Kinetics of dextromethorphan-O-demethylase activity and distribution of CYP2D in four commonly-used subcellular fractions of rat brain.
The purpose of this study was to compare the enzymatic kinetics and distribution of cytochrome P450 2D (CYP2D) among different rat brain subcellular fractions. Rat brains were used to prepare total membrane, crude mitochondrial, purified mitochondrial, and microsomal fractions, in addition to total homogenate. Michaelis-Menten kinetics of the brain CYP2D activity was estimated based on the conversion of dextromethorphan (DXM) to dextrorphan using UPLC-MS/MS. Protein levels of CYP2D and subcellular markers were determined by Western blot. Microsomal CYP2D exhibited high affinity and low capacity, compared with the mitochondrial CYP2D that had a much lower (∼50-fold) affinity but a higher (∼six-fold) capacity. The apparent CYP2D affinity and capacity of the crude mitochondria were in between those of the microsomes and purified mitochondria. Additionally, the CYP2D activity in the whole homogenate was much higher than that in the total membranes at higher DXM concentrations. A CYP2D immune-reactive band in the brain mitochondria appeared at a lower MW but had a much higher intensity than that in the microsomes. Mitochondrial brain CYP2D has a much higher capacity than its microsomal counterpart. Additionally, brain homogenate is more representative of the overall CYP2D activity than the widely-used total membrane fraction.


Controversies in the Management of Functional Constipation in Children.
Functional constipation (FC) in children is a common health problem with reported worldwide prevalence rates up to 32.2%. The majority of children with constipation respond to oral laxative treatment. After 5 years of intensive treatment, however, approximately 50% of children remain symptomatic. To discuss the evidence for new treatments in these children, including pre- and probiotics, pelvic physiotherapy, prucalopride, sacral nerve stimulation, and surgery, and to highlight the controversies surrounding them. Pre- and probiotics and prucalopride are not effective in the treatment of childhood constipation. Pelvic physiotherapy and sacral nerve stimulation are promising treatment options but larger trials are needed. Surgery for pediatric constipation is the treatment of last resort. Large, well-designed placebo-controlled trials with proper outcome measures, as suggested by the Rome foundation pediatric subcommittee on clinical trials, are necessary to provide more insight regarding the efficacy of new treatments in childhood constipation.


Untrivial Pursuit: Measuring Motor Procedures Learning in Children with Autism.
Numerous studies have underscored prevalence of motor impairments in children with autism spectrum disorders (ASD), but only few of them have analyzed motor strategies exploited by ASD children when learning a new motor procedure. To evaluate motor procedure learning and performance strategies in both ASD and typically developing (TD) children, we built a virtual pursuit rotor (VPR) task, requiring tracking a moving target on a computer screen using a digitalized pen and tablet. Procedural learning was measured as increased time on target (TT) across blocks of trials on the same day and consolidation was assessed after a 24-hour rest. The program and the experimental setting (evaluated in a first experiment considering two groups of TD children) allowed also measures of continuous time on target (CTT), distance from target (DT) and distance from path (DP), as well as 2D reconstructions of children's trajectories. Results showed that the VPR was harder for children with ASD than for TD controls matched for chronological age and intelligence quotient, but both groups displayed comparable motor procedure learning (i.e., similarly incremented their TT). However, closer analysis of CTT, DT, and DP as well as 2D trajectories, showed different motor performance strategies in ASD, highlighting difficulties in overall actions planning. Data underscore the need for deeper investigations of motor strategies exploited by children with ASD when learning a new motor procedure.


Solvent-Induced Aggregation of Self-Assembled Copper-Cysteine Nanoparticles Reacted with Glutathione: Enhancing Linear and Nonlinear Optical Properties.
Copper-thiolate self-assembly nanostructures are a unique class of nanomaterials because of their interesting properties such as hierarchical structures, luminescence, and large nonlinear optical efficiency. Herein, we synthesized biomolecule cysteine (Cys) and glutathione (GSH) capped sub-100 nm self-assembly nanoparticles (Cu-Cys-GSH NPs) with red fluorescence. The as-synthesized NPs show high emission enhancement in the presence of ethanol, caused by the aggregation-induced emission. We correlated the structure and optical properties of Cu-Cys-GSH NPs by measuring the mass, morphology, and surface charge as well as their two-photon excited fluorescence cross-section (σ2PEPL), two-photon absorption cross-section (σTPA) and first hyperpolarizability (β) of Cu-Cys-GSH NPs in water and water-ethanol using near-infrared wavelength. We found a high β value as (77 ± 10) × 10-28 esu (in water) compared to the reference medium water. The estimated values of σ2PEPL and σTPA are found to be (13 ± 2) GM and (1.4 ± 0.2) × 104 GM, respectively. We hope our investigations of linear and nonlinear optical properties of copper-thiolate self-assemblies in water and its solvent-induced aggregates will open up new possibilities in designing self-assembled systems for many applications including sensing, drug delivery, and catalysis.


Metabolic, Reproductive, and Neurologic Abnormalities in Agpat1-Null Mice.
Defects in the biosynthesis of phospholipids and neutral lipids are associated with cell membrane dysfunction, disrupted energy metabolism, and diseases including lipodystrophy. In these pathways, the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) enzymes transfer a fatty acid to the sn-2 carbon of sn-1-acylglycerol-3-phosphate (lysophosphatidic acid) to form sn-1, 2-acylglycerol-3-phosphate [phosphatidic acid (PA)]. PA is a precursor for key phospholipids and diacylglycerol. AGPAT1 and AGPAT2 are highly homologous isoenzymes that are both expressed in adipocytes. Genetic defects in AGPAT2 cause congenital generalized lipodystrophy, indicating that AGPAT1 cannot compensate for loss of AGPAT2 in adipocytes. To further explore the physiology of AGPAT1, we characterized a loss-of-function mouse model (Agpat1-/-). The majority of Agpat1-/- mice died before weaning and had low body weight and low plasma glucose levels, independent of plasma insulin and glucagon levels, with reduced percentage of body fat but not generalized lipodystrophy. These mice also had decreased hepatic messenger RNA expression of Igf-1 and Foxo1, suggesting a decrease in gluconeogenesis. In male mice, sperm development was impaired, with a late meiotic arrest near the onset of round spermatid production, and gonadotropins were elevated. Female mice showed oligoanovulation yet retained responsiveness to gonadotropins. Agpat1-/- mice also demonstrated abnormal hippocampal neuron development and developed audiogenic seizures. In summary, Agpat1-/- mice developed widespread disturbances of metabolism, sperm development, and neurologic function resulting from disrupted phospholipid homeostasis. AGPAT1 appears to serve important functions in the physiology of multiple organ systems. The Agpat1-deficient mouse provides an important model in which to study the contribution of phospholipid and triacylglycerol synthesis to physiology and diseases.


Effective improvement of doctor-patient communication: a randomised controlled trial.
Doctor-patient communication is an essential component of general practice. Improvement of GPs' communication patterns is an important target of training programmes. Available studies have so far failed to provide conclusive evidence of the effectiveness of educational interventions to improve doctor-patient communication. To examine the effectiveness of a learner-centred approach that focuses on actual needs, to improve GPs' communication with patients. Randomised controlled trial. One hundred volunteer GPs in the Netherlands. The intervention identified individual GPs' deficiencies in communication skills by observing authentic consultations in their own surgery. This performance assessment was followed by structured activities in small group meetings, aimed at remedying the identified shortcomings. Outcomes were measured using videotaped consultations in the GPs' own surgery before and after the intervention. Communication skills were rated using the MAAS-Global, a validated checklist. The scores in the intervention group demonstrated a significant improvement compared with those of the control group (95% confidence interval = 0.04 to 0.75). The effect size was moderate to large (d-value = 0.66). The level of participation significantly contributed to the effectiveness. Largest improvement was found on patient-centred communication skills. The approach of structured individual improvement activities based on performance assessment is more effective in improving communication skills than current educational activities.


