroid profiling. Heterogeneous CYP11B2 expression in KCNJ5-mutated adenoma was not associated with genetic heterogeneity. Different mutations were identified in secondary nodules expressing aldosterone synthase and in independent aldosterone-producing cell clusters from adrenals with adenoma; known KCNJ5 mutations were identified in 5 aldosterone-producing cell clusters. Genetic heterogeneity in different aldosterone-producing structures in the same adrenal suggests complex mechanisms underlying APA development.


The Categorical Stability of Gambling Motives Among Community-Recruited Gamblers: A Longitudinal Assessment.
Over the past decade, several motivational models have been proposed to explain the role of motives in gambling disorder. In the model captured by the four-factor Gambling Motives Questionnaire Financial (GMQ-F), gamblers are described as being primarily motivated to gamble for 'coping', 'enhancement', 'social', and 'financial' reasons. Although this model has received significant empirical support; to date, research assessing the role of motives in gambling disorder has been primarily cross-sectional in nature. Thus, the extent to which gambling motives remain stable over time has yet to be explored. In the current study, the stability versus fluidity of self-assessed gambling motives was investigated using the Quinte Longitudinal Study, a longitudinal dataset of gambling behaviour collected over 5 years. Gambling motives of 2795 gamblers were examined over all five annual assessments. The total proportion of gamblers who stayed in the same primary motive category across each of the 5 consecutive assessments was 22%, indicating substantial fluidity in category membership. Substantial movement between categories was seen for each GMQ-F group, as well as an additional group of non-classified motives. Logistic regression analyses suggest that greater resistance to gambling fallacies significantly predicted stability between the baseline assessment and a follow-up 1 year later, but gambling severity did not. Potential limitations in the study design and opportunities for future research are discussed.


Inhibition of heme biosynthesis prevents transcription of iron uptake genes in yeast.
Yeast are capable of modifying their metabolism in response to environmental changes. We investigated the activity of the oxygen-dependent high-affinity iron uptake system of Saccharomyces cerevisiae under conditions of heme depletion. We found that the absence of heme, due to a deletion in the gene that encodes delta-aminolevulinic acid synthase (HEM1), resulted in decreased transcription of genes belonging to both the iron and copper regulons, but not the zinc regulon. Decreased transcription of the iron regulon was not due to decreased expression of the iron sensitive transcriptional activator Aft1p. Expression of the constitutively active allele AFT1-1up was unable to induce transcription of the high affinity iron uptake system in heme-depleted cells. We demonstrated that under heme-depleted conditions, Aft1p-GFP was able to cycle normally between the nucleus and cytosol in response to cytosolic iron. Despite the inability to induce transcription under low iron conditions, chromatin immunoprecipitation demonstrated that Aft1p binds to the FET3 promoter in the absence of heme. Finally, we provide evidence that under heme-depleted conditions, yeast are able to regulate mitochondrial iron uptake and do not accumulate pathologic iron concentrations, as is seen when iron-sulfur cluster synthesis is disrupted.


Molecular genetics, physiology and biology of self-incompatibility in Brassicaceae.
Self-incompatibility (SI) is defined as the inability to produce zygotes after self-pollination in a fertile hermaphrodite plant, which has stamens and pistils in the same flower. This structural organization of the hermaphrodite flower increases the risk of self-pollination, leading to low genetic diversity. To avoid this problem plants have established several pollination systems, among which the most elegant system is surely SI. The SI trait can be observed in Brassica crops, including cabbage, broccoli, turnip and radish. To produce hybrid seed of these crops efficiently, the SI trait has been employed in an agricultural context. From another point of view, the recognition reaction of SI during pollen-stigma interaction is an excellent model system for cell-cell communication and signal transduction in higher plants. In this review, we describe the molecular mechanisms of SI in Brassicaceae, which have been dissected by genetic, physiological, and biological approaches, and we discuss the future prospects in relation to associated scientific fields and new technologies.


