Thirty Years of National Institute on Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model Systems Center Research-An Update.
The Traumatic Brain Injury Model Systems Center (TBIMSC) program was established by the National Institute on Disability, Independent Living, and Rehabilitation Research in 1987, with the goal of conducting research to improve the care and outcomes for individuals with moderate-to-severe traumatic brain injury (TBI). This article provides an update on TBIMSC research program activities since 2010 when a similar article was published. It includes (1) discussion of TBIMSC program management and infrastructure; (2) detail on the management, data quality, access, use, and knowledge translation of the TBIMSC National Database, with more than 16 000 participants with follow-up out to 25 years postinjury to date; (3) an overview of the TBIMSC site-specific studies and collaborative module research; (4) highlights of several collaborative initiatives between the TBIMSCs and other federal, advocacy, and research stakeholders; (5) an overview of the vast knowledge translation occurring through the TBIMSC program; and (6) discussion of issues that impact on the data collection methods for and contents of the TBIMSC National Database. On the occasion of the 30th anniversary of the TBIMSC program, this article highlights many of the accomplishments of this well-established, multicenter TBI research consortium.


Morphogenesis of Venezuelan equine encephalomyelitis virus.
Morphogenesis of Venezuelan equine encephalomyelitis virus was studied by means of electron microscopy. Virus-specific structures (factories, viroplasts) were found at early stages of infection; these structures were composed of fibrillar and cylindrical formations, aggregates of ribosomes, and viral nucleoids. The latter emerged from fibrillar and cylindrical structures. Aggregates of viral nucleoids were found in the cytoplasm and occasionally in the nuclei of virus-infected cells. Viral envelopes and mature virions were formed on the cell membranes and on the membranes of intracellular vacuoles. Anomalous forms of virions (both polygenomic and oligogenomic) were observed.


Are we underestimating the genetic variances of dimorphic traits?
Populations often contain discrete classes or morphs (e.g., sexual dimorphisms, wing dimorphisms, trophic dimorphisms) characterized by distinct patterns of trait expression. In quantitative genetic analyses, the different morphs can be considered as different environments within which traits are expressed. Genetic variances and covariances can then be estimated independently for each morph or in a combined analysis. In the latter case, morphs can be considered as separate environments in a bivariate analysis or entered as fixed effects in a univariate analysis. Although a common approach, we demonstrate that the latter produces downwardly biased estimates of additive genetic variance and heritability unless the quantitative genetic architecture of the traits concerned is perfectly correlated between the morphs. This result is derived for four widely used quantitative genetic variance partitioning methods. Given that theory predicts the evolution of genotype-by-environment (morph) interactions as a consequence of selection favoring different trait combinations in each morph, we argue that perfect correlations between the genetic architectures of the different morphs are unlikely. A sampling of the recent literature indicates that the majority of researchers studying traits expressed in different morphs recognize this and do estimate morph-specific quantitative genetic architecture. However, ca. 16% of the studies in our sample utilized only univariate, fixed-effects models. We caution against this approach and recommend that it be used only if supported by evidence that the genetic architectures of the different morphs do not differ.


Occupational performance of children with autism spectrum disorder and quality of life of their mothers.
Limited studies were found to investigate the occupational performance of autistic children and their parents' quality of life. Therefore, this study aimed to investigate occupational performance of children with Autism Spectrum Disorder (ASD) and QoL of their mothers. In this study, 88 participants were selected from autism centers in Arak, Iran, 2020. The Canadian Occupational Performance Measure (COPM) and the parent version of Quality of Life in Autism Questionnaire (QoLA-P) were used to assess the occupational performance of ASD children and their mothers QoL. QoLA-P consists of parts A which is related to the quality of life and part-B related to the problems that these children have and are related to the parents or their caregivers. Regarding occupational performance, the first priority of mothers is self-care with frequency 64.8%. The finding suggested a significant correlation between total function score of COPM and the score of part-A (r = 0.227, p = 0.033) of QoLA-P. Also, the results revealed a significant correlation between the total satisfaction score of COPM and the score of part-A (r = 0.236, p = 0.026) and part-B of QoLA-P questionnaire (r = 0.231, p = 0.030). The mothers' first priority is self-care and, the total satisfaction and function score of COPM showed a significant correlation with mothers' QoL.


Immunoglobulin mRNA and protein expression in human oral epithelial tumor cells.
In our previous work, we have reported the expression of immunoglobulin (Ig) molecules by numerous epithelial cancer cells and hyperplastic epithelial cells. In the present study, we extended our investigation to study the frequencies of expression of IgG and IgA in some types of oral epithelial tumor cells, and analyzed the oral tumor-derived V regions characteristic of Ig gamma chain gene transcripts by immunohistochemistry, in situ hybridization, laser capture microdissection-correlated reverse-transcription polymerase chain reaction, and sequencing. IgG and IgA immunoreactivity was prominent in the cytoplasmic or plasma membrane or secretion of malignant cells, pleomorphic adenoma tumor cells, and some normal glandular epithelial cells or squamous cells adjacent to tumors. More importantly, rearranged Ig gene transcripts were identified in these tumor cells, and in some normal glandular epithelial cells, the V-D-J region sequences revealed that IgG transcripts in 2 tested oral tumors were oligoclonal. These results support that the phenomenon of Ig could also be expressed in oral cavity epithelial tumor cells.


Cognitive behavioural therapy for men who physically abuse their female partner.
In national surveys between 10 % and 34 % of women have reported being physically assaulted by an intimate male partner. Cognitive behavioural therapy (CBT) or programmes with elements of CBT are frequently used treatments for physically abusive men. Participants either enroll voluntarily or are obliged to participate in CBT by means of a court order. CBT not only seeks to change behaviour using established behavioural strategies, but also targets the thinking patterns and beliefs that are thought to contribute to violence. To measure the effects of CBT and similar interventions on men's physical abuse of their female partners. We searched the Cochrane Controlled Trials Register (CENTRAL), C2-SPECTR, MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Care Data/Social Care Online, Sociological Abstracts, Criminal Justice Abstracts, Bibliography of Nordic Criminology (all to late 2006), and SIGLE to 2003. Santé mentale au Québec was handsearched from 1976 to 2003 and reference lists of articles. We also contacted field experts and the authors of included studies. Randomised controlled trials (including cluster-randomised and quasi-randomised trials) of cognitive behavioural therapy with men who physically abuse their partners and reporting effects on continued violence. Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Six trials, all from the USA, involving 2343 people, were included. A meta-analysis of four trials comparing CBT with a no-intervention control with 1771 participants, reported that the relative risk of violence was 0.86 (favouring the intervention group) with a 95% confidence interval (95% CI) of 0.54 to 1.38. This is a small effect size, and the confidence interval is so wide that there is no clear evidence for an effect. One study (Wisconsin Study) compared CBT with process-psychodynamic group treatment and found a relative risk of new violence of 1.07 (95% CI 0.68 to 1.68). Even though the process-psychodynamic treatment did marginally better than CBT, this result is also equivocal. Finally, one small study (N = 64) compared a combined treatment for substance abuse and domestic violence (SADV) with a Twelve-Step Facilitation (TSF) group. An analysis involving 58 participants investigated the effect on reduction in frequency of physical violence episodes. The effect size was 0.30 (favouring TSF) with 95% confidence interval from -0.22 to 0.81. There are still too few randomised controlled effect evaluations to conclude about the effects of cognitive behaviour therapy on domestic violence.


Is There a Lower Size Limit for Superconductivity?
The ultimate lower size limit for superconducting order to exist is set by the "Anderson criterion"-arising from quantum confinement-that appears to be remarkably accurate and universal. We show that carefully grown, phase-pure, nanocrystalline bcc-Ta remains superconducting (with ordering temperature, TC ≈ 0.9 K) down to sizes 40% below the conventional estimate of the Anderson limit of 4.0 nm. Further, both the TC and the critical magnetic field exhibit an unusual, nonmonotonic size dependence, which we explain in terms of a complex interplay of quantum size effects, surface phonon softening, and lattice expansion. A quantitative estimation of TC within first-principles density functional theory shows that even a moderate lattice expansion allows superconductivity in Ta to persist down to sizes much lower than the conventional Anderson limit, which can be traced to anomalous softening of a phonon due to its coupling with electrons. This appears to indicate the possibility of bypassing the Anderson criterion by suitable crystal engineering and obtaining superconductivity at arbitrarily small sizes, an obviously exciting prospect for futuristic quantum technologies. We take a critical look at how the lattice expansion modifies the Anderson limit, an issue of fundamental interest to the study of nanoscale superconductivity.


Innate immunity and exocytosis of antimicrobial peptides.
In Drosophila, anti-microbial peptides are activated and secreted in response to microbial challenge, but the intracellular route of anti-microbial peptide trafficking and the regulatory mechanism controlling their secretion are yet to be fully characterized. We have demonstrated that in Drosophila immune response cells (i.e., fat body cells and hemocytes) the anti-microbial peptide Drosomycin is localized within Rab4 and Rab11 intracellular vesicles. Moreover, both of these small GTPases were required for the delivery of this Drosomycin cargo to the plasma membrane. At the plasma membrane, exocytosis and Drosomycin secretion depend on the SNARE protein Syntaxin1A. Thus, the depletion of Syntaxin1A impaired the release of this antimicrobial peptide, and resulted in the accumulation of Drosomycin and Rab11 carrier vesicles near the plasma membrane. Intriguingly, a similar phenotype was generated by the loss of the adaptor protein 14-3-3ε; there was accumulation of Rab11 vesicles and Drosomycin containing vesicles near the plasma membrane, and a concomitant increase in the susceptibility of 14-3-3ε mutant Drosophila to acute bacterial infection. This suggested that 14-3-3ε, possibly via interaction with Syntaxin1A, is required to promote exocytosis of immune-mediators, thereby regulating innate immune secretion and organism survival under conditions of immune stress.