G-protein coupled estrogen receptor, estrogen receptor α, and progesterone receptor immunohistochemistry in the hypothalamus of aging female rhesus macaques given long-term estradiol treatment.
Steroid hormone receptors are widely and heterogeneously expressed in the brain, and are regulated by age and gonadal hormones. Our goal was to quantify effects of aging, long-term estradiol (E2 ) treatment, and their interactions, on expression of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα) and progesterone receptor (PR) immunoreactivity in two hypothalamic regions, the arcuate (ARC) and the periventricular area (PERI) of rhesus monkeys as a model of menopause and hormone replacement. Ovariectomized (OVX) rhesus macaques were young (∼ 11 years) or aged (∼ 25 years), given oil (vehicle) or E2 every 3 weeks for 2 years. Immunohistochemistry and stereologic analysis of ERα, PR, and GPER was performed. More effects were detected for GPER than the other two receptors. Specifically, GPER cell density in the ARC and PERI, and the percent of GPER-immunoreactive cells in the PERI, were greater in aged than in young monkeys. In addition, we mapped the qualitative distribution of GPER in the monkey hypothalamus and nearby regions. For ERα, E2 treated monkeys tended to have higher cell density than vehicle monkeys in the ARC. The percent of PR density in the PERI tended to be higher in E2 than vehicle monkeys of both ages. This study shows that the aged hypothalamus maintains expression of hormone receptors with age, and that long-term cyclic E2 treatment has few effects on their expression, although GPER was affected more than ERα or PR. This result is surprising in light of evidence for E2 regulation of the receptors studied here, and differences may be due to the selected regions, long-term nature of E2 treatment, among other possibilities.


Increase of oleic acid in erythrocytes associated with malignancies.
Total lipid extracts of erythrocyte cell membranes from 60 patients with documented malignancies, 41 patients with various acute and chronic diseases, and 40 healthy subjects were analysed. The results were expressed as ratios of stearic to oleic acid, reflecting the degree of desaturation of stearic acid. The mean ratios for the healthy subjects and controls without cancer were 1.5 (SD 0.27) and 1.45 (0.28), respectively, whereas the ratios for patients with malignancies were consistently lower than the cut off point of 1.0, with a mean of 0.69 (0.15) (p less than 0.001). The desaturation ratio was also significantly lower (p less than 0.001) in the group with recurrent tumours (mean 0.75 (0.04)) compared with those with no evidence of recurrent tumours (mean 1.55 (0.27)). It is suggested that the increased unsaturation (oleic acid) in the circulating erythrocytes may be useful in the diagnosis and postoperative monitoring of patients with cancer.


Prediction of Tumor Microenvironment Characteristics and Treatment Response in Lung Squamous Cell Carcinoma by Pseudogene OR7E47P-related Immune Genes.
Pseudogenes are initially regarded as nonfunctional genomic sequences, but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities. Olfactory receptor family 7 subfamily E member 47 pseudogene (OR7E47P) is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD). This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma (LUSC). Clinical and molecular information from The Cancer Genome Atlas (TCGA) LUSC cohort was used to identify OR7E47P-related immune genes (ORIGs) by weighted gene correlation network analysis (WGCNA). Based on the ORIGs, 2 OR7E47P clusters were identified using non-negative matrix factorization (NMF) clustering, and the stability of the clustering was tested by an extreme gradient boosting classifier (XGBoost). LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model (ORPScore) for immunotherapy. The Botling cohorts and 8 immunotherapy cohorts (the Samstein, Braun, Jung, Gide, IMvigor210, Lauss, Van Allen, and Cho cohorts) were included as independent validation cohorts. OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC. A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters (Cluster 1 and Cluster 2) with distinct immune, mutation, and stromal programs. Compared to Cluster 1, Cluster 2 had more infiltration by immune and stromal cells, lower mutation rates of driver genes, and higher expression of immune-related proteins. The clustering performed well in the internal and 5 external validation cohorts. Based on the 7 ORIGs (HOPX, STX2, WFS, DUSP22, SLFN13, GGCT, and CCSER2), the ORPScore was constructed to predict the prognosis and the treatment response. In addition, the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients. The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts. Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC. ORIGs can be applied to molecularly stratify patients, and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.


Preparation of Drosophila S2 cells for light microscopy.
The ideal experimental system would be cheap and easy to maintain, amenable to a variety of techniques, and would be supported by an extensive literature and genome sequence database. Cultured Drosophila S2 cells, the product of disassociated 20-24 hour old embryos, possess all these properties. Consequently, S2 cells are extremely well-suited for the analysis of cellular processes, including the discovery of the genes encoding the molecular components of the process or mechanism of interest. The features of S2 cells that are most responsible for their utility are the ease with which they are maintained, their exquisite sensitivity to double-stranded (ds)RNA-mediated interference (RNAi), and their tractability to fluorescence microscopy as either live or fixed cells. S2 cells can be grown in a variety of media, including a number of inexpensive, commercially-available, fully-defined, serum-free media. In addition, they grow optimally and quickly at 21-24 degrees C and can be cultured in a variety of containers. Unlike mammalian cells, S2 cells do not require a regulated atmosphere, but instead do well with normal air and can even be maintained in sealed flasks. Complementing the ease of RNAi in S2 cells is the ability to readily analyze experimentally-induced phenotypes by phase or fluorescence microscopy of fixed or live cells. S2 cells grow in culture as a single monolayer but do not display contact inhibition. Instead, cells tend to grow in colonies in dense cultures. At low density, S2 cultures grown on glass or tissue culture-treated plastic are round and loosely-attached. However, the cytology of S2 cells can be greatly improved by inducing them to flatten extensively by briefly culturing them on a surface coated with the lectin, concanavalin A (ConA). S2 cells can also be stably transfected with fluorescently-tagged markers to label structures or organelles of interest in live or fixed cells. Therefore, the usual scenario for the microscopic analysis of cells is this: first, S2 cells (which can possess transgenes to express tagged markers) are treated by RNAi to eliminate a target protein(s). RNAi treatment time can be adjusted to allow for differences in protein turn-over kinetics and to minimize cell trauma/death if the target protein is important for viability. Next, the treated cells are transferred to a dish containing a coverslip pre-coated with conA to induce cells to spread and tightly adhere to the glass. Finally, cells are imaged with the researcher's choice of microscopy modes. S2 cells are particularly good for studies requiring extended visualization of live cells since these cells stay healthy at room temperature and normal atmosphere.


Comprehensive development and testing of the ASIST-GBV, a screening tool for responding to gender-based violence among women in humanitarian settings.
Conflict affected refugees and internally displaced persons (IDPs) are at increased vulnerability to gender-based violence (GBV). Health, psychosocial, and protection services have been implemented in humanitarian settings, but GBV remains under-reported and available services under-utilized. To improve access to existing GBV services and facilitate reporting, the ASIST-GBV screening tool was developed and tested for use in humanitarian settings. This process was completed in four phases: 1) systematic literature review, 2) qualitative research that included individual interviews and focus groups with GBV survivors and service providers, respectively, 3) pilot testing of the developed screening tool, and 4) 3-month implementation testing of the screening tool. Research was conducted among female refugees, aged ≥15 years in Ethiopia, and female IDPs, aged ≥18 years in Colombia. The systematic review and meta-analysis identified a range of GBV experiences and estimated a 21.4 % prevalence of sexual violence (95 % CI:14.9-28.7) among conflict-affected populations. No existing screening tools for GBV in humanitarian settings were identified. Qualitative research with GBV survivors in Ethiopia and Colombia found multiple forms of GBV experienced by refugees and IDPs that occurred during conflict, in transit, and in displaced settings. Identified forms of violence were combined into seven key items on the screening tool: threats of violence, physical violence, forced sex, sexual exploitation, forced pregnancy, forced abortion, and early or forced marriage. Cognitive testing further refined the tool. Pilot testing in both sites demonstrated preliminary feasibility where 64.8 % of participants in Ethiopia and 44.9 % of participants in Colombia were identified with recent (last 12 months) cases of GBV. Implementation testing of the screening tool, conducted as a routine service in camp/district hospitals, allowed for identification of GBV cases and referrals to services. In this phase, 50.6 % of participants in Ethiopia and 63.4 % in Colombia screened positive for recent experiences of GBV. Psychometric testing demonstrated appropriate internal consistency of the tool (Cronbach's α = 0.77) and item response theory demonstrated appropriate discrimination and difficulty of the tool. The ASIST-GBV screening tool has demonstrated utility and validity for use in confidential identification and referral of refugees and IDPs who experience GBV.


Genetic instability and divergence of clonal populations in colon cancer cells in vitro.
The accumulation of multiple chromosomal abnormalities is a characteristic of the majority of colorectal cancers and has been attributed to an underlying chromosomal instability. Genetic instability is considered to have a key role in the generation of genetic and phenotypic heterogeneity in cancer cells. To shed light on the dynamics of chromosomal instability in colon cancer cells, we have analyzed genetic divergence in clonal and subclonal derivates of chromosomally unstable (SW480) and stable (HCT116, LoVo) cell lines. Conventional G-banding karyotyping and arbitrarily primed PCR (AP-PCR) fingerprinting were used to calculate genetic distances among clones and parental cells, and to trace tree-type phylogenies among individual cells and clonal cell populations. SW480 cells showed enhanced karyotypic heterogeneity in clones as compared with parental cells. Moreover, genetic clonal divergence was also increased after two consecutive episodes of single-cell cloning, demonstrating that the homogeneity induced by the bottleneck of cloning is disrupted by genetic instability during clonal expansion and, as a consequence, heterogeneity is restored. These results demonstrate genetic drift in clonal populations originated from isolated cells. The generated cell heterogeneity coupled with selection provides the grounds for the reported feasibility of pre-neoplastic and neoplastic cells to generate new phenotypic variants with increased evolutionary potential.