The effect of practice and musical structure on pianists' eye-hand span and visual monitoring.
This study examines short-term improvement of music performances and oculomotor behaviour during four successive executions of a brief musical piece composed by Bartók, "Slovak Boys' Dance". Pianists (n=22) were allowed to practice for two minutes between each trial. Eye-tracking data were collected as well as MIDI information from pianists' performances. Cognitive skills were assessed by a spatial memory test and a reading span test. Principal component analysis (PCA) enabled us to distinguish two axes, one associated with anticipation and the other with dependence/independence on written code. The effect of musical structure, determined by the emergence of different sections in the score, was observed in all the dependent variables selected from the PCA; we also observed the effect of practice on the number of fixations, the number of glances at the keyboard (GAK) and the awareness span. Pianist expertise was associated with fewer fixations and GAK, better anticipation capacities and more effective strategies for visual monitoring of motor movements. The significant correlations observed between the reading span test and GAK duration highlight the challenge of working memory involvement during music reading.


The exothermic reaction route of a self-heatable conductive ink for rapid processable printed electronics.
We report the exothermic reaction route and new capability of a self-heatable conductive ink (Ag2O and silver 2,2-dimethyloctanoate) in order to achieve both a low sintering temperature and electrical resistivity within a short sintering time for flexible printed electronics and display appliances. Unlike conventional conductive ink, which requires a costly external heating instrument for rapid sintering, self-heatable conductive ink by itself is capable of generating heat as high as 312 °C when its exothermic reaction is triggered at a temperature of 180 °C. This intensive exothermic reaction is found to result from the recursive reaction of the 2,2-dimethyloctanoate anion, which is thermally dissociated from silver 2,2-dimethyloctanoate, with silver oxide microparticles. Through this recursive reaction, a massive number of silver atoms are supplied from silver oxide microparticles, and the nucleation of silver atoms and the fusion of silver nanoparticles become the major source of heat. This exothermic reaction eventually realizes the electrical resistivity of self-heatable conductive ink as low as 27.5 μΩ cm within just 40 s by combining chemical annealing, which makes it suitable for the roll-to-roll printable electronics such as a flexible touch screen panel.


Autologous hematopoietic progenitor cell transplantation for multiple myeloma through an outpatient program.
There are considerable concerns regarding the appropriate use of health care resources to reduce costs and waiting lists associated with autologous hematopoietic progenitor cell transplantation (AHPCT). One of the strategies to reach this goal is outpatient-based (OpB) AHPCT. We reviewed all the reported experiences in this field and illustrated the various models of OpB AHPCT. The role of high-dose melphalan (HDM) followed by AHPCT in the treatment of Multiple Myeloma (MM) continues to evolve in the novel agent era and the International Myeloma Working Group recommends that AHPCT should be offered at some point in the course of the treatment program for a medically fit patient. The relatively short neutropenia and the limited extra-marrow toxicity after HDM support the hypothesis that MM patients are the most suitable for outpatient transplant programs. Various models have shown that the procedure is feasible and safe and may highly contribute to shorten waiting lists and to considerably cut health costs, with an improvement of quality of life. Ideal candidates may be those who are asymptomatic and fully active, who have a full-time caregiver and who can reside within easy reach from the transplant center.


Role of age in acute type A aortic dissection outcome: report from the International Registry of Acute Aortic Dissection (IRAD).
The increasing life expectancy of the population will likely be accompanied by a rise in the incidence of acute type A aortic dissection. However, because of an increased risk of cardiac surgery in an elderly population, it is important to define when, if at all, the risks of aortic repair outweigh the risk of death from unoperated type A aortic dissection. We analyzed 936 patients with type A aortic dissection enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2004. Patients with type A aortic dissection were categorized according to patient age by decade and by surgical versus medical management, and outcomes of both management types were investigated in the different age groups. The rate of surgical aortic repair decreased progressively with age, whereas surgical mortality significantly increased with age. Age 70 years or more was an independent predictor for mortality (38.2% vs 26.0%; P < .0001, odds ratio 1.73). The in-hospital mortality rate was significantly lower after surgical management compared with medical management until the age of 80 years. For patients aged 80 to 90 years, the in-hospital mortality appeared to be lower after surgical management (37.9% vs 55.2%; P = .188); however, this failed to reach clinical significance owing to the limited patient number in this age group. Although the surgical mortality significantly increased with increased age, surgical management was still associated with significantly lower in-hospital mortality rates compared with medical management until the age of 80 years. Surgery may decrease the in-hospital mortality rate for octogenarians with type A aortic dissection and might be considered in all patients with type A aortic dissection regardless of age.