Studies on anterograde trophic interactions based on general muscle properties.
General properties of rat skeletal muscle (extrajunctional membrane and contractile properties) are subjected to tight physiological neural regulation, as indicated by their striking alterations (up- or down-regulation) following denervation. The main contributions of the literature concerning the nature of the neural signals which mediate this regulation, are reviewed. The physiological regulation of these general properties appears to be operated by the action potential activity evoked by motoneurons in the muscle fibres. No need to postulate the participation of nerve-borne chemical substances, acetylcholine or unidentified "trophic factors", arises from the main experimental evidence. The stronger response to denervation of extrajunctional membrane properties with respect to pure paralysis is best explained by actions of factors released during wallerian degeneration of the transected nerves.


The effect of Piper betel extract on the wound healing process in experimentally induced diabetic rats.
Piper betel (PB) possesses antimicrobial, antifungal, antioxidant and wound healing properties due to its powerful antioxidant effect. Diabetes mellitus (DM) is a metabolic disorder which is associated with complications like impaired wound healing, nephropathy and neuropathy. The main aim of the study was to study the wound healing properties of PB. A total of 33 male Sprague-Dawley rats (250-300 g) were taken and divided into 3 groups: Group I (control) comprising of 14 rats; Group II (diabetic untreated) comprising of 9 rats; Group III (diabetic treated) comprising of 10 rats. After 10 days of acclimatization, the animals were fasted overnight and diabetes was induced by administration of streptozotocin (45 mg/Kg body weight in a single dose, through tail vein) to group II and III animals. Four 6 mm-diameter full thickness skin excision wounds were created and PB extract (50 mg diluted in 0.1 ml of normal saline) was applied locally for 10 days in group III. The group I and II received normal saline (0.1 ml) for 10 days. The total protein content and the wound contraction rate were determined. The wound contraction rate of group III (35.03 +/- 2.96) was higher as compared to group II (18.40 +/- 3.87) with p = 0.014. The total protein content for group III was 106.39 +/- 4.46 as compared to group II (72.86 +/- 12.86) with p = 0.050. PB acted as a protective agent in the early phase of wound healing by increasing total protein content and wound contraction rate.


[Lichenoid pityriasis. Clinical study of 13 cases].
13 patients with Pityriasis Lichenoides are studied clinical and histologically, showing a clinical polymorphism of the lesions, mainly in the papulous, vesiculous, and necrotic ones. The data about age, sex, evolution and response to the treatment in the present study are similar to those found by other authors. Constantly, we found, a variable degree of vasculitis. In almost all the cases there was a damage of the epithelium --exoserosis and exocytosis--, as well as presence in some cases, of red cells extravasated within the epidermis. In upper dermis we found in all biopsies, divers degrees of perivascular cell infiltration mainly composed of lymphocytes and histiocytes with predominance of the last ones, in five cases. In the majority of our cases, there was a strong relationship between the clinical and the histological aspects, but in some cases, mild lesions showed an acute microscopical picture. We are of the opinion that Pityriasis Lichenoides must be considered as a different entity from Parapsoriasis. In addition, we think that PL, is a clinical picture that manifests itself as a chronic or an acute form, and both types can be seen in the disease evolution. Finally, we could not find an evident influence and a positive response to the treatment in our patients with the classical therapeutics.


[Epistemology and medicine].
Within a conceptualization concerning the health-disease process as a whole (which systematically correlates its biological, psychological, social and historical aspects), it becomes very difficult to find something in the universe involving humankind, without any direct or indirect relationship with that vital process. This fact had expanded medicine toward a very extensive and complex field of knowledge and practices. Just considering it from the scientific perspective, different and opposing acquaintances and research methods vie with each other, equally claiming their own worth and stature within science. Because of all this and from its origin, allopathic medicine has required the assistance and support of philosophy and, in particular, from one specific branch: epidemiology. Nevertheless, since Bacon's empiricism (17th century) and, above all, since Comte's positivism (19th century), there had predominated until now (Piaget) a scientific current which was the enemy of philosophical thinking. In spite of the fact that it constituted, in itself, an epistemological position, being generalized also among biomedical scientists, there is in medicine at least disdain against the philosophy of science. Nevertheless, it is objectively indispensable. So, the present essay is presented in this sense, through the analytic characterization of the prototypic epistemologies and their relationships with medicine throughout history.


Relationship-specific social psychological adaptations.
Mainstream social psychology has sought parsimonious explanations of broad general applicability, and has in practice focused on stranger interactions. An evolutionary perspective; however, justifies predicting a rich diversity of relationship-specific social psychological adaptations. The demands of motherhood, fatherhood, mateship, sibship and other relationships are qualitatively distinct, and so, it appears, are the psychophysiological mechanisms that have evolved to deal with them. One window on what distinguishes social relationships is provided by the substance and epidemiology of interpersonal conflicts. Homicides exhibit victim-killer relationship-specific patterns in context, motive and demography, which we discovered only because we adopted an evolutionary psychological perspective. We offer a number of specific hypotheses about possible human psychological adaptations that have yet to be assessed, but are readily derived from consideration of the particular qualities of specific relationship types.


Anion regulation of [3H]strychnine binding to glycine-gated chloride channels is explained by the presence of two anion binding sites.
The effects of six monovalent anions (chloride, bromide, iodide, nitrate, perchlorate, and thiocyanate) on [3H]strychnine binding to glycine-gated chloride channels were examined. These anions have previously been shown to permeate glycine-gated chloride channels and stimulate [3H]strychnine binding. Whereas low concentrations (10-200 mM) of all these anions enhanced [3H]strychnine binding, higher concentrations (0.2-3 M) of thiocyanate, perchlorate, and iodide produced a robust inhibition of radioligand binding, and a more modest inhibition was observed with the same concentrations of nitrate and bromide. The presence of one binding site for anions at glycine-gated chloride channels can account for either the activation or the inhibition phase, but not both. However, these biphasic effects can be explained by the presence of two binding sites for anions at these channels. Two models with two anion binding sites were considered, the first assuming both allosteric activation and inhibition of the binding of the ligand, and the other explained by allosteric activation combined with competitive inhibition. Mathematical expressions for both models were formulated, and the equations obtained yielded satisfactory fitting to the results obtained with all anions tested in both concentration-response and saturation experiments. These equations also permitted the calculation of several parameters describing the interaction of the anions with these channels. The main difference in the behavior of these anions relates to the extent to which they produce activation of [3H]strychnine binding and to their cooperative interaction at the two putative anion binding sites. Thus, a strong negative cooperativity was observed for the simultaneous binding of two molecules of chloride, bromide, or nitrate, but not for the simultaneous binding of thiocyanate, perchlorate, or iodide. This latter property may be related to the conductance of these anions through glycine-gated chloride channels.


Optimization of plasmid maintenance in the attenuated live vector vaccine strain Salmonella typhi CVD 908-htrA.
The broad objective of the research presented here is to develop a noncatalytic plasmid maintenance system for the stabilization of multicopy expression plasmids encoding foreign antigens in a Salmonella typhi live-vector vaccine strain such as CVD 908-htrA. We have enhanced the maintenance of expression plasmids at two independent levels. First, we removed dependence upon balanced-lethal maintenance systems that involve catalytic enzymes expressed from multicopy plasmids; we accomplished this through incorporation into expression plasmids of a postsegregational killing system based on the noncatalytic hok-sok plasmid addiction system from the antibiotic resistance factor pR1. We also included at least one naturally occurring plasmid partition function in our expression plasmids, which eliminates random segregation of these plasmids, thereby enhancing their inheritance and stability; to accomplish this, we incorporated either the par locus from pSC101, the parA locus from pR1, or both. We monitored the stability of optimized expression plasmids within CVD 908-htrA by quantitating expression of a variant of green fluorescent protein (GFPuv) by using flow cytometry. In this report, we demonstrate the utility of this novel plasmid maintenance system in enhancing the stability of our expression plasmids and go on to show that as the copy number of stabilized plasmids increases, the toxicity of GFPuv synthesis also increases. The implications of these observations for the rational design of immunogenic and protective bacterial live vector vaccines are discussed.


Management of blepharospasm.
From 1950 through 1984, 123 patients underwent surgical treatment of blepharospasm at the Mayo Clinic. During this period, four different operations (proximal and distal neurectomy and two types of myectomy) were used. Significant recurrent or residual blepharospasm was observed more frequently (p less than 0.01) and need for subsequent operations was greater (p less than 0.01) among patients who had undergone distal neurectomy than among those who had had myectomy. These data support the view that myectomy is a more effective procedure than neurectomy. Initial results with botulinum toxin injection seem to indicate that it is an effective short-term treatment for blepharospasm. However, its long-term efficacy and safety need further study, as does the role it should play in combination with myectomy.


Effect of malnutrition on methotrexate toxicity and tissue levels of dihydrofolate reductase in the rat.
The effect of malnutrition on the toxicity of methotrexate (MTX) and the dihydrofolate reductase (DHFR) content of the liver, small intestinal mucosa, kidney, and bone marrow of male Sprague-Dawley rats was studied. Malnutrition was induced by reducing the daily intake of chow to one third for 14 days. A single ip treatment with MTX was lethal to three of nine rats at a dose of 37.5 mg/kg and to three of five rats at a dose of 50.0 mg/kg but caused only transient weight loss to similarly treated full-fed, age-matched controls. Although the body weights and absolute tissue weights were reduced in malnourished rats, only the liver and small intestinal mucosa were smaller relative to their respective body weights. The cellular DHFR content of liver and bone marrow from malnourished rats was lower than that from the controls, although in terms of the content per gram of tissue, there was no significant change. While the total DHFR in malnourished rat tissues was significantly lower than that for the controls, only the total-liver DHFR was lower relative to the body weight. The increased toxicity of MTX to malnourished rats may be related to the DHFR levels in the liver and bone marrow.