[Foramen arcuale and vertigo].
From 1985 to 1989, 923 patients with cervical syndrome were treated; and among them, 69 complained chiefly of vertigo, somewhat like Barre-Lieou syndrome. Out of their X-ray films, those of the 69 patients showed foramen arcuale on the posterior arch of atlas, an incidence of 7.4%; and so it was, unilateral or bilateral, proved by operative findings. The foramen arcuale, being either a complete ring or a incomplete ring, restricted or compressed the vertebral artery passing through. Excision of the foramen arcuale and sympathectomy done on this artery released the vessel and freed the patient from symptoms up to time of the writing. Diagnostic criteria are tabulated, operative procedures described and related matters discussed in the paper. It is emphasized that the foramen arcuale must be excised completely and sympathectomy should be performed on the vertebral artery under view for cure.


[Effect of restricting the action of an amber-mutation suppressor contained in bacteriophage T4 genome].
The action of a bacteriophage suppressor can be restricted due to mutations arising in the genome of the host bacteria. Bacterial strains Escherichia coli BN and CAN were isolated in which a complete restriction of the action of phage suppressor psu+ took place. In thees strains obtained the restriction of serin-specific phage suppressors psu + a and psu + b is brought about. The action of bacteriophage suppressor su3+ containing in E. coli CAN is not abolished in this strain. The abolish of the action of glutamine-specific phage suppressor in both strains is not realized. Thus, in bacterial strains of E. coli BN and CAN the restriction of action of only definite tRNA type takes place. Mutation alterations in the bacterial strains obtained can be due to the change of 1) ribosomes, 2) aminoacyl-tRNA-synthetase, 3) suppressor tRNA. In this case the possibility of mutation alterations in the gene controlling the synthesis of suppressor tRNA is excluded, but there is a possibility of changing the tRNA molecule itself during maturation.


Enoxaparin Population Pharmacokinetics in the First Year of Life.
Enoxaparin dosing requirements in the first year of life can be highly variable. Characterization of pharmacokinetics in this patient population can assist in dosing. Patients less than 1 year postnatal age who received enoxaparin and had an anti-factor Xa activity level drawn as inpatients were identified through the pharmacy database over a 5-year period. Patients on renal replacement therapy or with hyperbilirubinemia were excluded. Data collection included demographic variables, indication for enoxaparin, enoxaparin doses, anti-factor Xa activity levels, serum creatinine, hemoglobin, hematocrit, platelet count, and urine output over the previous 24 hours. Population pharmacokinetic analysis was performed with NONMEM. A total of 182 patients [male 50%, median 100 days postnatal age (range: 4-353 days)] met the study criteria. Patients received median 22 doses (range: 1-526) at a mean starting dose of 1.38 ± 0.43 mg/kg with median 5 (range: 1-56) anti-factor Xa activity levels measured. A 1-compartment proportional and additive error model best fits the data. Allometrically scaled weight significantly decreased the objective function value, as did serum creatinine on clearance, and postmenstrual age (PMA) on volume of distribution. When evaluated graphically, dosing based on PMA appeared to have less variability as compared to postnatal age-based dosing. Dosing of enoxaparin in infants younger than 1 year should incorporate PMA.


1,3-Thiazole Derivatives as a Promising Scaffold in Medicinal Chemistry: A Recent Overview.
The thiazole ring is a unique heterocyclic motif among heterocyclic compounds. This five-member ring with one nitrogen and one sulphur atom displays a wide array of pharmacological activities, including anti-inflammatory, antimicrobial, anticancer, antidiabetic, antiviral, etc., by acting on several targets. Its broad range of medical applications has inspired us to study this opulent heterocyclic molecule. The current review summarizes synthetic approaches for the preparation of thiazole derivatives in brief and discusses the promising biological activities of this scaffold. This review will be useful to the drug discovery community and will facilitate the synthesis and development of novel and potent thiazole derivatives, which may serve as lead molecules for the treatment of various diseases.


Altered renal vascular tone and plasma renin activity due to fastigial and baroreceptor activation.
The effects of stimulating the cerebellar fastigial nucleus in altering renal vascular resistance were assessed at three levels of carotid sinus pressure (CSP). In alpha-chloralose-anesthetized, vagotomized, and salt-depleted cats, renal vascular resistance changes were established by perfusing the isolated carotid sinus at high (197 +/- 17 mmHg), medium (117 +/- 8 mmHg), and low (60 +/- 7 mmHg) pressure. The hemodynamic state of the perfused kidney was determined from flow-pressure curves. In relative units, the flow resistance in the renal bed was for low CSP, 2.60 PRU100, for medium CSP, 2.25 PRU100, and for high CSP, 1.22 PRU100. The fastigial pressor response was imposed at each flow-presure determination with or without superior cerebellar peduncle lesions. An increase in the resistance with the fastigial stimulation was noted at each of the three hemodynamic states; 14% at low, 26% at medium, and 22% at high CSP. With increased renal vascular resistance evoked through the baroreflex, there was an increase in plasma renin activity. The rise in plasma renin activity could be attributed in large part to an increase in sympathetic renal nerve activity wherein the fastigial pressor response shared a synergistic action at medium and high carotid sinus pressure. The effect of the fastigial stimulation on renal vascular resistance and renin secretion was abolished by transections of the superior cerebellar peduncles.


[The dental profession in The Netherlands before 1865].
The dental profession before 1865 has been described with the help of sources from the 19th century, in combination with prosopographical research. During this period, dentists had no exclusive rights in dentistry: other surgical professions were also involved both with its theory and practice. Their specialised colleagues comprised a group of 137 dentists, largely related to a few Jewish families. This characteristic, underlined by their intensive migration and training within the family, had been responsible for the divergent position of the dentists in Dutch medical legislature of the 19th century. While in the medical profession the organisation and structure (1865) was the first te be revised, followed by a reorganisation of education (1876); in dentistry the recruitment and education had to be reformed (1865-1876) before the building up of a new professional structure. This process speeded up by the rapid mortification of the ancient group of dentists.


Inquiries into Malaysia's socio-technical disasters: recommendations and lessons learnt.
Most democratic countries hold inquiries into disasters. One of their key functions is to establish the cause of an event and to learn lessons in order to prevent a recurrence. In addition, they offer an opportunity for communal catharsis, permitting the public to vent anger, distress and frustration and to exert pressure for policy changes. Malaysia has experienced six landmark socio-technical disasters since 1968, which resulted in the proposal or amendment of various safety/emergency acts and regulations. The authors used a grounded theory approach utilising a constant comparative method to analyse the recommendations made by the inquiries into these events. Data indicate that social and technical recommendations comprise 85 and 15 per cent, respectively, of the total recommendations made by the inquiry committees. This paper offers suggestions for improving the management of inquiry tribunals, as they will remain a valuable source of information for society and corporations to learn from past incidents.


Biological Control of Fusarium oxysporum, the Causal Agent of Fusarium Basal Rot in Onion by Bacillus spp.
Fusarium oxysporum is the main pathogen causing Fusarium basal rot in onion (Allium cepa L.), which incurs significant yield losses before and after harvest. Among management strategies, biological control is an environmentally safe and sustainable alternative to chemical control. In this study, we isolated and screened bacteria for antifungal activity against the basal rot pathogen F. oxysporum. Isolates 23-045, 23-046, 23-052, 23-055, and 23-056 significantly inhibited F. oxysporum mycelial growth and conidial germination. Isolates 23-045, 23-046, 23-052, and 23-056 suppressed the development of Fusarium basal rot in both onion seedlings and bulbs in pot and spray inoculation assays. Isolate 23-055 was effective in onion seedlings but exhibited weak inhibitory effect on onion bulbs. Based on analyses of the 16S rRNA and rpoB gene sequences together with morphological analysis, isolates 23-045, 23-046, 23-052, and 23-055 were identified as Bacillus thuringiensis, and isolate 23-056 as Bacillus toyonensis. All five bacterial isolates exhibited cellulolytic, proteolytic, and phosphate-solubilizing activity, which may contribute to their antagonistic activity against onion basal rot disease. Taken together B. thuringiensis 23-045, 23-046, 23-052, and 23-055 and B. toyonensis 23-056 have potential for the biological control of Fusarium basal rot in onion.