A challenging interpretation of a hexagonally layered protein structure.
The carboxysome is a giant protein complex that acts as a metabolic organelle in cyanobacteria and some chemoautotrophs. Its outer structure is formed by the assembly of thousands of copies of hexameric shell protein subunits into a molecular layer. The structure determination of a CcmK1 shell protein mutant (L11K) from the β-carboxysome of the cyanobacterium Synechocystis PCC6803 led to challenges in structure determination. Twinning, noncrystallographic symmetry and packing of hexameric units in a special arrangement led to initial difficulties in space-group assignment. The correct space group was clarified after initial model refinement revealed additional symmetry. This study provides an instructive example in which broken symmetry requires a new choice of unit-cell origin in order to identify the highest symmetry space group. An additional observation related to the packing arrangement of molecules in this crystal suggests that these hexameric shell proteins might have lower internal symmetry than previously believed.


[Reducing the frequency of fresh frozen donor plasma transfusion on the basis of the results of thromboelastographic study in neurosurgical patients with intraoperative blood loss].
The paper gives the results of a study of the time course of changes in the major laboratorily determined hemostatic parameters, as well as the main characteristics of a thromboelastographic curve in 95 neurosurgical patients who developed significant intraoperative blood loss at surgery. The patients were divided into 2 comparable groups: 1) a decision on fresh frozen donor plasma transfusion was taken only on the basis of laboratory parameters; 2) this was done on the basis of thromboelastographic data. In Group 2, the frequency of fresh frozen donor plasma transfusion proved to be 4 times less than that in Group 1. The use of thromboelastography to evaluate the hemostatic system during operations with a significant blood loss volume permits a reduction in the frequency of fresh frozen donor plasma, without deteriorating the results of treatment.


Human papillomavirus type 16 cooperates with activated ras and fos oncogenes in the hormone-dependent transformation of primary mouse cells.
The effect of human papillomavirus (HPV) and activated oncogenes on the growth and morphology of primary baby mouse kidney (BMK) cells has been studied. Early region DNA from HPV types 16, 18, 31, and 33, but not type 6, under the transcriptional control of a heterologous, retroviral promoter cooperated with EJ-ras to produce cell lines that gave rise to carcinomas in syngeneic immunocompetent animals. The same HPV constructs, when cotransfected with a plasmid containing sequences from the Finkel-Biskis-Jinkins murine sarcoma virus provirus (v-fos), produced cell lines that were tumorigenic in nude mice. None of the other activated oncogenes tested, including activated c-myc, displayed any activity with HPV in this cotransfection assay. When the heterologous promoter was replaced by the homologous HPV16 promoter, the transforming effect of HPV16 with either EJ-ras or v-fos required the presence of either glucocorticoid or progestogen. Cell lines derived from transfection of HPV16 with either EJ-ras or v-fos required the continued presence of hormones for proliferation.


Permanent lesion to the corticospinal tract after therapy with capecitabine.
Capecitabine is an oral fluoropyrimidine used to treat solid tumours such as colorectal and breast cancer. A rare but severe side effect is capecitabine-induced leukoencephalopathy, including bilateral lesion to the corticospinal tract. However, neurological symptoms due to capecitabine treatment are usually reported to be reversible after discontinuation of capecitabine. Here, we present the case of a patient with bilateral degeneration of the corticospinal tract and progressive spastic tetraplegia after chemotherapy with capecitabine mimicking primary lateral sclerosis. Although therapy with capecitabine was ended, symptoms substantially worsened over the following years and the patient finally died from aspiration pneumonia almost 3 years after the application of capecitabine.


Functional decay in tree community within tropical fragmented landscapes: Effects of landscape-scale forest cover.
As tropical rainforests are cleared, forest remnants are increasingly isolated within agricultural landscapes. Understanding how forest loss impacts on species diversity can, therefore, contribute to identifying the minimum amount of habitat required for biodiversity maintenance in human-modified landscapes. Here, we evaluate how the amount of forest cover, at the landscape scale, affects patterns of species richness, abundance, key functional traits and common taxonomic families of adult trees in twenty Brazilian Atlantic rainforest landscapes. We found that as forest cover decreases, both tree community richness and abundance decline, without exhibiting a threshold. At the family-level, species richness and abundance of the Myrtaceae and Sapotaceae were also negatively impacted by the percent forest remaining at the landscape scale. For functional traits, we found a reduction in shade-tolerant, animal-dispersed and small-seeded species following a decrease in the amount of forest retained in landscapes. These results suggest that the amount of forest in a landscape is driving non-random losses in phylogenetic and functional tree diversity in Brazil's remaining Atlantic rainforests. Our study highlights potential restraints on the conservation value of Atlantic rainforest remnants in deforested landscapes in the future.