Coastal loading and transport of Escherichia coli at an embayed beach in Lake Michigan.
A Chicago beach in southwest Lake Michigan was revisited to determine the influence of nearshore hydrodynamic effects on the variability of Escherichia coli (E. coli) concentration in both knee-deep and offshore waters. Explanatory variables that could be used for identifying potential bacteria loading mechanisms, such as bed shear stress due to a combined wave-current boundary layer and wave runup on the beach surface, were derived from an existing wave and current database. The derived hydrodynamic variables, along with the actual observed E. coli concentrations in the submerged and foreshore sands, were expected to reveal bacteria loading through nearshore sediment resuspension and swash on the beach surface, respectively. Based on the observation that onshore waves tend to result in a more active hydrodynamic system at this embayed beach, multiple linear regression analysis of onshore-wave cases further indicated the significance of sediment resuspension and the interaction of swash with gull-droppings in explaining the variability of E. coli concentration in the knee-deep water. For cases with longshore currents, numerical simulations using the Princeton Ocean Model revealed current circulation patterns inside the embayment, which can effectively entrain bacteria from the swash zone into the central area of the embayed beach water and eventually release them out of the embayment. The embayed circulation patterns are consistent with the statistical results that identified that 1) the submerged sediment was an additional net source of E. coli to the offshore water and 2) variability of E. coli concentration in the knee-deep water contributed adversely to that in the offshore water for longshore-current cases. The embayed beach setting and the statistical and numerical methods used in the present study have wide applicability for analyzing recreational water quality at similar marine and freshwater sites.


SARS-CoV-2 immune response and reinfection in vaccinated Maya and mestizo in Southeast of Mexico.
Immune response to pathogens, including coronaviruses, is influenced by HLA haplotypes. 1,2. Maya ethnic group is predominant in Yucatan peninsula, this Amerindian group present allele frequency HLA-G*01:01:02, HLA-G*01:01:01, HLA-G*01:04:01, HLA-A*68 not found in another Amerindians.3-5 Immune response to SARS-CoV-2 vaccination and reinfection particularly after Omicron variant appeared was explored in 118 vaccinated subjects with complete two shots immunization in Maya ascendant and mestizo no-Maya. 1172 epidemiological survey applied to university staff in Campeche, Mexico to evaluate reinfection, co-morbidities, variant virus, disease severity, aftermaths, clinical outcomes, age, sex, ethnicity, and vaccination shots. Multiple logistic regression, correspondence analysis, and association tests were used to analysis data. Sixteen percent of vaccinated subjects became seronegative after 11 months. We found that vaccinated Maya subjects respond with higher IgG immune response compared to no-Maya subjects, similarly women respond with higher IgG response than men (p<0.05). During an eleven-month period and after two vaccination shots, 7% of the vaccinated subjects reported a confirmed positive infection, and after the third vaccine shot a higher IgG immune response than two vaccination shots or natural infection was detected. However, we observed 23.7% reinfection in people after the third shot. This data represents almost three times the reinfection rate reported when compared to previous third vaccine shots. The increase of reinfection in vaccinated subjects was associated with circulation of Omicron variant by 71.5%. Others have reported reinfection of 40% and vaccine effectiveness of 60% during Omicron dominance.6 To understand COVID-19 severity after reinfection in vaccinated subjects and the associated variables, we carried out a multiple logistic regression, and found a strong association between less severe symptoms with Alfa and Omicron variants (B 5.3; Error 0.39; Wald 0.00; Significance 0.00; OR201). However, subjects with severe symptoms and or hospitalization correspondent to individuals with multiplex comorbidities and Gamma SARS-CoV-2 variants (B 5.06; Error 0.97; Wald 26.8; Significance 0.00; OR 158). A follow-up survey of COVID-19 recovered patients experienced diverse digestive, respiratory, cardiac, neurological, or joints involvement sequelae. We looked for SARS-CoV-2 variant and COVID-19 sequelae in a correspondence analysis. Our data suggest that Beta and Delta variants are associated with respiratory and digestive symptoms, whereas Omicron was more closely associated with joints and digestive symptoms, and finally the Gamma variant displayed wider and more diverse symptoms. Our results suggest that genetic background and gender influence IgG response to SARS-CoV-2 vaccine, and Maya ascendant has higher immune IgG response to vaccine than mestizos. Reinfection in our population studied fluctuate from 7% to 23.7% nevertheless is higher if Omicron variant is involved, but symptoms are less severe and more closely associated with joints and digestive symptoms.


Study of yttrium containing bioactive glasses behaviour in simulated body fluid.
The influence of yttrium oxide on the bioactivity of glasses in the system SiO(2)-Na(2)O-P(2)O(5)-CaO-B(2)O(3)-K(2)O-MgO was studied in a simulated body fluid (SBF). Two series of glasses with different bioactivity were investigated. The reaction layers formed on the surface of the exposed glasses were evaluated by means of back scattered electron imaging of scanning electron microscopy equipped with energy dispersive X-ray analysis (BEI-SEM/EDXA). The concentration of Y, Ca and P released from the glasses into SBF, during 21 days was determined using inductively coupled plasma-emission spectroscopy ICP-AES and inductively coupled plasma-mass spectroscopy ICP-MS. Introducing yttrium in the selected bioactive glass tended to diminish the bioactivity of the glasses. The thickness of the calcium phosphate layer decreased with increasing yttrium oxide content. The same effect was also observed when yttrium oxide partially replaced only calcium, magnesium and phosphorous oxide in the precursor glass. The data show that we can produce bioactive glasses with yttrium oxide as a component. By suitable tailoring of the rest of the glasses the yttrium effect on the glass behavior in SBF should be possible to control and thus produce yttrium containing glasses with desired bioactivity.


The temporal trend of influenza-associated morbidity and the impact of early appearance of antigenic drifted strains in a Southeast Asian country.
Globally, influenza infection is a major cause of morbidity and mortality in the elderly, who are suggested to be the major target group for trivalent influenza vaccine (TIV) vaccination by World Health Organization. In spite of an increasing trend in vaccine coverage rates in many countries, the effect of vaccination among the elderly in reducing hospitalization and mortality remains controversial. In this study, we conducted a historical cohort study to evaluate the temporal pattern of influenza-associated morbidity among persons older than 64 years over a decade. The temporal patterns of influenza-associated morbidity rates among the elderly older than 64 years indicated that Taiwan's elderly P&I outpatient visits have been decreasing since the beginning of the 1999-2000 influenza season; however, hospitalization has been increasing despite significant increases in vaccine coverage. The propensity score logistic regression model was implemented to evaluate the source of bias and it was found that the TIV-receiving group had a higher propensity score than the non-receiving group (P<0.0001). In order to investigate the major factors affecting the temporal pattern of influenza-associated morbidity, we then used the propensity score as a summary confounder in a multivariate Poisson regression model based on the trimmed data. Our final models suggested that the factors affected the temporal pattern of morbidity differently. The variables including co-morbidity, vaccination rate, influenza virus type A and B isolation rate were associated with increased outpatient visits and hospitalization (p<0.05). In contrast, variables including high propensity score, increased 1°C in temperature, matching vaccine strains of type A/H1N1 and type B were associated with decreased outpatient visits and hospitalization (p<0.05). Finally, we assessed the impact of early appearance of antigenic-drifted strains and concluded that an excess influenza-associated morbidity substantial trends toward higher P&I hospitalization, but not outpatient visits, during the influenza season with early appearance of antigenic-drifted strains.


Burnout, engagement and resident physicians' self-reported errors.
Burnout is a work-related syndrome that may negatively affect more than just the resident physician. On the other hand, engagement has been shown to protect employees; it may also positively affect the patient care that the residents provide. Little is known about the relationship between residents' self-reported errors and burnout and engagement. In our national study that included all residents and physicians in The Netherlands, 2115 questionnaires were returned (response rate 41.1%). The residents reported on burnout (Maslach Burnout Inventory-Health and Social Services), engagement (Utrecht Work Engagement Scale) and self-assessed patient care practices (six items, two factors: errors in action/judgment, errors due to lack of time). Ninety-four percent of the residents reported making one or more mistake without negative consequences for the patient during their training. Seventy-one percent reported performing procedures for which they did not feel properly trained. More than half (56%) of the residents stated they had made a mistake with a negative consequence. Seventy-six percent felt they had fallen short in the quality of care they provided on at least one occasion. Men reported more errors in action/judgment than women. Significant effects of specialty and clinical setting were found on both types of errors. Residents with burnout reported significantly more errors (p < 0.001). Highly engaged residents reported fewer errors (p <or= 0.01). Overall residents disclosed that in their perception they regularly make errors throughout their residency. Steps should be taken to help residents minimize the number of perceived errors made. Therefore, it is important to prevent residents from developing burnout and to keep residents engaged in their work.


Split-thickness skin grafts for closure of diabetic foot and ankle wounds: a retrospective review of 83 patients.
The aim of this study was to determine if split-thickness skin grafts could be successfully used for closure of foot and ankle wounds in diabetic patients. The authors retrospectively reviewed the charts of 100 consecutive patients who underwent a soft tissue surgical reconstruction with split-thickness skin grafts to their foot and/or ankle in our institution from 2005 to 2008. After application of inclusion criteria, 83 eligible charts remained. Of the 83 patients, 54 (65%) healed uneventfully, 23 (28%) required regrafting, and 6 (7%) had a complication resolved with conservative management. All patients had a successful surgical outcome, defined as having achieved complete wound closure at the final follow-up. Surgical outcome was not significantly associated with age, gender, race, hemoglobin A1C, wound size, wound location, illicit drug use, amputation history, Charcot history, or preoperative infection. However, postoperative graft complications were significantly associated with current or previous smoking history (P = .016) and the level of previous pedal amputation to which the split-thickness skin graft was applied (P = .009). This study demonstrates that application of split-thickness skin grafts with an appropriate postoperative regimen is a beneficial procedure to achieve foot and ankle wound closure in diabetic patients.


Biogenesis of Salmonella enterica serovar typhimurium membrane vesicles provoked by induction of PagC.
Gram-negative bacteria ubiquitously release membrane vesicles (MVs) into the extracellular milieu. Although MVs are the product of growing bacteria, not of cell lysis or death, the regulatory mechanisms underlying MV formation remained unknown. We have found that MV biogenesis is provoked by the induction of PagC, a Salmonella-specific protein whose expression is activated by conditions that mimic acidified macrophage phagosomes. PagC is a major constituent of Salmonella MVs, and increased expression accelerates vesiculation. Expression of PagC is regulated at the posttranscriptional and/or posttranslational level in a sigmaS (RpoS)-dependent manner. Serial quantitative analysis has demonstrated that MV formation can accelerate when the quantity of the MV constituents, OmpX and PagC, rises. Overproduction of PagC dramatically impacts the difference in the relative amount of vesiculation, but the corresponding overproduction of OmpX was less pronounced. Quantitative examination of the ratios of PagC and OmpX in the periplasm, outer membrane, and MVs demonstrates that PagC is preferentially enriched in MVs released from Salmonella cells. This suggests that specific protein sorting mechanisms operate when MVs are formed. The possible role(s) of PagC-MV in host cells is discussed.