Implementation of an Italian multicentric care network for early HIV infection diagnosis: 1999-2001 report.
Diagnosis of a new HIV infection during the primary phase (PHI) is sometimes misleading in a primary care setting. Since 1999 the Italian network for the study of acute HIV infection (ISAI) has been operative. At the time of PHI diagnosis the case is reported to the coordinating centre and enrolled in the National Register which records all epidemiological, demographic and clinical information. From 1999 to September 2001, 51 symptomatic or asymptomatic patients with diagnosis of primary HIV infection were signalled to the coordinating centre. At screening, assessments were: interview to collect demographic and epidemiological data, clinical history (regarding PHI signs and symptoms) and, if available, relevant index case information; physical examination; routine hematology and chemistry; lymphocyte count; plasma HIV-RNA. In a subset of patients PBMC HIV-DNA, HIV-RNA, resistance genotyping and HIV subtype characterization were assessed. 74.5% of patients were males and all but four were Italian. Hetero and homosexual contacts were the prevalent route of HIV transmission. Forty-five patients (89%) were symptomatic and the most frequent signs and symptoms were: fever, lymphadenopathy, malaise and pharyngodinia. Baseline reverse-transcriptase (RT) and protease (PR) genotyping analysis was available for 29 patients. Only one of 29 patients harbored a virus with a resistance-associated mutation in the RT region (215Y); NNRTI mutations were identified in 3 of 29 patients. In the remaining 20 (69%) patients no mutations were found in the RT region. Sequence data from PR region were successfully obtained in 21 patients. Only one of these had a high-level resistance mutation (46L); in an additional 10 cases 1 or more secondary mutations were identified. The remaining 10 patients harbored a PR region wild type virus. One patient presenting two secondary mutations in the PR region, even if highly adherent and tolerant to drug regimen, showed a slow viral load decrease. Our cohort confirms the uptrend of new infections through unsafe sexual contacts involving both homosexual and heterosexual couples. Genotype sequencing for antiretroviral resistant viral variants describes a low prevalence of RT resistance-associated mutations, as well as primary mutations in the PR region. On the contrary, a higher prevalence of PR gene polymorphisms and mutations is not known with any certainty to confer resistance to NRTI and NNRTI. The identification of antiretroviral drug resistant HIV strains is strategic for clinical and therapeutical intervention, even though from a public health point of view cost-efficacy must be considered.


The Allan factor: a new model of mathematical interpretation of heart rate variability in stable coronary artery disease. Preliminary results.
The current analysis of heart rate variability (HRV) is one of the noninvasive methods of cardiovascular system assessment. The quantitative characteristics of the RR interval sequence and its dynamics are still under development as regards measurement techniques and development of new HRV interpretation models. The practical clinical application of the standard measurements is still insufficient and improvement of sensitivity and specificity of HRV parameters is needed. To assess a novel mathematical model of HRV interpretation and compare it with standard HRV measurements for patients with stable coronary artery disease (CAD), based on the virtual instrumentation technique. The study group consisted of 24 patients with CAD confirmed by coronary angiography and a control group of 15 volunteers. Short-term electrocardiographic signals were recorded by a computer system and analysed for estimation of several HRV descriptors in time, frequency and combined time-frequency domains. Calculations included standard HRV measures and the Allan factor, a parameter based on the Haar wavelet transform. None of the investigated measurements derived from power spectral analysis has shown a statistically significant difference between healthy controls and patients with CAD, with the exception of rMSSD (Wilcoxon test: supine position *p=0.0018, erect position p=0.0708; discriminant function analysis: supine position *p=0.0069, erect position p=0.7851). Compared with standard HRV variables, the Allan factor better discriminated patients with CAD from healthy subjects (Wilcoxon test: supine position *p=0.0172, erect position *p=0.0001; discriminant function analysis: supine position p=0.8962, erect position *p=0.0200). The observations related to the novel parameter based on combined time and frequency domains may provide better quantitative measurements of heart rate variability in patients with coronary artery disease and require further investigations to assess their sensitivity and specificity.


Telehealth as a Bright Spot of the COVID-19 Pandemic: Recommendations From the Virtual Frontlines ("Frontweb").
The coronavirus disease (COVID-19) pandemic has accelerated the telehealth tipping point in the practice of family medicine and primary care in the United States, making telehealth not just a novel approach to care but also a necessary one for public health safety. Social distancing requirements and stay-at-home orders have shifted patient care from face-to-face consultations in primary care offices to virtual care from clinicians' homes or offices, moving to a new frontline, which we call the "frontweb." Our telehealth workgroup employed the Clinical Transformation in Technology implementation framework to accelerate telehealth expansion and to develop a consensus document for clinician recommendations in providing remote virtual care during the pandemic. In a few weeks, telehealth went from under 5% of patient visits to almost 93%, while maintaining high levels of patient satisfaction. In this paper, we share clinician recommendations and guidance gleaned from this transition to the frontweb and offer a systematic approach for ensuring "webside" success.


Effect of acute maximal aerobic exercise upon the trace element levels in blood.
This study was carried out in order to determine the effect of acute maximal aerobic exercise on the copper and zinc levels in blood. The study was participated by 16 healthy male university students with an average age of 19.44+/-1.63. There were 5 cc blood samples taken from the participants before and after they had been subjected to aerobic loading process (20 m shuttle run). The copper and zinc levels in the blood samples were determined by the use of Anodic Stripping Voltammetry (ASV) technique. The data obtained were evaluated by simple t test and SPSS software. The results revealed the fact that the blood Zn levels of the participants increased and Cu levels decreased with statistical significant extent (p<0.01) after maximal aerobic loading. There found no correlation between the maximal aerobic power levels (Max VO2) of the participants and their resting copper and zinc blood levels. However blood zinc and Max VO2 levels of the participants were positively correlated after maximal aerobic loading. The participants were fed on a zinc and copper free diet six week prior to the program. They were also asked not to use copper and zinc containing vitamins during this period.


Effects of Selective iNOS Inhibitor on Spatial Memory in Recovered and Non-Recovered Ketamine Induced Anesthesia.
Nitric oxide (NO) is thought to be involved in spatial learning and memory in several brain areas such as hippocampus. This study examined the effects of post-training intrahippocampal microinjections of 1400W as a selective iNOS inhibitor on spatial memory, in anesthetized and non-anesthetized situations in rats. In the present work, 4-day training trials of animals were conducted. Spatial memory was tested 48 hours after the drug infusions. For microinjection of 1400W into CA1 region of the hippocampus in conscious animals, guide cannula was implanted into the CA1 area and 1400W was infused after recovery from surgical anesthesia. In anesthetized animals, 1400W was microinjected directly into CA1 region by Hamilton syringe during anesthesia. After completion of training, 1400W (10, 50 and 100 μM/side) were microinjected bilaterally (1 μL/side) and testing trials were performed 48 h after drug infusions in both groups of cannulated and non-cannulated rats. Significant reduction was observed in escape latency and traveled distance in animals that received 1400W (100 μM/side, *p < 0.05) via cannula after recovery in comparison with control group. Also, microinjection of 1400W (100 μM/side) in post recovery phase caused a significant (***p < 0.001) reduction in time and distance of finding the hidden platform in comparison with anesthetized situation. These findings suggest that 1400W has a significant improvement on spatial memory and memory enhancement induced by iNOS inhibitor can be affected by anesthesia in a period of time.


Time-dependent associations between iron and mortality in hemodialysis patients.
The independent association between the indices of iron stores or administered intravenous iron, both of which vary over time, and survival in patients who are on maintenance hemodialysis (MHD) is not clear. It was hypothesized that the observed associations between moderately high levels of three iron markers (serum ferritin, iron, and iron saturation ratio) or administered intravenous iron and all-cause and cardiovascular death is due to the time-varying confounding effect of malnutrition-inflammation-cachexia syndrome (MICS). Time-dependent Cox regression models were examined using prospectively collected data of the 2-yr (July 2001 to June 2003) historical cohort of 58,058 MHD patients from virtually all DaVita dialysis clinics in the United States. After time-dependent and multivariate adjustment for case mix, administered intravenous iron and erythropoietin doses, and available surrogates of MICS, serum ferritin levels between 200 and 1200 ng/ml (reference 100 to 199 ng/ml), serum iron levels between 60 and 120 microg/ml (reference 50 to 59 microg/ml), and iron saturation ratio between 30 and 50% (reference 45 to 50%) were associated with the lowest all-cause and cardiovascular death risks. Compared with those who did not receive intravenous iron, administered intravenous iron up to 400 mg/mo was associated with improved survival, whereas doses >400 mg/mo tended to be associated with higher death rates. The association between serum ferritin levels >800 ng/ml and mortality in MHD patients seems to be due mostly to the confounding effects of MICS. For ascertaining whether the observed associations between moderate doses of administered intravenous iron and improved survival are causal or due to selection bias by indication, clinical trials are warranted.