Biochemical and antibiotic susceptibility studies of H2S-negative Citrobacter.
Ninety-four strains of H(2)S-negative Citrobacter were biochemically characterized and their antibiograms were determined. The antibiograms demonstrated not only a difference from Enterobacter cloacae but also a difference within the Citrobacter group between the indole-negative and indole-positive strains. These differences were statistically significant and emphasize the importance of the indole reaction as an aid to speciation of the H(2)S-negative Citrobacter.


Hippocampal and temporal lobe atrophy and age-related decline in memory.
To evaluate the relationship of memory decline that accompanies aging with structural changes in the medial temporal lobe, in healthy middle-aged and older subjects. A sample of 35 neurologically non-diseased subjects, between 55 and 70 years of age, were examined in a 5-year follow-up study. Neuropsychological investigation included tests of learning, verbal memory, and visual memory. MRI was performed with a superconducting MRI system operating at 1.0 T, using coronal slices of T1-weighted images. Medial temporal lobe atrophy was rated separately in the neocortical, entorhinal and hippocampal regions. We did not find any statistically significant relationship between mild hippocampal or temporal atrophy and memory test performance. Nor did the longitudinal decline in memory show a relationship with temporal lobe atrophy. The main outcome of our study was that age-related memory decline was not related to mild temporal lobe atrophy in healthy subjects without mild cognitive impairment. There could be other factors influencing memory functions besides age-related structural changes in temporal lobes.


Moderate Ringer's lactate solution resuscitation yields best neurological outcome in controlled hemorrhagic shock combined with brain injury in rats.
Anesthetized rats were assigned to sham; brain injury (BI); controlled hemorrhagic shock (CHS); BI combined with CHS (combined injury [CI]); and CI groups resuscitated with 2.5 mL/kg Ringer's lactate solution (RL-2.5), 10 mL/kg RL (RL-10), or 40 mL/kg RL (RL-40). Brain injury was induced by applying 400 millibar negative pressure for 10 s through a hollow screw inserted into a 4.5-mm burr hole drilled into the left parietal region of the skull. Five minutes after BI, 30% of circulating blood volume was withdrawn for 10 min to induce CHS. One hour of fluid resuscitation commenced 20 min posthemorrhage. MAP, lactate, and base excess levels were significantly improved in the RL-40 group compared with all other hemorrhaged groups. The hematocrit level 1 h after resuscitation began was significantly lower in the RL-40 group (27.6% +/- 0.57%) than in all other groups. The RL-40 group had the worst neurological severity score 24 h postsurgery. MAP, lactate, and base excess levels were not significantly improved in the RL-2.5 group, however, the number of surviving neuronal cells in the perilesional brain region was significantly higher than in the CI or RL-40 groups. MAP, lactate, and base excess levels were significantly improved in the RL-10 group (P < 0.05). Mobility and the number of surviving neurons in the perilesional region of the brain were significantly better in the RL-10 group than in the CI or RL-40 groups (P < 0.05). Although massive fluid resuscitation yields preferable hemodynamic and metabolic outcomes, neurological outcomes are better after moderate fluid resuscitation for BI combined with controlled hemorrhagic shock.