[Evaluation of a training programme for health professionals on smoking cessation in hospitalized patients].
The promotion of smoking cessation in hospital settings is uncommon. One of the main barriers to such promotion is lack of knowledge on how to proceed. The objective of this study is to assess changes in professionals' knowledge, attitudes and actions after having received training in brief intervention. Self-perceived knowledge, actions and status in relation to smoking status were assessed in 66 healthcare professionals before and after training. Furthermore, we compared the actions carried out by these professionals with 170 inpatients before the professionals' training and with another 170 after the training (patient's report), to corroborate professionals' self-reported actions. Brief intervention training significantly increased professionals' knowledge of psychological skills (by 23.3%) and of pharmacological resources (by 27.1%). Nevertheless, changes were not observed in the extent to which professionals: ask (30.8% vs. 38.2%, before and after the training, respectively); register patients' smoking status (73.4% vs. 65.9%); assess willingness to quit (25% vs 12.5%); or advise patients to quit (21.9% vs. 20.8%), according to the information provided by patients, which is consistent with that provided by the professionals. It is necessary to examine other barriers to the application of the knowledge gained.


Energy, phosphorus, and amino acid digestibility of high-protein distillers dried grains and corn germ fed to growing pigs.
Three experiments were conducted to measure energy, P, and AA digestibility in 2 novel co-products from the ethanol industry [i.e., high-protein distillers dried grains (HP DDG) and corn germ]. These products are produced by dehulling and degerming corn before it enters the fermentation process. Experiment 1 was an energy balance experiment conducted to measure DE and ME in HP DDG, corn germ, and corn. Six growing pigs (initial BW, 48.9 +/- 1.99 kg) were placed in metabolism cages and fed diets based on corn, corn and HP DDG, or corn and corn germ. Pigs were allotted to a replicated, 3 x 3 Latin square design. The DE and ME in corn (4,056 and 3,972 kcal/kg of DM, respectively) did not differ from the DE and ME in corn germ (3,979 and 3,866 kcal/kg of DM, respectively). However, HP DDG contained more (P < 0.05) energy (4,763 kcal of DE/kg of DM and 4,476 kcal of ME/kg of DM) than corn or corn germ. Experiment 2 was conducted to measure apparent total tract digestibility (ATTD) and true total tract digestibility of P in HP DDG and corn germ. Thirty growing pigs (initial BW, 33.2 +/- 7.18 kg) were placed in metabolism cages and fed a diet based on HP DDG or corn germ. A P-free diet was used to measure endogenous P losses. Pigs were assigned to treatments in a randomized complete block design, with 10 replications per treatment. The ATTD and the retention of P were calculated for the diets containing HP DDG and corn germ, and the endogenous loss of P was estimated from pigs fed the P-free diet. The ATTD was lower (P < 0.05) in corn germ (28.6%) than in the HP DDG (59.6%). The retention of P was also lower (P < 0.05) in pigs fed corn germ (26.7%) than in pigs fed HP DDG (58.9%). The endogenous loss of P was estimated to be 211 +/- 39 mg per kg of DMI. The true total tract digestibility of P for HP DDG and corn germ was calculated to be 69.3 and 33.7%, respectively. In Exp. 3, apparent ileal digestibility and standardized ileal digestibility values of CP and AA in HP DDG and corn germ were measured using 6 growing pigs (initial BW, 78.2 +/- 11.4 kg) allotted to a replicated, 3 x 3 Latin square design. The apparent ileal digestibility for CP and all AA except Arg and Pro, and the standardized ileal digestibility for CP and all AA except Arg, Lys, Gly, and Pro were greater (P < 0.05) in HP DDG than in corn germ. It was concluded that HP DDG has a greater digestibility of energy, P, and most AA than corn germ.


Comparison of health related quality of life with cardiopulmonary exercise testing in adolescents and adults with congenital heart disease.
To compare self reported quality of life with measured exercise capacity in patients with congenital heart disease. Prospective cross sectional clinical study. Tertiary referral centre for congenital cardiology. 149 patients (60 female, 14-60 years old) with various congenital heart defects completed a health related quality of life questionnaire (medical outcomes study 36 item short form). Then they performed a cardiopulmonary exercise test on a bicycle in a sitting position. Peak oxygen uptake correlated significantly with the physical functioning (r = 0.521, p < 0.0005) and general health scales (r = 0.313, p < 0.0005) but not with role-physical, bodily pain, vitality, social functioning, role-emotional, mental health, and health transition scales. Closer examination of the data showed that despite an overall good correlation a substantial number of patients overestimated their physical capabilities. Exercise tests and quality of life instruments should be used together to get an appropriate overview of the health status of patients with congenital heart disease.


Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis.
Accumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear. ALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression. In comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell-derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated. We report here the association of ALDH3A1 with PC progression.


Effects of binge alcohol exposure on Burkholderia thailandensis-alveolar macrophage interaction.
Alcohol consumption has diverse and well-documented effects on the human immune system and its ability to defend against infective agents. One example is melioidosis, a disease caused by infection with Burkholderia pseudomallei, which is of public health importance in Southeast Asia and Northern Australia, with an expanding global distribution. While B. pseudomallei infections can occur in healthy humans, binge alcohol use is progressively being recognized as a major risk factor. Although binge alcohol consumption has been considered as a risk factor for the development of melioidosis, no experimental studies have investigated the outcomes of alcohol exposure on Burkholderia spp. infection. Therefore, we proposed the use of non-pathogenic B. thailandensis E264 as a useful BSL-1 model system to study the effects of binge alcohol exposure on bacteria and alveolar macrophage interactions. The MH-S alveolar macrophage (AMs) cell line was used to characterize innate immune responses to infection in vitro. Our results showed that alcohol exposure significantly suppressed the uptake and killing of B. thailandensis by AMs. Alveolar macrophages incubated in alcohol (0.08%) for 3 h prior to infection showed significantly lower bacterial uptake at 2 and 8 h post infection. Activated AMs with IFN-γ and pre and post-incubation in alcohol when exposed to B. thailandensis released lower nitric oxide (NO) concentrations, compared to activated AMs with IFN-γ from non-alcoholic controls. As a result, B. thailandensis survival and replication increased ∼2.5-fold compared to controls. The presence of alcohol (1%) also increased bacterial survival within AMs. Alcohol significantly decreased bacterial motility compared to non-alcoholic controls. Increased biofilm formation was observed at 3 and 6 h when bacteria were pre-incubated in (0.08%) alcohol. These results provide insights into binge alcohol consumption, a culturally prevalent risk factor, as a predisposing factor for melioidosis.


Incidence and risk factors for multiple antibiotic-resistant Pseudomonas aeruginosa in cystic fibrosis.
Infection with multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) in individuals with cystic fibrosis (CF) has caused much concern among caregivers, yet little is known about the risks associated with acquiring resistance. The main objective of the study was to estimate the incidence and identify risk factors for the acquisition of MARPA among individuals with CF. Five-year cohort study of individuals followed in the Cystic Fibrosis Foundation Registry from 1998 through 2002. Demographics, anthropometrics, spirometry, respiratory culture results, comorbidities, antibiotic usage, and hospitalizations were collected. Of the 4,293 patients with P aeruginosa infection during the study period, MARPA developed in 341. The overall incidence of MARPA was 1.8%/yr. Independent risk factors for MARPA included CF-related diabetes mellitus (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11 to 2.43), long-term inhaled tobramycin usage (HR, 2.08; 95% CI, 1.56 to 2.77), and care at a CF center with a baseline MARPA prevalence in the top quartile (HR, 2.00; 95% CI, 1.31 to 3.04). Frequent courses of IV antibiotics and repeated hospitalizations were also found to independently increase the risk for MARPA. Infection with MARPA is common among patients with CF. Diabetes, long-term inhaled tobramycin usage, and frequent acute pulmonary exacerbations requiring hospitalization or IV antibiotics increase the risk for MARPA. Receiving CF care at a center with a high prevalence of resistant Pseudomonas also increases the risk for MARPA in patients with CF. Further study is needed to investigate the mechanisms of acquiring resistant strains and the clinical impact of MARPA on CF outcomes.


[History of Charles Nicolle's discovery of the route of typhus infection].
In 1909 French microbiologist, director of the Pasteur Institute in Tunis Charles Nicolle discovered the ways of the louse-borne typhus infection. With his numerous experiments on apes he proved that body louse is a transmitting gent of louse-borne infection. This great discovery which has formed the basis of modern concepts of the disease epidemiology and led to its prophylaxis has become lasting contribution to the history of medical science.


Structural definition of the lysine swing in Arabidopsis thaliana PDX1: Intermediate channeling facilitating vitamin B6 biosynthesis.
Vitamin B6 is indispensible for all organisms, notably as the coenzyme form pyridoxal 5'-phosphate. Plants make the compound de novo using a relatively simple pathway comprising pyridoxine synthase (PDX1) and pyridoxine glutaminase (PDX2). PDX1 is remarkable given its multifaceted synthetic ability to carry out isomerization, imine formation, ammonia addition, aldol-type condensation, cyclization, and aromatization, all in the absence of coenzymes or recruitment of specialized domains. Two active sites (P1 and P2) facilitate the plethora of reactions, but it is not known how the two are coordinated and, moreover, if intermediates are tunneled between active sites. Here we present X-ray structures of PDX1.3 from Arabidopsis thaliana, the overall architecture of which is a dodecamer of (β/α)8 barrels, similar to the majority of its homologs. An apoenzyme structure revealed that features around the P1 active site in PDX1.3 have adopted inward conformations consistent with a catalytically primed state and delineated a substrate accessible cavity above this active site, not noted in other reported structures. Comparison with the structure of PDX1.3 with an intermediate along the catalytic trajectory demonstrated that a lysine residue swings from the distinct P2 site to the P1 site at this stage of catalysis and is held in place by a molecular catch and pin, positioning it for transfer of serviced substrate back to P2. The study shows that a simple lysine swinging arm coordinates use of chemically disparate sites, dispensing with the need for additional factors, and provides an elegant example of solving complex chemistry to generate an essential metabolite.