Continuous measurement of vascular diameters via television microscopy.
In the past 10 years, microcirculation studies have emphasized quantitative measurements of microvascular diameters to characterize in vivo small vessel responses to experimental forcings such as hemorrhage, anesthesia, and hypoxia. We have developed an instrument to obtain continuous diameter measurements of a small artery and vein (40-200 mu) via closed-circuit television microscopy. The outputs are analog voltages proportional to the vessel diameters. Video processing is limited to two image areas termed "windows," which are defined by markers on the monitor and positioned over separate vertically aligned vessels. Each vessel, which appears darker than the surrounding tissue, is located by comparing the video signal to a reference voltage that adapts to changes in the relative contrast within the window. In the presence of a vessel, a ramp voltage is generated, the peak value of which is proportional to the vessel diameter. These peaks are averaged over the 15-video lines of the window and over several video frames to reduce noise sensitivity. In order to accommodate preparation movement such as skeletal muscle contraction, window position and width automatically adapt to changes in vessel position and width. Visual verification of system performance is provided by clamping the video signal to white on that portion of the image which the instrument identifies as vessel.


Involvement of Streptococcus gordonii beta-glucoside metabolism systems in adhesion, biofilm formation, and in vivo gene expression.
Streptococcus gordonii genes involved in beta-glucoside metabolism are induced in vivo on infected heart valves during experimental endocarditis and in vitro during biofilm formation on saliva-coated hydroxyapatite (sHA). To determine the roles of beta-glucoside metabolism systems in biofilm formation, the loci of these induced genes were analyzed. To confirm the function of genes in each locus, strains were constructed with gene inactivation, deletion, and/or reporter gene fusions. Four novel systems responsible for beta-glucoside metabolism were identified, including three phosphoenolpyruvate-dependent phosphotransferase systems (PTS) and a binding protein-dependent sugar uptake system for metabolizing multiple sugars, including beta-glucosides. Utilization of arbutin and esculin, aryl-beta-glucosides, was defective in some mutants. Esculin and oligochitosaccharides induced genes in one of the three beta-glucoside metabolism PTS and in four other genetic loci. Mutation of genes in any of the four systems affected in vitro adhesion to sHA, biofilm formation on plastic surfaces, and/or growth rate in liquid medium. Therefore, genes associated with beta-glucoside metabolism may regulate S. gordonii in vitro adhesion, biofilm formation, growth, and in vivo colonization.


[Active oxygen in the treatment of (root) caries and its suitability for frail older people].
In 2000 it was suggested that there was a new, fast and simple way to treat dental caries based on the outcomes of an in vitro study of the antimicrobial effect of ozone, a form of active oxygen, on caries lesions in dental roots. The aim of the review of literature described in this article was to determine the effectiveness of active oxygen in the treatment of dental (root) caries as demonstrated by in vivo research of frail older people'. From the results it became clear that the quality of the various trials is not very high and that there is, at least at the present time, an insufficient solid scientific evidence base that the use of ozone is an effective treatment for dental (root) caries. It is, however, still too early to conclude that active oxygen, in whatever form, cannot contribute positively to the fight against caries.


Synthesis and spectroscopic properties of (N/O) mono- and dispirocyclotriphosphazene derivatives with benzyl pendant arms: study of biological activity.
The Cl replacement reactions of hexachlorocyclotriphosphazene (trimer; N 3 P 3 Cl 6 ) with sodium (N-benzyl)- aminopropanoxides (1 and 2) produced monospiro- (3 and 4), cis-, and trans-dispirocyclotriphosphazenes (13-16). The monospiro tetrakis-aminocyclotriphosphazenes (5-12) were obtained by the Cl substitutions of 3 and 4 with different secondary amines. The cis- (13 and 14) and trans-dispirophosphazenes (15 and 16) possessed 2 chiral P centers, and they were able to present meso and racemic forms, respectively. Moreover, the structures of compounds 5 and 14 were designated using X-ray data. The absolute configuration of compound 14 was found as SR in the solid state. Analytical and spectroscopic data of the phosphazenes were consistent with their suggested structures. Antimicrobial activities of the benzyl-pendant-armed cyclotriphosphazenes were scrutinized against G(+) and G(-) bacteria and yeast strains. The bacterium most affected by the synthesized compounds was Pseudomonas aeruginosa . Minimum inhibitory concentrations and minimal bacterial concentrations were in the range of 125-500 μM. Interactions between the phosphazenes (3-12 and 15) and plasmid DNA were studied with agarose gel electrophoresis. The phosphazene- DNA interaction studies of the cyclotriphosphazenes revealed that phosphazenes 3, 4, and 15 had a substantial effect on supercoiled DNA by cleavage of the double helix.


Complex Posttraumatic Stress Disorder and a Biopsychosocial Model of Borderline Personality Disorder.
This review offers a critique of recent attempts to reconceptualize some cases of borderline personality disorder (BPD) within the newer diagnosis of complex posttraumatic stress disorder (CPTSD). The CPTSD construct focuses on the role of childhood trauma in shaping relational problems in adulthood, difficulties that have been previously seen as features of a personality disorder. The CPTSD model fails to consider the role of heritable personality traits, as well as a broader range of psychosocial risk factors. This review proposes that a biopsychosocial model of BPD is more comprehensive, taking into account a wider range of risk factors, while viewing BPD as rooted in gene-environment interactions. In this model, heritable traits are amplified by an adverse psychosocial environment. One can acknowledge the role of trauma as a risk factor without assuming that it fully accounts for the development of personality pathology.


School-milk intervention trial enhances growth and bone mineral accretion in Chinese girls aged 10-12 years in Beijing.
A 2-year milk intervention trial was carried out with 757 girls, aged 10 years, from nine primary schools in Beijing (April 1999 - March 2001). Schools were randomised into three groups: group 1, 238 girls consumed a carton of 330 ml milk fortified with Ca on school days over the study period; group 2, 260 girls received the same quantity of milk additionally fortified with 5 or 8 microg cholecalciferol; group 3, 259 control girls. Anthropometric and bone mineralisation measurements, as well as dietary, health and physical-activity data, were collected at baseline and after 12 and 24 months of the trial. Over the 2-year period the consumption of this milk, with or without added cholecalciferol, led to significant increases in the changes in height (> or =0.6 %), sitting height (> or =0.8 %), body weight (> or 2.9 %), and (size-adjusted) total-body bone mineral content (> or =1.2 %) and bone mineral density (> or =3.2 %). Those subjects receiving additional cholecalciferol compared with those receiving the milk without added 25-hydoxycholecalciferol had significantly greater increases in the change in (size-adjusted) total-body bone mineral content (2.4 v. 1.2 %) and bone mineral density (5.5 v. 3.2 %). The milk fortified with cholecalciferol significantly improved vitamin D status at the end of the trial compared with the milk alone or control groups. It is concluded that an increase in milk consumption, e.g. by means of school milk programmes, would improve bone growth during adolescence, particularly when Ca intake and vitamin D status are low.


[Preventive use of diltiazem to suppress supraventricular tachyarrhythmia in the patients after esophagectomy].
We investigated the efficacy of preventive use of diltiazem to suppress supraventricular tachyarrhythmia such as paroxysmal atrial tachycardia (PAT) and atrial fibrillation (Af) in the patients who underwent transthoracic esophagectomy. We divided 52 patients into 2 groups; the diltiazem group (n = 26) and the control group (n = 26). In the diltiazem group continuous intravenous infusion of diltiazem (1-3mcg.kg-1.min-1) was started when the patient's heart rate remained over 110.min-1 without any predisposing factor. On the other hand, in the control group we did not use it preventively. In both groups, we did not restrict the use of antiarrhythmic agents if necessary. We recognized PAT or Af in the control group (54%) more often than in the diltiazem group (19%). PAT or Af seldom occurred after the 4th post-operative day in the both groups. Serum diltiazem concentrations of 9 patients after about 10 hours infusion showed great variation (between 30 and 250 ng.ml-1). In 7 of them the diltiazem concentration increased as the duration of infusion was prolonged. However, we did not observe bradyarrhythmia. We consider that the continuous diltiazem infusion is effective in suppressing supraventricular tachyarrhythmia after esophagectomy.