Binding of pyrazine-functionalized calix[4]arene ligands with lanthanides in an ionic liquid: thermodynamics and coordination modes.
The complexation of representative lanthanides with three calix[4]arenes functionalized with four pyrazine pendent arms containing different substituents such as carbamoyl dioctyl (), diisopropyl phosphonate (), and diphenyl phosphoryl () was investigated in water-saturated 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (BumimTf2N) by absorption spectroscopy, luminescence spectroscopy, and microcalorimetry. All three ligands form 1 : 1 ML complexes (M = Eu(3+) and L = ligand), and the stability constants (log β) follow the order: (-1.38 ± 0.66) ≪ (3.71 ± 0.02) < (7.47 ± 0.03), similar to the trend in the metal distribution coefficients in solvent extraction using these ligands as extractants. The enthalpy of complexation, determined by microcalorimetry, shows that the complexation of lanthanides with these bulky ligands is exothermic, and proceeds via replacement of water molecules from the primary coordination spheres. The 1 : 1 stoichiometry of the ML complexes was confirmed by electrospray ionization mass spectrometry. Results from optical absorption, luminescence and (31)P-NMR spectroscopy suggest that, out of four pendent arms on the rigid calixarene platform, only two arms coordinate with the lanthanide ion and each arm is tridentate. The influence of structural features of the ligand on the complexation of lanthanides is explained with the help of thermodynamic parameters.


Synaptic physiology and ultrastructure in comatose mutants define an in vivo role for NSF in neurotransmitter release.
N-Ethylmaleimide-sensitive fusion protein (NSF) is a cytosolic protein thought to play a key role in vesicular transport in all eukaryotic cells. Although NSF was proposed to function in the trafficking of synaptic vesicles responsible for neurotransmitter release, only recently have in vivo experiments begun to reveal a specific function for NSF in this process. Our previous work showed that mutations in a Drosophila NSF gene, dNSF1, are responsible for the temperature-sensitive paralytic phenotype in comatose (comt) mutants. In this study, we perform electrophysiological and ultrastructural analyses in three different comt alleles to investigate the function of dNSF1 at native synapses in vivo. Electrophysiological analysis of postsynaptic potentials and currents at adult neuromuscular synapses revealed that in the absence of repetitive stimulation, comt synapses exhibit wild-type neurotransmitter release at restrictive (paralytic) temperatures. In contrast, repetitive stimulation at restrictive temperatures revealed a progressive, activity-dependent reduction in neurotransmitter release in comt but not in wild type. These results indicate that dNSF1 does not participate directly in the fusion of vesicles with the target membrane but rather functions in maintaining the pool of readily releasable vesicles competent for fast calcium-triggered fusion. To define dNSF1 function further, we used transmission electron microscopy to examine the distribution of vesicles within synaptic terminals, and observed a marked accumulation of docked vesicles at restrictive temperatures in comt. Together, the results reported here define a role for dNSF1 in the priming of docked synaptic vesicles for calcium-triggered fusion.


Correlation of desensitisation of platelet activating factor (PAF) receptors with intensity of inflammation and intestinal PAF content during experimental ileitis in guinea pig.
To determine the kinetics of platelet activating factor (PAF) and prostaglandin E2 (PGE2) receptor desensitisation during intestinal inflammation induced by trinitrobenzenesulphonic acid (TNB) instillation and to study the relation between receptor regulation, inflammatory lesions, and PAF content of the gut wall. Receptor desensitisation was assessed on isolated smooth muscle cells from the circular layer. PAF content of the intestinal wall was determined by thin layer chromatography and radioimmunoassay. After an acute inflammatory phase on day 1, subacute changes appeared in TNB instilled ileum, with a maximal intensity on day 6. In control animals, PAF 10 nM and PGE2 10 nM provoked a maximal contraction in the range of 24% of cell shortening. On days 1 and 3 after intestinal instillation of TNB, PAF induced contraction was not altered whereas the effect of PGE2 was progressively desensitised (2 logM rightward shift of its concentration-response curve: Cmax = 1 microM; p < 0.01). Between days 4 and 6, the concentration-response curve of PGE2 shifted by only 1 logM (p < 0.05) whereas the curve of PAF induced contraction shifted by 2 logM (Cmax = 1 microM; p < 0.01). The PAF content of the ileal wall was maximal between days 3 and 5 (300 ng/mg tissue). On days 10 and 15, PAF and PGE2 induced contractions were similar to those observed on day 1, and PAF content returned to basal. Inflammation induced by TNB instillation triggers PAF and PGE2 receptor desensitisation; this is dependent on the duration of inflammation and correlates with PAF content in the ileum. This receptor desensitisation may play a protective role by preventing overstimulation of intestinal smooth muscle cells.