Novel trisubstituted acridines as human telomeric quadruplex binding ligands.
A novel series of trisubstituted acridines were synthesized with the aim of mimicking the effects of BRACO19. These compounds were synthesized by modifying the molecular structure of BRACO19 at positions 3 and 6 with heteroacyclic moieties. All of the derivatives presented in the study exhibited stabilizing effects on the human telomeric DNA quadruplex. UV-vis spectroscopy, circular dichroism, linear dichroism and viscosimetry were used in order to study the nature of the DNA binding in more detail. The results show that all of the novel derivatives were able to fold the single-stranded DNA sequences into antiparallel G-quadruplex structures, with derivative 15 exhibiting the highest stabilizing capability. Cell cycle analysis revealed that a primary trend of the "braco"-like derivatives was to arrest the cells in the S- and G2M-phases of the cell cycle within the first 72h, with derivative 13 and BRACO19 proving particularly effective in suppressing cell proliferation. All studies derivatives were less toxic to human fibroblast cell line in comparison with HT 29 cancer cell line.


Metabolome Profiling of Marrubium peregrinum L. and Marrubium friwaldskyanum Boiss Reveals Their Potential as Sources of Plant-Based Pharmaceuticals.
Marrubium species have been used since ancient times as food additives and curative treatments. Their phytochemical composition and various pharmacological activities were the focus of a number of scientific investigations but no comprehensive metabolome profiling to identify the numerous primary and secondary metabolites has been performed so far. This study aimed to generate a comprehensive picture of the total metabolite content of two Marrubium species-M. peregrinum and M. friwaldskyanum-to provide detailed information about the main primary and secondary metabolites. In addition, the elemental composition was also evaluated. For this purpose, non-targeted metabolomic analyses were conducted using GC-MS, UPLC-MS/MS and ICP-MS approaches. Nearly 500 compounds and 12 elements were detected and described. The results showed a strong presence of phenolic acids, flavonoids and their glucosides, which are generally of great interest due to their various pharmacological activities. Furthermore, tissue-specific analyses for M. friwaldskyanum stem, leaves and flowers were carried out in order to outline the sources of potentially important bioactive molecules. The results generated from this study depict the Marrubium metabolome and reveal its dual scientific importance-from one side, providing information about the metabolites that is fundamental and vital for the survival of these species, and from the other side, defining the large diversity of secondary substances that are a potential source of phytotherapeutic agents.


Computational prediction of type III secreted proteins from gram-negative bacteria.
Type III secretion system (T3SS) is a specialized protein delivery system in gram-negative bacteria that injects proteins (called effectors) directly into the eukaryotic host cytosol and facilitates bacterial infection. For many plant and animal pathogens, T3SS is indispensable for disease development. Recently, T3SS has also been found in rhizobia and plays a crucial role in the nodulation process. Although a great deal of efforts have been done to understand type III secretion, the precise mechanism underlying the secretion and translocation process has not been fully understood. In particular, defined secretion and translocation signals enabling the secretion have not been identified from the type III secreted effectors (T3SEs), which makes the identification of these important virulence factors notoriously challenging. The availability of a large number of sequenced genomes for plant and animal-associated bacteria demands the development of efficient and effective prediction methods for the identification of T3SEs using bioinformatics approaches. We have developed a machine learning method based on the N-terminal amino acid sequences to predict novel type III effectors in the plant pathogen Pseudomonas syringae and the microsymbiont rhizobia. The extracted features used in the learning model (or classifier) include amino acid composition, secondary structure and solvent accessibility information. The method achieved a precision of over 90% on P. syringae in a cross validation study. In combination with a promoter screen for the type III specific promoters, this classifier trained on the P. syringae data was applied to predict novel T3SEs from the genomic sequences of four rhizobial strains. This application resulted in 57 candidate type III secreted proteins, 17 of which are confirmed effectors. Our experimental results demonstrate that the machine learning method based on N-terminal amino acid sequences combined with a promoter screen could prove to be a very effective computational approach for predicting novel type III effectors in gram-negative bacteria. Our method and data are available to the public upon request.


Highly heritable and functionally relevant breed differences in dog behaviour.
Variation across dog breeds presents a unique opportunity to investigate the evolution and biological basis of complex behavioural traits. We integrated behavioural data from more than 14 000 dogs from 101 breeds with breed-averaged genotypic data (n = 5697 dogs) from over 100 000 loci in the dog genome. We found high levels of among-breed heritability for 14 behavioural traits (the proportion of trait variance attributable to genetic similarity among breeds). We next identified 131 single nucleotide polymorphisms associated with breed differences in behaviour, which were found in genes that are highly expressed in the brain and enriched for neurobiological functions and developmental processes, suggesting that they may be functionally associated with behavioural differences. Our results shed light on the heritability and genetic architecture of complex behavioural traits and identify dogs as a powerful model in which to address these questions.


Biochemistry and clinical chemistry of vitamin B12 transport and the related diseases.
This review focusses on research performed by the author and coworkers. The absorption, turnover and excretion of cobalamin and the pathogenesis of cobalamin deficiency states are described and the laboratory tests used to diagnose these states are discussed. Topics dealt with in detail include: overall turnover, daily need, enterohepatic circulation and excretion of cobalamin and other corrins . The soluble proteins mediating cobalamin transport and their cellular receptors are described and their nomenclature, isolation, structure and mode of action, the role of calcium in the membrane transport, the evolution of these systems and the analogies with transport systems for other substrates are discussed together with deficiency states, especially fish tapeworm anemia and familial selective vitamin B12 malabsorption with proteinuria. Folate deficiency is a relatively rare cause of megaloblastic anemia in Scandinavia but common in North America and explanations for this difference are suggested. The methods of assaying cobalamin in serum and plasma and the performance of radiovitamin B12 absorption tests are critically evaluated. The measurement of intrinsic factor in gastric juice, serum, amniotic fluid and urine is described.


The Early Humor Survey (EHS): A reliable parent-report measure of humor development for 1- to 47-month-olds.
We created a 20-item parent-report measure of humor development from 1 to 47 months: the Early Humor Survey (EHS). We developed the EHS with Study 1 (N = 219) using exploratory factor analysis, demonstrating the EHS works with 1- to 47-month-olds with excellent reliability and a strong correlation with age, showing its developmental trajectory. We replicated the EHS with Study 2 (N = 587), revealing a one-factor structure, showing excellent reliability, and replicating a strong correlation with age. Study 3 (N = 84) found the EHS correlated with a humor experiment, however it no longer correlated once age was accounted for, suggesting low convergent validity. Subsamples of parents from Studies 2 and 3 showed excellent inter-observer reliability between both parents, and good longitudinal stability after 6 months. Combining participants from all studies, we found the EHS is reliable across countries (Australia, United Kingdom, United States), parent education levels, and children's age groups. We charted expected humor development by age (in months), and the expected proportion of children who would appreciate each humor type by age (in months). Finally, we found no demographic differences (e.g., country: Australia, Canada, United Kingdom, United States; parents' education) in humor when pooling all data. The EHS is a valuable tool that will allow researchers to understand how humor: (1) emerges; and (2) affects other aspects of life, e.g., making friends, coping with stress, and creativity. The EHS is helpful for parents, early years educators, and children's media, as it systematically charts early humor development.


Spectral morphological analysis of skin lesions with a polarization multispectral dermoscope.
Dermoscopy is the conventional technique used for the clinical inspection of human skin lesions. However, the identification of diagnostically relevant morphologies can become a complex task. We report on the development of a polarization multispectral dermoscope for the in vivo imaging of skin lesions. Linearly polarized illumination at three distinct spectral regions (470, 530 and 625 nm), is performed by high luminance LEDs. Processing of the acquired images, by means of spectral and polarization filtering, produces new contrast images, each one specific for melanin absorption, hemoglobin absorption, and single scattering. Analysis of such images could facilitate the identification of pathological morphologies.


A multimarker risk stratification approach to non-ST elevation acute coronary syndrome: implications of troponin T, CRP, NT pro-BNP and fibrin D-dimer levels.
Biomarkers have emerged as interesting predictors of risk in non-ST elevation acute coronary syndromes (non-ST ACS). The aim of this study was to define the utility of the combined measurement of troponin T (TnT), C-reactive protein (CRP), NT pro-brain natriuretic peptide (NT pro-BNP) and D-dimer as biomarkers to predict adverse events. We included 358 consecutive patients admitted in two hospitals for non-ST ACS. Baseline measurements of TnT (associated with myocardial injury, positive, if > or =0.1 ng mL(-1)), CRP (a marker of inflammation), NT-proBNP (associated with left ventricular (dys)function) and fibrin D-dimer (and index of thrombogenesis) were performed. A positive CRP, NT-proBNP and D-dimer test was considered upper than the 75th percentile of our population. The risk for major events (death, new ACS, revascularization and heart failure) at 6 months' follow-up was analysed. Troponin T, NT pro-BNP and CRP were predictors of adverse events in the multivariate analysis [hazards ratio (HR): 2.00 (1.30-3.07), P = 0.0016; HR: 2.27 (1.47-3.50), P = 0.0002; HR: 1.90 (1.24-2.92), P = 0.0034 respectively], but not D-dimer levels [HR: 1.26 (0.79-2.02), P = 0.337). After adjusting for baseline characteristics and electrocardiographic changes, multimarker risk approach was associated with adverse events at 6 months, especially with the presence of three positive biomarkers [HR 2.80 (95%CI 1.68-4.68), P < 0.001]. When we divided patients by risk groups [Thrombolysis in Myocardial Infarction (TIMI) risk score], patients with two or three elevated biomarkers had higher event rates [HR 2.59 (95% CI 1.37-4.91), P = 0.004]. A multimarker approach based on TnT, CRP and NT-proBNP provides added information to the TIMI risk score in terms of ACS prognosis at 6 months, with a worse outcome for those with two or three elevated biomarkers.