Differences in patient perceptions of integrated care among black, hispanic, and white Medicare beneficiaries.
This study sought to identify potential disparities among racial/ethnic groups in patient perceptions of integrated care (PPIC) and to explore how methodological differences may influence measured disparities. Data from Medicare beneficiaries who completed the 2015 Medicare Current Beneficiary Survey (MCBS) and were enrolled in Part A benefits for an entire year. We used 4-point measures of eight dimensions of PPIC and assessed differences in dimensions among racial/ethnic groups. To estimate differences, we applied a "rank and replace" method using multiple regression models in three steps, balancing differences in health status among racial groups and adjusting for differences in socioeconomic status. We reran all analyses with additional SES controls and using standard multiple variable regression. Not applicable. We found several significant differences in perceived integrated care between Black versus White (three of eight measures) and Hispanic versus White (one of eight) Medicare beneficiaries. On average, Black beneficiaries perceived more integrated support for self-care than did White beneficiaries (mean difference = 0.14, SE = 0.06, P =.02). Black beneficiaries perceived more integrated specialists' knowledge of past medical history than did White beneficiaries (mean difference = 0.12, SE = 0.06, P =.01). Black and Hispanic beneficiaries also each reported, on average, 0.18 more integrated medication and home health management than did White beneficiaries (P <.01 and P <.01). These findings were robust to sensitivity analyses and model specifications. There exist some aspects of care for which Black and Hispanic beneficiaries may perceive greater integrated care than non-Hispanic White beneficiaries. Further studies should test theories explaining why racial/ethnic groups perceive differences in integrated care.


Causal Attribution and Coping Maxims Differences between Immigrants and Non-Immigrants Suffering from Back Pain in Switzerland.
This study aimed at investigating the relationship between causal attributions and coping maxims in people suffering from back pain. Further, it aimed at identifying in how far causal attributions and related coping maxims would defer between immigrants and non-immigrants in Switzerland. Data for this study came from a larger survey study that was conducted among immigrant populations in the German- and Italian-speaking part of Switzerland. Included in the analyses were native Swiss participants, as well as Albanian- and Serbian-speaking immigrants, who had indicated to have suffered from back pain within the last 12 months prior to the study. Data was analyzed for overall 495 participants. Items for causal attributions and coping maxims were subject to factor analyses. Cultural differences were assessed with ANOVA and regression analyses. Interaction terms were included to investigate whether the relationship between causal attributions and coping maxims would differ with cultural affiliation. For both immigrant groups the physician's influence on the course of their back pain was more important than for Swiss participants (p <.05). With regard to coping, both immigrant groups were more likely to agree with maxims that were related to the improvement of the back pain, as well as the acceptance of the current situation (p <.05). The only consistent interaction effect that was found indicated that being Albanian-speaking negatively moderated the relationship between physical activity as an attributed cause of back pain and all three identified coping maxims. The study shows that differences in causal attribution and coping maxims between immigrants and non-immigrants exist. Further, the results support the assumption of an association between causal attribution and coping maxims. However cultural affiliation did not considerably moderate this relationship.


Effect of pressure on molecular and ionic motions in ultraviscous acetaminophen-aspirin mixture.
Effect of pressure and temperature on molecular motions and dc conductivity in ultraviscous, 50 wt% acetaminophen-aspirin melt has been studied by dielectric relaxation spectroscopy. The spectra obtained over the pressure range, 5-300 MPa and temperature range, 295-320 K show a distribution of relaxation times greater than found in pure acetaminophen. The equilibrium dielectric permittivity and relaxation time, tau, of the melt increase with increase in pressure and decrease in temperature and the dc conductivity, sigma(dc), decreases. The pressure and temperature variation of the limiting high frequency permittivity shows significant contribution from infrared polarization. The volumes of activation for sigma(dc) and tau vary with both the pressure and temperature, indicating that there is also a structural effect that determine sigma(dc). This effect would add a non-linear term to the Debye-Stokes-Einstein equation for variation of sigma(dc) with tau. The ultraviscous liquid remains stable with time, and with change in temperature and pressure, suggesting that a more stable glassy state of a pharmaceutical may be obtained by mixing a second component.


Cross-species utility of microsatellite markers in trichostrongyloid nematodes.
The development of microsatellite markers for parasitic nematodes has been hampered by technical difficulties in isolation and PCR amplification. We have investigated the potential for circumventing these problems using microsatellites from 3 trichostrongyloid species on a panel of 7 species. Ten of the 22 PCR primer pairs tested amplified in species other than the target species, usually in closely related species, and 2 new variable loci were discovered in the sheep parasite Trichostrongylus vitrinus. This study provides evidence that cross-species testing of microsatellite primers can be an effective alternative to isolation de novo.


Emil Godlewski, Jr. (1875-1944) pioneer of embryology at the Jagiellonian University of Krakow (Poland).
Emil Godlewski, Jr. (1875-1944) lived and worked in Krakow. He graduated from the Faculty of Medicine of the Jagiellonian University with the title of Doctor of Medical Science. He worked at the Faculty of Medicine, first in the Institute of Descriptive Anatomy and later as Professor of Biology and Embryology in the Department of Biology and Embryology, which he founded and led for many years. After early research on the development and histogenesis of muscles, professor Godlewski's scientific interests focused on regeneration and mechanisms regulating the process of fertilization, as well as early embryo development, blastulation and gastrulation. He was also interested in the origin of the primary differentiating cells in regenerates. He postulated the importance of epithelial tissue in this process and was the first to point out the change in the function, organization and role of the cells under the influence of external stimuli. Investigating fertilization and early development, he focused on the cooperation between the nucleus and the cytoplasm in the regulation of the early stages of development. Godlewski was also the author of the theory of migration of the inherited substances from the nucleus to the cytoplasm and, after their processing, from the cytoplasm to the nucleus. His works were never fragmentary, but always synthetical attempts at explaining important issues relating to the mechanisms of development. In 1936 Professor Godlewski was awarded the title of Member of the Pontifica Accademia delle Scienze. Apart from doing research and teaching, Emil Godlewski devoted a lot of time to social issues, especially those connected to medicine. When Poland regained independence after World War I, he actively participated in the reopening of the Jagiellonian University.


A Computational Framework to Identify Metabolic Engineering Strategies for the Co-Production of Metabolites.
Microbial production of chemicals is a more sustainable alternative to traditional chemical processes. However, the shift to bioprocess is usually accompanied by a drop in economic feasibility. Co-production of more than one chemical can improve the economy of bioprocesses, enhance carbon utilization and also ensure better exploitation of resources. While a number of tools exist for in silico metabolic engineering, there is a dearth of computational tools that can co-optimize the production of multiple metabolites. In this work, we propose co-FSEOF (co-production using Flux Scanning based on Enforced Objective Flux), an algorithm designed to identify intervention strategies to co-optimize the production of a set of metabolites. Co-FSEOF can be used to identify all pairs of products that can be co-optimized with ease using a single intervention. Beyond this, it can also identify higher-order intervention strategies for a given set of metabolites. We have employed this tool on the genome-scale metabolic models of Escherichia coli and Saccharomyces cerevisiae, and identified intervention targets that can co-optimize the production of pairs of metabolites under both aerobic and anaerobic conditions. Anaerobic conditions were found to support the co-production of a higher number of metabolites when compared to aerobic conditions in both organisms. The proposed computational framework will enhance the ease of study of metabolite co-production and thereby aid the design of better bioprocesses.


Biomarkers in ACS and heart failure: should men and women be interpreted differently?
Sex-based differences exist in the circulating concentrations of certain novel and established biomarkers in patients with acute coronary syndromes (ACS) and heart failure (HF). However, to date, few studies have compared the diagnostic and prognostic utility of these markers in men vs women. This mini-review contains a discussion of the published reports of studies that have explored whether differences in biomarker concentrations exist between men and women with ACS or HF. It also examines those studies that have compared the utility of biomarkers for diagnosis or risk stratification in women vs men. Because biomarkers are often used to make therapeutic and triage decisions in patient care, the potential clinical implications for any observed differences in biomarker reference limits for men and women is discussed. Although the concentration distributions may differ between men and women for certain biomarkers in clinical use, the clinical implications of these observations remain unclear. Because elements of the pathophysiology of ACS and HF may differ between the sexes, further research is needed to better evaluate the diagnostic and prognostic utility of biomarkers in men vs women.


Separation of Na-Ca exchange and transient inward currents in heart cells.
Enzymatically dispersed single cells from rabbit ventricle were voltage clamped using the suction pipette method to investigate whether in isolated cardiac cells a recently described slow inward current (IEX) due to the electrogenic Na+-dependent Ca2+ extrusion also underlies a transient inward current (ITI), which can trigger certain cardiac arrhythmias. The cells were held at -40 mV to inactivate the fast sodium current. After depolarizing pulses (to 0 or +10 mV for 50 to 200 ms), slow inward "tail" currents were consistently recorded. Previous results indicate that this tail current IEX is generated by the Na+-Ca2+ exchanger. After loading the cells with Ca2+ by blocking the Na+-K+ pump [either with strophanthidin (10(-5) M) treatment or by reducing external K+ to 1 mM or less], ITIS appeared. These were usually spontaneous but occasionally were time locked to the clamp pulses. It was possible to separate IEX and ITI by a variety of methods. These include the following. 1) Different stimulation protocols; repolarizing to more negative potentials augmented IEX and decreased or eliminated ITI. Increasing the rate of stimulation diminished IEX and increased ITI. 2) Pharmacological methods; adding BaCl2 (0.5-2.0 mM) or caffeine (5-10 mM) decreased IEX but abolished ITI. The findings suggest that different mechanisms regulate these two currents.