Profiling Prokaryotic Communities and Aaptamines of Sponge Aaptos suberitoides from Tulamben, Bali.
Sponges (Porifera) harbor a diversity of microorganisms that contribute largely to the production a vast array of bioactive compounds. The microorganisms associated with sponge have an important impact on the chemical diversity of the natural products. Herein, our study focuses on an Aaptos suberitoides commonly found in Indonesia. The objective of this study was to investigate the profile of prokaryotic community and the presence of aaptamine metabolites in sponge Aaptos suberitoides. Sponges were collected from two site locations (Liberty Wreck and Drop Off) in Tulamben, Bali. The sponges were identified by barcoding DNA cytochrome oxidase subunit I (COI) gene. The profile of prokaryotic composition was investigated by amplifying the 16S rRNA gene using primers 515f and 806r to target the V4 region. The metabolites were analyzed using LC-MS, and dereplication was done to identify the aaptamines and its derivates. The barcoding DNA of the sponges confirmed the identity of samples as Aaptos suberitoides. The prokaryotic communities of samples A. suberitoides were enriched and dominated by taxa Proteobacteria, Chloroflexi, Actinobacteria, and Acidobacteria. The chemical analysis showed that all sponges produce aaptamine and isoaaptamine except A. suberitoides S2421 produce analog of aaptamines. This is the first report on the profile of prokaryotic community and the aaptamine of tropical marine sponges, A. suberitoides, from Tulamben, Bali.


Impact of analysis of frozen-section margin on reoperation rates in women undergoing lumpectomy for breast cancer: evaluation of the National Surgical Quality Improvement Program data.
Reoperation for positive margins after lumpectomy for breast cancer is common. Intraoperative analysis of frozen-section (FS) margins permits immediate re-excision, avoiding reoperation. The aim of this study was to compare reoperation rates between an institution using routine FS analysis of all margins and the National Surgical Quality Improvement Program (NSQIP) data. We designed a retrospective cohort analysis comparing the NSQIP data from a FS single institution with the national NSQIP data from 2006 to 2010. Women undergoing lumpectomy for cancer were identified (N = 24,217), and reoperation rates were compared by the use of χ(2) analyses and multivariable logistic regression. During this time period, NSQIP did not differentiate between reoperations for complications or oncologic reasons. Reoperation rates for mastectomy patients (N = 21,734) and lumpectomy patients without cancer (N = 2,777) over the same time period were analyzed as controls, because reoperations after these procedures likely would be for reasons other than positive margins. The 30-day reoperation rate after lumpectomy for cancer was greater nationally than at the FS institution (13.2% vs 3.6%, P < .001). Multivariable analysis showed that patients in the national NSQIP data set were over four times as likely to undergo reoperation as those at the FS institution's (odds ratio 4.19). The reoperation rates were similar between the two, both for patients undergoing mastectomy (4.7% vs 4.5%, P = .84) and those undergoing lumpectomy for benign diagnosis (2.9% vs 5.9%, P = .39). Intraoperative FS margin analysis decreases the number of reoperations for patients undergoing breast conservation for breast cancer. This technique has important implications for patient satisfaction and cost of care.


Impact of donor characteristics and HLA matching on survival of chinese patients with hematologic malignancies undergoing unrelated hematopoietic stem cell transplantation.
We retrospectively analyzed the impact of donor characteristics and HLA matching on outcomes in Chinese patients undergoing unrelated hematopoietic stem cell transplantation (HSCT). A total of 693 patients with hematologic malignancies who underwent HSCT between 2005 and 2010 had available survival data at 100 days or 1 year posttransplantation in the Buddhist Tzu-Chi Stem Cell Center database. The overall survival rates at 100 days and 1 year were 83.3% and 65.2%, respectively. Mismatches of HLA-A, -B, and -DRB1 at the antigen or allele level, along with inadequate cell dose, were associated with a significant risk of mortality (hazard ratio [HR] = 2.36, P < .001; HR = 1.44, P = .005; and HR = 2.20, P = .009, respectively). In 107 donors with matched HLA-A, -B and -DRB1 and known HLA-C match status, 22.4% had an HLA-C antigen mismatch, resulting in an HR of 2.87 for mortality relative to complete 8/8 matches (P = .005). Recipients with unknown HLA-C match status also had a significantly worse outcome (HR = 1.73; P = .039). Multivariate analysis revealed that cell dose and HLA-A, -B, -C, and -DRB1 antigen match status significantly affected the final outcome of survival (P = .012 and <.001, respectively). Our data indicate that HLA-C match status should be confirmed before HSCT from an unrelated donor. Inadequate cell dose remains an important determinant of poor transplantation survival. Further studies to elucidate the importance of matching of specific HLA loci are needed to better understand the risk of HSCT and improve patient outcomes.