Dye alignment in luminescent solar concentrators: II. Horizontal alignment for energy harvesting in linear polarizers.
We describe Linearly Polarized Luminescent Solar Concentrators (LP-LSCs) to replace conventional, purely absorptive, linear polarizers in energy harvesting applications. As a proof of concept, we align 3-(2-Benzothiazolyl)-N,N-diethylumbelliferylamine (Coumarin 6) and 4- dicyanomethyl-6-dimethylaminostiryl-4H-pyran (DCM) dye molecules linearly in the plane of the substrate using a polymerizable liquid crystal host. We show that up to 38% of the photons polarized on the long axis of the dye molecules can be coupled to the edge of the device for an LP-LSC based on Coumarin 6 with an order parameter of 0.52.


Acoustic streaming in micromachined flexural plate wave devices: numerical simulation and experimental verification.
This paper presents the numerical simulation and experimental validation of acoustic streaming in micromachined flexural plate wave (FPW) devices. Two-dimensional and three-dimensional models of two device types were considered: the classical device with parallel interdigitated electrodes and the focused device with curved electrodes. Influences of different parameters on the time-averaged velocity were investigated. Thermal transport effects of the acoustic streaming were also considered. We observed the amplifying effect of the streaming in the second type numerically and experimentally. To verify simulation results, the method of the particle image velocimetry (PIV) was applied in the experimental investigation.


Adolescents who use the emergency department as their usual source of care.
To examine the factors associated with use of the emergency department (ED) as the only source of health care among adolescents. Analyses of the 1997 Commonwealth Fund Survey of the Health of Adolescent Girls, a nationally representative sample of 6748 in-school male and female adolescents in 5th through 12th grade. The X2 statistics and logistic regression analyses were computed with the use of SUDAAN. Overall, 4.6% of the adolescents in the survey, or 1.5 million adolescents in the United States, reported that the ED was their usual source of health care. In multivariate models, factors associated with the use of the ED included male sex, African American ethnicity, fewer financial resources, and living in a rural area. Adolescents with higher levels of risky behaviors, a history of physical or sexual abuse, and higher depression scores were all more likely to use the ED as their usual source of care. Adolescents who reported using the ED as their usual care source were also less likely to have had regular well visits and were more likely to report having missed needed care than those with other sources of primary care. Adolescents who use the ED as their usual source of care are often from vulnerable populations. Many have special mental or physical needs that are unlikely to be met with ED visits only, and they are likely to have missed care they needed. Creating linkages between EDs and other services could help at-risk adolescents identify and use more appropriate sources of primary care.


LeHeR, a simple novel approach for difficult airway in non-trauma patients.
Managing the difficult airway presents a great challenge to anaesthesiologists and emergency physicians. Although there are many methods and scoring systems available to predict and anticipate difficult airway, the dictum in emergency airway is to always expect the unexpected. We have encountered a novel simple method of improving laryngoscopic view in difficult airway. We report four cases of difficult airway encountered in our district hospital from November 2017 to December 2018, in which intubation was performed using a simple manoeuvre called supine left head rotation (LeHeR). In all these cases, LeHeR manoeuvre has proven to be successful after more than a single attempt at intubation using various methods. The manoeuvre improves drastically the laryngoscopic view of Cormack-Lehane from 3B and 4 to 1 and 2.


An OspB mutant of Borrelia burgdorferi has reduced invasiveness in vitro and reduced infectivity in vivo.
Most Borrelia burgdorferi strains have two major surface proteins, OspA and OspB. In the present study, we selected from a clonal population of infectious B. burgdorferi an OspB escape mutant, identified the genetic basis for this phenotype, and evaluated its functional activities. Selection with the anti-OspB antibody H614 was performed in vitro in medium and extended in vivo in scid mice. Mutants with a truncated OspB protein were selected at a frequency of 1 x 10(-5) to 3 x 10(-5). After no major rearrangements in DNA were detected, sequence analysis of the mutant's ospAB locus revealed a single base change in the consensus ribosomal binding sequence for ospB and a single nucleotide deletion in the ospB gene itself. The effect of these mutations was reduced expression of a truncated OspB protein. When functional abilities of the wild type and mutant were compared, the mutant had a threefold-lower capacity to penetrate a human endothelium umbilical vein cell monolayer. Infectivity of wild-type and mutant cells for scid mice was evaluated by culturing different organs, and the median infectious dose was calculated. The inoculum of mutant cells for infecting the mice was 30- to 300-fold higher than that of wild-type cells. This study shows that reduced size and expression of OspB are associated with lowered virulence of B. burgdorferi. Selection of mutants that to some degree remain infectious is one approach to defining the role of different surface proteins in the pathogenesis of Lyme disease.


Mathematical modelling of chronic acetaminophen metabolism and liver injury.
Acetaminophen (APAP) overdose is the leading cause of acute liver injury in the USA and the UK. Increasingly, liver injury is caused by sustained overuse rather than a single-time overdose. We have recently developed a mathematical model, the Model of APAP-induced Liver Damage (MALD), to predict the outcome of patients with APAP-induced liver damage. The model is based on a single-time overdose and uses measurable markers of liver injury to estimate time since overdose and overdose amount, two variables critical for survival. Here, we extend the model to study liver injury from chronic APAP use. We find that there is a threshold in the model, such that liver injury occurs rapidly or not at all, even with chronic use. Fits of synthetic data derived from chronic use overdose scenarios to MALD lead to accurate predictions of outcome, even when liver injury is the result of sustained overuse.


von Hippel-Lindau syndrome: target for anti-vascular endothelial growth factor (VEGF) receptor therapy.
von Hippel-Lindau (VHL) syndrome is a familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene. Mutations in the VHL gene result in the constitutive stabilization of transcription factors hypoxia-inducible factors 1alpha and 2alpha, which bind to specific enhancer elements in the vascular endothelial growth factor (VEGF) gene and stimulate angiogenesis. This increase in angiogenesis under normoxic conditions in key target organs such as the brain, kidney, and eye leads to high morbidity and reduced life expectancy. Drugs designed to block the VEGF signaling pathway may prevent the long-term complications of the disease. To test this hypothesis, a clinical study was initiated to evaluate the effect of the VEGF tyrosine kinase receptor inhibitor SU5416 in patients with VHL syndrome. Preliminary data on SU5416 indicate that it is well tolerated when administered chronically in such patients. However, since little is known about the long-term use of such inhibitors, patients will need careful monitoring. Data obtained from monitoring these patients will provide valuable information for adjuvant treatment trials in cancer patients.


Human papillomavirus and p53 protein immunoreactivity in condylomata acuminatum and squamous cell carcinoma of penis.
To determine the immunoreactive pattern of human papillomavirus (HPV) antigen and p53 protein in condylomata acuminatum (CA) and squamous cell carcinoma (SCC) of penis. Immunohistochemistry for HPV and p53 were performed in 40 specimens of formalin fixed, paraffin embedded tissues using a polyclonal (rabbit) antibody against HPV and a monoclonal (mouse) antibody against human p53 protein. Twenty one cases of CA and nineteen cases of SCC were examined. HPV antigen was detected in all 21 CA and 2 penile SCC. p53 protein overexpression was observed in 12 of 19 (63%) SCC in which 6 cases were strong positive. Five of 21 CA (24%) showed low-grade p53 protein overexpression. CA is related to HPV infection and some cases show p53 protein low-grade overexpression. In contrast, p53 protein overexpression is common in penile SCC, which is seldom related to HPV infection.


Classic congenital adrenal hyperplasia and puberty.
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. The most common form of the disease is classic 21-hydroxylase deficiency, which is characterized by decreased synthesis of glucocorticoids and often mineralocorticoids, adrenal hyperandrogenism and impaired development and function of the adrenal medulla. The clinical management of classic 21-hydroxylase deficiency is often suboptimal, and patients are at risk of developing in tandem iatrogenic hypercortisolism and/or hyperandogenism. Limitations of current medical therapy include the inability to control hyperandrogenism without employing supraphysiologic doses of glucocorticoid, hyperresponsiveness of the hypertrophied adrenal glands to adrenocorticotropic hormone (ACTH) and difficulty in suppressing ACTH secretion from the anterior pituitary. Puberty imposes increased difficulty in attaining adrenocortical suppression despite optimal substitution therapy and adherence to medical treatment. Alterations in the endocrine milieu at puberty may influence cortisol pharmacokinetics and, consequently, the handling of hydrocortisone used as replacement therapy. Recent studies have demonstrated a significant increase in cortisol clearance at puberty and a shorter half-life of free cortisol in pubertal females compared with males. Furthermore, children with classic CAH have elevated fasting serum insulin concentrations and insulin resistance. The latter may further enhance adrenal and/or ovarian androgen secretion, decrease the therapeutic efficacy of glucocorticoids and contribute to later development of the metabolic syndrome and its complications.


COVID-19 reminds us: community vitamin D deficiency.
AİM: The aim of this study was to compare the vitamin D levels between the group of patients diagnosed with COVID- 19 and healthy controls, and to investigate the relationship between vitamin D levels and various clinical findings. MATERİAL AND METHODS: A total of 262 COVID-19-confirmed patients and 157 healthy controls were included in the study. RESULTS: The mean vitamin D level in the COVID-19 group (12.8±8.9 ng/mL) was significantly lower than the control group (15.2±12.1 ng/mL) (p=0.015). The rate of those with vitamin D levels below 10 ng/mL in the COVID- 19 group (49.6%) was significantly higher than the control group (39.5%) (p=0.044). In the logistic regression analysis, it was found that those with a vitamin D level below 10 ng/mL had a 1.508-fold increased risk of COVID-19 compared to those who had 10 ng/mL and above (Odds ratio: 1.01-2.252). According to the risk analysis, those who have vitamin D levels below 20 ng/mL are 1,224 times higher than those who have 20 ng/mL and above; those under 30 ng/mL were found to have an increased risk of 2.01 times compared to those of 30 ng/mL and above. CONCLUSİONS: From the point of view of the literature data, we think that the findings we obtained may support researches that vitamin D level is significantly associated with both COVID-19 and other infections and many serious autoimmune and malignant diseases. As a result, rehabilitation programs on vitamin D deficiency should be organized and the society should be raised. KEY WORDS: Covid-19, Vitamin D25 (Oh) D.