Systematic Comparison of Plant Promoters in Nicotiana spp. Expression Systems.
We report a systematic comparison of 19 plant promoters and 20 promoter-terminator combinations in two expression systems: agroinfiltration in Nicotiana benthamiana leaves, and Nicotiana tabacum BY-2 plant cell packs. The set of promoters tested comprised those not present in previously published work, including several computationally predicted synthetic promoters validated here for the first time. The expression of EGFP driven by different promoters varied by more than two orders of magnitude and was largely consistent between two tested Nicotiana systems. We confirmed previous reports of significant modulation of expression by terminators, as well as synergistic effects of promoters and terminators. Additionally, we observed non-linear effects of gene dosage on expression level. The dataset presented here can inform the design of genetic constructs for plant engineering and transient expression assays.


Context-dependent expression of a conditionally-inducible form of active Akt.
Akt kinases are key signaling components in proliferation-competent and post-mitotic cells. Here, we sought to create a conditionally-inducible form of active Akt for both in vitro and in vivo applications. We fused a ligand-responsive Destabilizing Domain (DD) derived from E. coli dihydrofolate reductase to a constitutively active mutant form of Akt1, Akt(E40K). Prior work indicated that such fusion proteins may be stabilized and induced by a ligand, the antibiotic Trimethoprim (TMP). We observed dose-dependent, reversible induction of both total and phosphorylated/active DD-Akt(E40K) by TMP across several cellular backgrounds in culture, including neurons. Phosphorylation of FoxO4, an Akt substrate, was significantly elevated after DD-Akt(E40K) induction, indicating the induced protein was functionally active. The induced Akt(E40K) protected cells from apoptosis evoked by serum deprivation and was neuroprotective in two cellular models of Parkinson's disease (6-OHDA and MPP+ exposure). There was no significant protection without induction. We also evaluated Akt(E40K) induction by TMP in mouse substantia nigra and striatum after neuronal delivery via an AAV1 adeno-associated viral vector. While there was significant induction in striatum, there was no apparent induction in substantia nigra. To explore the possible basis for this difference, we examined DD-Akt(E40K) induction in cultured ventral midbrain neurons. Both dopaminergic and non-dopaminergic neurons in the cultures showed DD-Akt(E40K) induction after TMP treatment. However, basal DD-Akt(E40K) expression was 3-fold higher for dopaminergic neurons, resulting in a significantly lower induction by TMP in this population. Such findings suggest that dopaminergic neurons may be relatively inefficient in protein degradation, a property that could relate to their lack of apparent DD-Akt(E40K) induction in vivo and to their selective vulnerability in Parkinson's disease. In summary, we generated an inducible, biologically active form of Akt. The degree of inducibility appears to reflect cellular context that will inform the most appropriate applications for this and related reagents.


[Effect of different levels of carbonic acid on glutamate dehydrogenase activity].
The initial rate of direct and reverse reactions catalyzed by crystalline NAD(P)+-dependent glutamate dehydrogenase from bovine liver as well as Km, V and some other kinetic parameters were studied as affected by carbonic acid in different concentrations (0, 10, 20, 40, 60 mM) at p Hof the incubation media 6.4-9.1. It is shown that the dependence of the initial rate on pH both of the direct and reverse reactions varies with the carbonic acid concentration. In the pH alkaline range the glutamate dehydrogenase activity is inhibited in the presence of a mixture of HCO3 and pCO2 (soluble carbonic acid) and in the acid range pH it has a tendency to increase. The pKb value lowers by an order and the pKa value remains practically unchanged. The interaction of pCO2 with E-amino group of the lysin residue in the enzyme molecule accompanied by formation of carbamate is supposed to be possible. The bicarbonate ion may also affect the enzyme.


Association SOD2 and PON1 Gene Polymorphisms with Polycystic Ovary Syndrome in Saudi Women.
Polycystic ovary syndrome (PCOS) is a considered one of the most common female disorders associated with reproductive, metabolic, and psychological problems. The etiology of PCOS is still not yet disclosed; however, evidence for a genetic basis has been reported. In this study, we investigate the associations between superoxide dismutase 2 (SOD2) (rs4880) and paraoxonase 1 (PON1) (rs705379) polymorphisms in PCOS in Saudi women. The study included 99 females with PCOS and 98 healthy women as a control. Single nucleotide polymorphisms (SNPs) of promoter regions were determined using TaqMan genotyping assays. Regarding the polymorphism at SOD2 (rs4880), the CC, CT, and TT genotypes were present at rates of 32, 61, and 7% in PCOS patients, and 47, 43, and 10% in controls, respectively. The frequency of the CT genotype in PCOS patients (0.61) was significantly higher than in controls (0.43) (OR = 2.05, CI: 1.16-3.61; p = 0.015). The wild homozygous genotype (CC) with the phenotype alanine appears to confer protection against the disease compared to molecules sharing at least one valine (genotypes, CT + TT). Regarding the polymorphism at PON1 (rs705379), the rates of CC, CT, and TT genotypes were 34, 50, and 16% in PCOS patients and 33, 63, and 2% in controls, respectively. The rate of the TT genotype in PCOS patients was significantly higher than that in controls (p = 0.0058). SOD2 and PON1 polymorphisms may be genetic factors that affect the occurrence of PCOS in Saudi females.


Detection of retroperitoneal hemorrhage by transesophageal echocardiography during cardiac surgery.
To present a case of massive retroperitoneal hemorrhage during cardiopulmonary bypass (CPB) which was detected using transesophageal echocardiography (TEE). A 50-yr-old man suffering from severe mitral regurgitation (MR) was admitted for mitral valvuloplasty. After the beginning of CPB, the volume in the reservoir was noticed to be gradually decreasing. Although venous cannulation had been properly performed, TEE showed an echo free space around the liver, the spleen and in front of the abdominal aorta showed intraabdominal hemorrhage. After cardiac surgery, emergency laparotomy revealed about 5,000 ml of blood in the retroperitoneal space probably as a result of femoral artery cannulation prior to CPB. Hemostasis was achieved, and the patient made complete cardiac and neurological recovery. Retrospective review of the TEE imaging revealed that the kidneys were surrounded by blood bilaterally confirming the diagnosis of retroperitoneal hemorrhage. Retroperitoneal hemorrhage during CPB is rare, but may be lethal. Transesophageal echocardiography is a useful monitor not only to evaluate cardiac performance, but also to detect unexpected intraabdominal bleeding during cardiac surgery.


A topological semimetal Li2CrN2 sheet as a promising hydrogen storage material.
An ideal electrode for electrochemical storage of hydrogen needs to be conductive for electrons. The robust conductivity protected by topology in topological quantum materials just meets this requirement. However, such a study is still lacking so far. Herein, for the first time, we explore the performance of hydrogen storage in a topological quantum material Li2CrN2 sheet, and have found that the interaction between H2 and the sheet is mainly attributed to the polarization mechanism, resulting in a gravimetric capacity of 4.77% that is higher than the value of the Li decorated MoS2 (4.4%), Li-decorated phosphorene (4.4%) and Li substituted BHNH sheet (3.16%). The hydrogen adsorption energy is found to be in the range of 0.16-0.33 eV, which is in the required energy window for balancing the adsorption stability and fast kinetics, and the releasing temperature is in the range of 160-270 K, desirable for practical operations. This study is of significance for fuel cell applications going beyond the conventional materials for hydrogen storage.