Raltegravir-based therapy in a cohort of HIV/HCV co-infected individuals.
The relationship between hepatic tolerance and hepatitis C virus (HCV) co-infection has not been extensively studied in clinical practice. We assessed the efficacy and safety of raltegravir-based therapy in an Italian cohort of HIV/HCV co-infected patients. One hundred and forty patients with HIV/HCV co-infection initiating raltegravir from SCOLTA project (Surveillance Cohort Long-Term Toxicity Antiretrovirals) were examined. Of them, 43 were women, with mean age of 45.4±6.4years; 65 (46%) had undetectable HIV-RNA<50copies/mL and 75 (54%) HIV-RNA≥50copies/mL. According to CDC classification, 49 (35%) were in stage C. Based on Fib4 score at the time of starting raltegravir, patients were classified in class I in 41 cases, class II in 68 and in class III in 31 cases. Globally, the Fib4 score slightly decreased during 24months follow-up, from 2.2 to a value of 1.8. Hepatic adverse events of any grade were observed in 67 patients, of which only 2 cases (3%) had severe liver toxicity (grade 3-4). Only one patient had to discontinue the therapy because of adverse events. According to univariate analysis, being in CDC stage C represented a risk for the development of liver toxicity, with a hazard ratio (HR) of 2.27 (95% CI 1.06-4.84, P=0.033). None of the other variables considered (age, sex, years since detection of HIV and HCV-RNA detectable, years of previous HIV therapy, concomitant therapy with PI or NRTI, CD4+ cell count, Fib4, and transaminases level at baseline) resulted statistically correlated to the outcome. In conclusion, raltegravir-based regimens can be safely used in HCV infected patients; in this study, the hepatic toxicity has been found to be more frequent in patients with an advanced HIV disease (CDC stage C), independently of HIV-RNA suppression at raltegravir initiation.


Nursing responsibility in the diagnosis, care, and treatment of the child with gastroesophageal reflux.
Gastroesophageal reflux (GER) has been known to occur in infants but was thought to be normal. As a result of increased recognition of GER and a clear documentation of GER with extended (18 to 24 hour) esophageal pH monitoring, several severe complications of GER in children have become apparent. An immature cardiorespiratory system is susceptible to some complications of GER such as apnea, choking, recurrent cough or wheezing, and recurrent aspiration pneumonia. Noncardiorespiratory complications include weight loss, esophagitis, anemia, irritability, posturing, malnutrition, and developmental delays. Nursing assessment contributes to a complete clinical picture and the subsequent treatment choice of the physician. To form an accurate assessment of the child with suspected GER, the nurse must be aware of the symptoms and complications of this condition and must precisely execute diagnostic studies, particularly extended esophageal pH monitoring. Nursing responsibilities also include providing a safe yet stimulating environment for the child, teaching parents to participate in the child's care, supporting parents through hospitalization, and preparing both the parents and child for discharge and follow-up care at home.