[The effect of sedation on pulmonary function].
Opioids, benzodiazepines and hypnotics all affect central respiratory drive, muscular activity of the oropharynx, thoracic wall and diaphragm, bronchomotor tone and pulmonary vascular resistance (PVR), and may thus influence respiratory function during sedation and weaning. Opioids and benzodiazepines will attenuate hypercapnic and hypoxic stimulation of the respiratory centres. Compromise of respiratory drive must also be anticipated with ketamine, in view of recent evidence contradicting earlier findings of central respiratory stimulation. Coordinated muscular activity of the oropharynx is important for airway patency. Since this mechanism is impaired more by benzodiazepines than by ketamine the latter may be advantageous during weaning. Respiratory frequency and tidal volume are both diminished by opioids, benzodiazepines and propofol. The differential impact on intercostal and diaphragmatic muscle activity may prove important in COPD and emphysema. With ketamine spontaneous respiration is increased. Gas distribution and airway pressures are influenced by bronchomotor tone. Bronchodilator effects are well known to arise with ketamine, but have also been demonstrated with benzodiazepines, propofol and some opioids. PVR is a critical factor in respiratory insufficiency. An increase in PVR with ketamine has been found during spontaneous respiration. Since evidence for pulmonary vasodilation during controlled ventilation has been recorded in humans and in vitro experiments, sedation regimens applied in respiratory insufficiency can also include ketamine.


Regulation of bacterial methane oxidation: transcription of the soluble methane mono-oxygenase operon of Methylococcus capsulatus (Bath) is repressed by copper ions.
Methane is oxidized to methanol by the enzyme methane mono-oxygenase (MMO) in methanotrophic bacteria. In previous work, this multicomponent enzyme system has been extensively characterized at the biochemical and molecular level. Copper ions have been shown to irreversibly inhibit MMO activity in vivo and in vitro, but the effect of copper ions on transcription of the genes encoding the soluble (cytoplasmic) MMO (sMMO) has not previously been investigated. To examine more closely the regulation of bacterial methane oxidation and to determine the role of copper in this process, we have investigated transcriptional regulation of the sMMO gene cluster in the methanotrophic bacterium Methylococcus capsulatus (Bath). Using Northern blot analysis and primer extension experiments, it was shown that the six ORFs of the sMMO gene cluster are organized as an operon and the transcripts produced upon expression of this operon have been identified. The synthesis of these transcripts was under control of a single copper-regulated promoter, which is as yet not precisely defined.


A wind energy powered wireless temperature sensor node.
A wireless temperature sensor node composed of a piezoelectric wind energy harvester, a temperature sensor, a microcontroller, a power management circuit and a wireless transmitting module was developed. The wind-induced vibration energy harvester with a cuboid chamber of 62 mm × 19.6 mm × 10 mm converts ambient wind energy into electrical energy to power the sensor node. A TMP102 temperature sensor and the MSP430 microcontroller are used to measure the temperature. The power management module consists of LTC3588-1 and LT3009 units. The measured temperature is transmitted by the nRF24l01 transceiver. Experimental results show that the critical wind speed of the harvester was about 5.4 m/s and the output power of the harvester was about 1.59 mW for the electrical load of 20 kΩ at wind speed of 11.2 m/s, which was sufficient to power the wireless sensor node to measure and transmit the temperature every 13 s. When the wind speed increased from 6 m/s to 11.5 m/s, the self-powered wireless sensor node worked normally.


Association of anti-tuberculosis drug concentrations in hair and treatment outcomes in MDR- and XDR-TB.
Therapeutic drug monitoring for drug-resistant tuberculosis (TB) is likely to improve treatment outcomes. While assessments of plasma drug levels can explain pharmacokinetic variability among trial participants, these measures require phlebotomy and a cold chain, and are generally not repeated frequently enough to characterise drug exposure over time. Using a novel multi-analyte assay, we found evidence that higher anti-TB drug concentrations in hair, a non-biohazardous and noninvasively collected biomatrix, predict extensively-drug resistant-TB clinical outcomes in a high-burden setting.


Systematic biopsies: do they add prognostic information in men with clinically localized prostate cancer treated with radiation therapy alone?
To determine whether systematic biopsy can help predict treatment outcome in men with clinically localized prostate cancer treated with external-beam radiation therapy alone. Two hundred twenty-four men with clinically localized prostate cancer underwent ultrasound-guided systematic biopsies before undergoing external-beam radiation therapy. Median follow-up was 25 (range, 4-80) months. Treatment failure after irradiation was defined as a prostate-specific antigen (PSA) level greater than 1.5 ng/mL and rising. Univariate analysis demonstrated that the percentage of biopsy specimens involved by cancer was predictive of relapse-free survival. Patients in whom more than 50% of biopsy specimens were positive had significantly lower relapse-free survival rates at 36 months than patients with 50% or fewer positive biopsy specimens. After stratifying patients according to pretreatment PSA level, however, the percentage of positive biopsy specimens was no longer prognostic. Multivariate analysis demonstrated that pretreatment PSA level was the only variable that enabled prediction of relapse-free survival. Systematic biopsy added little further prognostic information beyond that provided by pretreatment PSA level. A larger series with longer follow-up is necessary to verify these results.


Chromosome analysis of workers occupationally exposed to radiation at the Sellafield nuclear facility.
To investigate the relationship between stable chromosome aberration frequency in peripheral blood lymphocytes and occupational cumulative radiation exposure. Cytogenetic analysis using G-banding was performed on peripheral blood lymphocyte cultures from 104 workers from the British Nuclear Fuels PLC facility at Sellafield, UK. The study group comprised 61 men with lifetime cumulative doses > 500 mSv, 39 men with minimal exposure (i.e. < 50 mSv) who formed a control group and 4 men with intermediate doses. The slope of the dose-response, adjusted for smoking status, for translocations and insertions was 0.55+/-0.31 x 10(-2)/cell/Sv. Consideration of chromosome breakpoints for all aberrations combined in the radiation workers revealed an excess in the C group chromosomes and a deficit in the F group chromosomes with breakpoints being concentrated in the terminal regions whereas the distribution in the control group did not deviate from expectation. The dose-response was not significantly different from the parallel FISH analysis (Tucker et al. 1997) and confirms that chronic radiation exposure appears to be substantially less effective at inducing stable chromosome aberrations in comparison with acute exposure.


Eugenol dilates rat cerebral arteries by inhibiting smooth muscle cell voltage-dependent calcium channels.
Plants high in eugenol, a phenylpropanoid compound, are used as folk medicines to alleviate diseases including hypertension. Eugenol has been demonstrated to relax conduit and ear arteries and reduce systemic blood pressure, but mechanisms involved are unclear. Here, we studied eugenol regulation of resistance-size cerebral arteries that control regional brain blood pressure and flow and investigated mechanisms involved. We demonstrate that eugenol dilates arteries constricted by either pressure or membrane depolarization (60 mM K) in a concentration-dependent manner. Experiments performed using patch-clamp electrophysiology demonstrated that eugenol inhibited voltage-dependent calcium (Ca) currents, when using Ba as a charge carrier, in isolated cerebral artery smooth muscle cells. Eugenol inhibition of voltage-dependent Ca currents involved pore block, a hyperpolarizing shift (∼-10 mV) in voltage-dependent inactivation, an increase in the proportion of steady-state inactivating current, and acceleration of inactivation rate. In summary, our data indicate that eugenol dilates cerebral arteries by means of multimodal inhibition of voltage-dependent Ca channels.


Distribution of pathogenic indicator bacteria in structural best management practices.
This study evaluated the bacterial distribution and the survivability of bacteria associated with different particle size ranges in the sump water and sediments within two structural Best Management Practices (BMPs), called Vortechs, installed at two different sites in Providence, Rhode Island. Ten rain storms were sampled in year 2004. Five pathogenic indicator bacteria, E. coli, enterococci, fecal streptococci, total coliform, fecal coliform, were analyzed for samples in the sump water and sediments within two Vortechs. In both sump water and sediments within Vortechs, most of the bacterial were found to be associated with smaller particles, i.e., 80-95% of all pathogenic indicator bacteria were associated with particles less than 50 micro meter in the sump water, and 60-80% of all indicator bacteria were associated with particles less than 106 micro meter in the sediments. In the sump water, it was found that a surge of all indicator bacteria concentrations happened one-day after the rainfall stopped. This result was most significant for the bacteria associated with smaller particles. On the contrary, in the sediments, no dramatic change of bacterial concentrations was detected over the 5-day dry period following rain. At both sampling sites, much higher bacterial concentrations were detected in the sediments than in the sump water suggesting that sediments may have provided a favorable living environment for bacteria. The two sampling sites showed almost identical results in many aspects. Except the sump water at Site 2 had much lower bacterial concentrations than that at Site 1 suggesting higher bacterial contamination from highway runoff.


Essentials in cardiac arrest during cesarean section.
Cardiac arrest during cesarean section is very rare. Obstetrical teams have low exposure to these critical situations necessitating frequent rehearsal and knowledge of its differential diagnosis and treatment. A 40-year-old woman pregnant with triplets underwent cesarean sections because of vaginal bleeding due to a placenta previa at 35.2 weeks of gestation. Spinal anesthesia was performed. Asystole occurred during uterotomy. Immediate resuscitation and delivery of the neonates eventually resulted in good maternal and neonatal outcomes. The differential diagnosis is essential and should include obstetric and non-obstetric causes. We describe the consideration of Bezold Jarisch reflex and amniotic fluid embolism as most appropriate in this case.