Adequacy of pharmacological information provided in pharmaceutical drug advertisements in African medical journals.
Pharmaceutical advertisement of drugs is a means of advocating drug use and their selling but not a substitute for drug formulary to guide physicians in safe prescribing. To evaluate drug advertisements in Nigerian and other African medical journals for their adequacy of pharmacological information. Twenty four issues from each of West African Journal of Medicine (WAJM), East African Medical Journal (EAMJ), South African Medical Journal (SAMJ), Nigerian Medical Practitioner (NMP), Nigerian Quarterly Journal of Hospital Medicine (NQJHM) and Nigerian Postgraduate Medical Journal (NPMJ) were reviewed. While EAMJ, SAMJ and NMP are published monthly, the WAJM, NQJHM and NPMJ are published quarterly. The monthly journals were reviewed between January 2005 and December 2006, and the quarterly journals between January 2001 and December 2006. The drug information with regards to brand/non-proprietary name, pharmacological data, clinical information, pharmaceutical information and legal aspects was evaluated as per World Health Organisation (WHO) criteria. Counts in all categories were collated for each advertiser. Forty one pharmaceutical companies made 192 advertisements. 112 (58.3%) of these advertisements were made in the African medical journals. Pfizer (20.3%) and Swipha (12.5%) topped the list of the advertising companies. Four (2.1%) adverts mentioned generic names only, 157 (81.8%) mentioned clinical indications. Adults and children dosage (39.6%), use in special situations such as pregnancy and renal or liver problems (36.5%), adverse effects (30.2%), average duration of treatment (26.0%), and potential for interaction with other drugs (18.7%) were less discussed. Pharmaceutical information such as available dosage forms and product and package information {summary of the generic and proprietary names, the formulation strength, active ingredient, route of administration, batch number, manufactured and expiry dates, and the manufacturer on both the container and pack of the drug} were mentioned in 65.6% and 50% adverts, respectively. The product and package descriptions were provided in 57 (72.2%) Nigerian medical journals, which was significantly higher than in other African medical journals 39 (37.9%) (P<0.001). None of the drug advertisements in the journals adequately provided the basic information required by the WHO for appropriate prescribing. More guidance and regulation is needed to ensure adequate information is provided.


Money, Status, Love, and Death: Sexual Relations With Considerably Older Persons in African Societies-A Systematic Review.
Sexual relations between adolescents or young persons and considerably older persons are considered illegal or deviant in many countries. Yet legal and social definitions and constructions do not capture the complexity of such relations and the various perspectives surrounding them, including that of those involved and other members in the community. In a previous publication, the author examined perspectives on sexual relationships between minors and older persons in Western societies. The current review broadens the perspective on this phenomenon by examining perceptions of sexual relationships between minors, young adults and older persons in African societies, using a similar approach informed by and adapted according to the unique sociocultural context of the articles reviewed. All samples were located in Africa. All studies were published in English. In the current review, the ages of the adolescents or young adults were higher than in the review of Western societies, up to 25, and the age gaps were higher as well. Three main themes emerged from the meta-analysis: adolescents and young adults' motivations to be involved in sexual relations with an older person, relationship characteristics as perceived by both partners, and the negative consequences of such relationships for the younger partner. The findings are discussed and implications for future studies and practices are suggested, highlighting the important role of sociocultural perceptions and calling for a more nuanced and intellectually modest understanding of the complexity of these relationships.


[The biological role of D-glucaric acid and its derivatives: potential use in medicine].
D-glucaric acid is a natural non-toxic compound produced in small amounts by mammals, including humans. In mammals, D-glucaric acid and D-glucaro-l,4-lactone are end-products of the D-glucuronic acid pathway. The enzyme D-glucuronolactone dehydrogenase has been found to be responsible for the oxidation of the lactone of D-glucuronic acid to D-glucaro-l,4;6,3-dilactone. This dilactone hydrolyzes spontaneously in aqueous solution to D-glucaro-l,4-lactone, a potent beta-glucuronidase inhibitor. D-glucaric acid is also found in many fruits and vegetables, with the highest concentrations found in grapefruits, apples, oranges, and cruciferous vegetables. b-glucuronidase is present in the circulation and probably all vertebrate tissues and is capable of hydrolyzing glucuronide conjugates. This enzyme is also produced by colonic microflora. Elevated b-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast and prostate cancer. D-glucaro-l,4-lactone increases detoxification of carcinogens and tumor promoters by inhibiting b-glucuronidase and preventing the hydrolysis of their glucuronides. D-glucaro-l,4-lactone was found to be formed from supplemented D-glucarate salt in the stomach and it is absorbed from the intestinal track, transported with the blood to different internal organs, and excreted in urine and, to a lesser extent, in bile. D-glucaro-l,4-lactone and its precursors exert their anticancer action in part through alterations in steroidogenesis accompanied by changes in the hormonal environment and proliferative status of the target organs. D-glucarates not only suppress cell proliferation and inflammation, but also induce apoptosis. By supplementing D-glucarates, one can favor the body's natural defense mechanism for eliminating carcinogens and tumor promoters and their effects.