Effect of comorbidity adjustment on CMS criteria for kidney transplant center performance.
The Centers for Medicare & Medicaid Services (CMS) uses kidney transplant outcomes, unadjusted for standard comorbidity, to identify centers with sufficiently higher than expected rates of graft failure or patient death (underperforming centers) that they may be denied Medicare participation. To examine whether comorbidity adjustment would affect this determination, we identified centers that would have failed to meet 1-year graft survival criteria, 1992-2005, with and without adjustment using the Elixhauser Comorbidity Index. Adjustment was performed for each U.S. center for 24 consecutive (overlapping) 30-month intervals, including 102 176 adult deceased-donor and living-donor kidney transplant patients with Medicare as primary payer 6 months pretransplant. For each interval, we determined percent positive agreement (PPA) (number of centers underperforming both before and after adjustment, divided by number underperforming either before or after adjustment). Overall PPA was 80.8%, with no evidence of a trend over time. Among deceased-donor recipients, 10 of 31 comorbid conditions were predictors of graft failure in at least half of the intervals, as were six conditions among living-donor recipients. Lack of comorbidity adjustment may disadvantage centers willing to accept higher risk patients. Risk of jeopardizing Medicare funding may give centers incentive to deny transplantation to higher risk patients.


Tetracycline analogue-regulated transgene expression in Plasmodium falciparum blood stages using Toxoplasma gondii transactivators.
Genetic manipulation has revolutionized research in the Apicomplexan parasite Plasmodium falciparum, the most important causative agent of malaria. However, to date no techniques have been established that allow modifications that are deleterious to blood-stage growth, such as the disruption of essential genes or the expression of dominant-negative transgenes. The recent establishment of a screen for functional transactivators in the related parasite Toxoplasma gondii prompted us to identify transactivators in T. gondii and to examine their functionality in P. falciparum. Tetracycline-responsive minimal promoters were generated based on the characterized P. falciparum calmodulin promoter and used to assess transactivators in P. falciparum. We demonstrate that artificial tetracycline-regulated transactivators isolated in T. gondii are also functional in P. falciparum. By using the tetracycline analogue anhydrotetracycline, efficient, stage-specific gene regulation was achieved in P. falciparum. This regulatable expression technology has clear potential for the study of essential gene function in P. falciparum blood stages. On the other hand, the identified transactivators are not functional in mammalian cells, consistent with the fundamental differences in the mechanism of gene regulation between Apicomplexan parasites and their human hosts.


Pilot study of concurrent 5-fluorouracil/paclitaxel plus radiotherapy in patients with carcinoma of the esophagus and gastroesophageal junction.
Preoperative concurrent chemotherapy and radiotherapy can be highly effective but are often associated with significant rates of morbidity and even mortality. We studied the toxicity of continuous infusion of 5-fluorouracil (5-FU) and weekly paclitaxel combined with radiotherapy. Patients had histologic proof of local-regional carcinoma of the esophagus or gastroesophageal (GE) junction, a Karnofsky performance status of 70 or greater, and normal liver, renal, and bone marrow functions. Chemotherapy consisted of continuous infusion of 5-FU (300 mg/m2/d) for 5 days a week for 5 weeks, plus paclitaxel (45 mg/m2) given during 3 hours every week for 5 weeks. Based on the tumor location and its resectability, the total dose of concurrent radiation varied between 45 Gy and 50.4 Gy. Nine men and one woman, with a median age of 61 years, were evaluated. One had GE junction cancer, six had distal esophageal cancer, and three had midesophageal cancer. Weight loss, nausea, vomiting, and dysphagia of grades I and II were noted. The hematologic toxicity was mild. No patients required transfusion. There was no leukopenia or thrombocytopenia. None of the patients was hospitalized during chemoradiation; all patients completed treatment as outpatients. Five patients had subsequent surgical resections: one had a pathologically complete response, and two had a partial response (>90% necrosis). Continuous infusion of 5-FU plus paclitaxel given concurrently with radiotherapy was well tolerated. We plan to study this regimen further in upper gastrointestinal cancers.


[Recurrent bacterial meningitis].
Recurrent bacterial meningitis (RBM) is an unusual entity and usually poses a considerable diagnostic challenge. Different conditions can predispose for recurrence of episodes and the isolated pathogen can guide the diagnosis. The aim of this study was to characterize all RBM admitted to our tertiary paediatric hospital. Retrospective analysis of the medical records of all children with RBM, between January 1994 and December 2007 (14 years). During this period, 107 children with bacterial meningitis (BM) were admitted. Among those, 10 (9.3%) had more than 1 episode of BM. Five (4.7%) had cerebrospinal fluid shunt. In the other 5 (4.3%), 11 episodes of BM were identified. S. pneumoniae was isolated in the majority of episodes (4) followed by N. meningitis (2). An anatomical defect, namely post-traumatic CSF leakage, was present in 3 children and S. pneumoniae was isolated in all. A predisposing condition has not yet been identified in 2 children and no anatomical defect or immunodeficiency was found despite full investigation. It was identified a high proportion of RBM compared to other series, that could be explained by the fact of being a tertiary hospital. An anatomical defect was the most frequent cause and S. pneumoniae the most frequent bacteria. In cases without an obvious predisposing condition an exhaustive evaluation, including search for anatomical and immunological defects, was performed but no changes were identified.


Some aspects of the pathophysiology of homozygous Hb CC erythrocytes.
We have studied erythrocytes from homozygous CC patients in vitro and in perfused rat mesoappendix vasculature to answer some long-standing questions. By examination of wet whole blood preparations, and by comparing the cell distribution on isopycnic continuous density gradients of whole blood samples from a splenectomized CC patient with those from three intact CC patients, we have demonstrated the presence of a distinct crystal-containing band of cells that is present in the former, but totally absent from the latter. We conclude that Hb CC cells containing crystals circulate in Hb CC individuals, but in intact patients they are effectively removed by the spleen. By use of 31P nuclear magnetic resonance and viscosity measurements on cells, we have demonstrated that intracellular aggregation of hemoglobin C occurs on deoxygenation even when no crystal formation is detectable by morphological methods. These two observations are in apparent contradiction with the absence of clinical microcirculatory impairment found in both intact and splenectomized CC patients. The contradiction was resolved by rheological studies on isolated rat mesoappendix preparations and erythrocyte diameter measurements that lead to the conclusion that the hemorheological properties of CC cells in the microcirculation are nearly normal because their increased viscosity is offset by their smaller diameter and size.


Comparative trial of large and small fractions in the radiotherapy of head and neck cancer.
A random controlled trial was performed to compare long and short fractionation of radiotherapy in patients with head and neck cancer with a poor prognosis. Ninety-eight matched pairs were treated, one member of each pair received 10 fractions in 22 days, the other 30 fractions in 42 days. The same nominal standard dosages were used in each arm of the trial. Mucosal reactions were more severe with 10 fractions, skin reactions more severe with 30 fractions. No difference in survival, local tumour control rates or late normal tissue effects could be demonstrated. It is suggested that any possible therapeutic advantage of prolonged fractionation is minimal and that it is justified to use a small number of large fractions in clinical trials involving hyperbaric oxygen or electron-affinic sensitizers.


[Deglycosylation of glycoproteins].
Glycosylation procedures and their application for the elucidation of glycoprotein structure and structure-function relations, as well as for the development of analytical systems for clinical practice are reviewed. For some common cases found in research practice, the choice of optimal deglycosylation methods is discussed. Current views on the primary structure of glycoproteins are described briefly.


Metabolic polymorphisms as susceptibility markers for lung and oral cavity cancer.
Lung and oral cavity cancers are causally associated with tobacco use. Alcohol is an independent risk factor for oral cavity cancer. Major classes of carcinogens present in tobacco and tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYP)-related enzymes, several of which display genetic polymorphism. Individual susceptibility to cancer is likely to be modified by the genotype for enzymes involved in the activation or detoxification of carcinogens in tobacco and repair of DNA damage. Molecular epidemiological studies to assess the risk associated with metabolic polymorphisms for cancers of the lung and head and neck have shown that the overall effect of common polymorphisms is moderate in terms of penetrance and relative risk. However, some gene combinations like mutated CYP1A1/GSTM1-null genotype seem to predispose the lung and oral cavity of smokers to an even higher risk for cancer or DNA damage, although these results require confirmation in larger well defined studies that take into account the existence of ethnic variations even within the commonly defined groups. Retinoids, isothiocyanates and tea polyphenols have been identified as possible chemopreventive agents for cancers of the lung and oral cavity. While a number of trials have been conducted with retinoids or beta-carotene, the results were ambiguous and the causes are still being debated. The possible interaction of chemopreventive agents with metabolic polymorphisms as biomarkers in chemoprevention trials is discussed.


[Therapeutic indications in male sterility and hypofertility].
The therapeutic indications, even in potentially curable masculine sterility, and in hypofertility, in particular that due to idiopathic oligo-asthenospermia, give irregular and disappointing results, but the absence of a truly efficacious remedy never justifies the prescription of ineffective or harmful medication. The author concludes by emphasising that our therapeutic power is often opportunely assisted by good luck.


Lethal effect of recombinant human Fas ligand in mice pretreated with Propionibacterium acnes.
Fas ligand (FasL) is a type II membrane protein. Binding of FasL to its receptor, Fas, induces apoptosis. Matrix metalloproteinase cleaves the membrane-bound human FasL to yield the active soluble form. Here, we have produced a large amount of human soluble rFasL using the yeast, Pichia pastoris. The purified rFasL was found to be glycosylated and to exist as a trimer. The rFasL was effective in inducing apoptosis in a Fas-expressing T cell or a fibroblast cell line. The ID50 of rFasL for mouse Fas-expressing T cells was about 0.5 ng/ml. The killing process with rFasL was quick. That is, >80% Fas-expressing mouse cells were killed within 1 h by a saturation concentration of human rFasL. Intravenous administration of 500 microg of human rFasL had a lethal effect in mice. When the mice were pretreated with Propionibacterium acnes, the subsequent injection of 30 microg of human rFasL induced hepatic failure and killed the mice within 24 h. These results indicated that the soluble human FasL is active in inducing apoptosis in vitro and in vivo, and its deleterious effect may be strengthened in patients who are suffering from bacterial infection.