Postoperative radiotherapy for non-small cell lung cancer.
The role of postoperative radiotherapy in the treatment of patients with completely resected non-small cell lung cancer was not clear. A systematic review and quantitative meta-analysis was therfore undertaken to evaluate the available evidence from randomised trials. To evaluate the effect of post-operative radiotherapy (PORT) on survival and recurrence in patients with completely resected non-small cell lung cancer. To investigate whether or not pre-defined patient sub-groups benefit more or less from PORT. MEDLINE and CANCERLIT searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists and organisations. Both published and unpublished trials were eligible for inclusion provided the patients had undergone a complete resection; had been randomised between radiotherapy and no immediate further treatment; that the method of randomisation precluded prior knowledge of the treatment to be assigned; and that recruitment was between 1965 and 1995. A quantitative meta-analysis using updated information from individual patients from all available randomised trials was carried out. Data from all patients randomised in all eligible trials were sought directly from those responsible. Updated information on survival, recurrence and date of last follow up were obtained, as were details of treatment allocated, date of randomisation, age, sex, histological cell type, stage and performance status. To avoid potential bias, information was requested for all randomised patients including those who had been excluded from the investigators' original analyses. All analyses were done on intention to treat on the endpoints of survival and recurrence-free survival. Subgroup analyses by age, sex, histological cell type, tumour stage and performance status were also done. 2128 patients from 9 trials were included (median follow-up of 3.9 years). The results show a significant adverse effect of PORT on survival with a hazard ratio of 1.21 or 21% relative increase in the risk of death. This is equivalent to an absolute detriment of 7% at 2 years (95% confidence interval 3 to 11%) reducing overall survival from 55% to 48%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0-N1 disease, whereas for stage III, N2 patients there was no clear evidence of an adverse effect. PORT is detrimental to patients with early stage completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. The role of PORT in the treatment of N2 tumours is not clear and may justify further research.


The cellular and molecular basis of peripheral nerve regeneration.
Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regenerations may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.


Safety and tolerability of intermittent androgen deprivation therapy: a literature review.
Androgen deprivation therapy is commonly used in men with advanced prostate cancer; however, it is associated with many short- and long-term side-effects. Intermittent androgen deprivation therapy was first suggested as an alternative regimen in the early 1990s and is now part of treatment guidelines as a result of its ability to reduce adverse events associated with continuous androgen deprivation therapy without decreasing its efficacy. Although many publications evaluated intermittent androgen deprivation therapy's efficacy, the safety and tolerability information of this regimen is relatively limited. The goal of this literature review was to analyze clinical trials that have reported safety and tolerability data in prostate cancer patients treated with intermittent androgen deprivation therapy, as well as assessing quality of life outcomes. A literature search was carried out using biomedical and pharmaceutical databases for published information comparing intermittent androgen deprivation therapy with continuous androgen deprivation therapy. A total of 13 randomized and non-randomized studies were selected and reviewed based on their relevance to the safety, tolerability and quality of life of intermittent androgen deprivation therapy. Benefits for intermittent androgen deprivation therapy were observed for the short-term side-effects (hot flushes and sexual functions) mainly during the off-treatment phase, whereas the data for the long-term side-effects were not as conclusive. Quality of life evaluations are more in support of intermittent androgen deprivation therapy. Although there are some safety, tolerability and quality of life benefits associated with intermittent androgen deprivation therapy, the overall evidence is still limited.


A QTL located on chromosome 4A associated with dormancy in white- and red-grained wheats of diverse origin.
Improved resistance to preharvest sprouting in modern bread wheat (Triticum aestivum. L.) can be achieved via the introgression of grain dormancy and would reduce both the incidence and severity of damage due to unfavourable weather at harvest. The dormancy phenotype is strongly influenced by environmental factors making selection difficult and time consuming and this trait an obvious candidate for marker assisted selection. A highly significant Quantitative Trait Locus (QTL) associated with grain dormancy and located on chromosome 4A was identified in three bread wheat genotypes, two white- and one red-grained, of diverse origin. Flanking SSR markers on either side of the putative dormancy gene were identified and validated in an additional population involving one of the dormant genotypes. Genotypes containing the 4A QTL varied in dormancy phenotype from dormant to intermediate dormant. Based on a comparison between dormant red- and white-grained genotypes, together with a white-grained mutant derived from the red-grained genotype, it is concluded that the 4A QTL is a critical component of dormancy; associated with at least an intermediate dormancy on its own and a dormant phenotype when combined with the R gene in the red-grained genotype and as yet unidentified gene(s) in the white-grained genotypes. These additional genes appeared to be different in AUS1408 and SW95-50213.


Oral hairy leukoplakia. A distinctive marker of human T-cell lymphotropic virus type III (HTLV-III) infection.
Oral hairy leukoplakia (HL) is a newly described lesion occurring principally on the lateral borders of the tongue in immunosuppressed homosexual men infected with human T-cell lymphotropic virus type III (HTLV-III). Clinically, HL appears as a slightly raised, poorly demarcated lesion with a corrugated or "hairy" surface. Histologically, the lesion is characterized by keratin projections on the surface (which often resemble hairs), parakeratosis, and acanthosis. In addition, large pale-staining cells with pyknotic nuclei are seen in the upper stratum malpighii, which appear similar to the koilocytes described in uterine condylomata. Candida organisms are frequently observed on the lesion surface. Little, if any, subepithelial inflammation is present. Human papillomavirus and Epstein-Barr virus have been identified in biopsy specimens from lesions of oral HL. The association of this lesion in patients with HTLV-III infection has been established. We saw a patient with HTLV-III infection and HL, in whom the immunochemical and ultrastructural findings revealed the presence of a mixed viral infection. Because oral HL may be of diagnostic value as an early indicator of HTLV-III infection, awareness of its characteristic clinical, histologic, immunochemical, and ultrastructural features is important.


Huntington's disease presenting as amyotrophic lateral sclerosis.
We present the clinical, electrophysiological and molecular genetic findings of a 58-year-old male with genetically confirmed Huntington's disease (HD) and concurrent clinically definite ALS by El Escorial criteria. The patient presented with asymmetric upper limb amyotrophy and weakness, and subsequently developed chorea and cognitive change. Genetic testing confirmed the presence of expanded trinucleotide repeats in huntingtin, consistent with a diagnosis of Huntington's disease. This case confirms the rare coexistence of Huntington's disease and motor neuron degeneration.


Initiation of antidepressant therapy: do patients follow the GP's prescription?
The question whether patients actually start drug taking after having received a first antidepressant prescription is often overlooked. To determine the incidence of patients who do not fill or fill only a single antidepressant prescription at the pharmacy, and to identify associated patient characteristics. Retrospective study linking a general practice to a pharmacy dispensing database. General practice in the Netherlands. patients who received a first-time antidepressant prescription from a GP. Three patient groups were identified: patients who did not fill the prescription (non-fillers); patients who filled only a single prescription (single Rx-fillers); and patients who filled at least two consecutive prescriptions. Non-fillers and single Rx-fillers were combined into a group of decliners. Of all 965 patients, 41 (4.2%) did not fill the prescription, and 229 (23.7%) filled only a single prescription. Patients who consulted their GP for a non-specific indication, rather than for depression, anxiety, panic, or obsessive-compulsive disorder, were almost three times more likely (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.8 to 3.9) to decline treatment. Further, the risk of declining was almost fivefold higher (OR = 4.8, 95% CI = 2.1 to 11.3) in non-Western immigrants, and almost twofold higher (OR = 1.8, 95% CI = 1.2 to 2.8) in patients >60 years of age. Over one in four patients who receive a first-time antidepressant prescription decline treatment; they either do not initiate drug taking or do not persist with antidepressant use for longer than 2 weeks.


Effects of intravenous low-dose dopamine infusion on glucose regulation during prolonged aerobic exercise.
The carotid body chemoreceptors are activated during hypoglycemia and contribute to glucoregulation during prolonged exercise in dogs. Low-dose intravenous infusions of dopamine have been shown to blunt the activation of the carotid body chemoreceptors during hypoxia. Therefore, we tested the hypotheses that dopamine would blunt glucoregulatory responses and attenuate plasma glucose during prolonged aerobic exercise in healthy participants. Twelve healthy participants completed two randomized exercise sessions at 65% peak oxygen consumption for up to 120 min. Saline was infused during one exercise session, and dopamine (2 μg·kg-1·min-1) was infused during the other session. Arterial plasma glucose, growth hormone, glucagon, cortisol, norepinephrine, and epinephrine were measured every 10 min. Exercise duration during dopamine infusion was 107 ± 6 and 119 ± 0.8 min during saline infusion. Glucose area under the curve during exercise was lower during dopamine (9,821 ± 686 vs. 11,194 ± 395 arbitrary units; P = 0.016). The ratio of circulating growth hormone to glucose and the ratio of glucagon to glucose were greater during dopamine ( P = 0.045 and 0.037, respectively). These results indicate that the infusion of dopamine during aerobic exercise impairs glucoregulation. This suggests that the carotid body chemoreceptors contribute to glucoregulation during prolonged exercise in healthy exercise-trained humans.


Epilepsy in children with cerebral palsy.
To describe the prevalence and characteristics of epilepsy in patients with cerebral palsy in a tertiary center. a total of 100 consecutive patients with cerebral palsy were retrospectively studied. Criteria for inclusion were follow-up period for at least 2 years. Types and incidence of epilepsy were correlated with the different forms of cerebral palsy. Other factors associated with epilepsy such as age of first seizure, neonatal seizures and family history of epilepsy were also analysed. follow-up ranged between 24 and 151 months (mean 57 months). The overall prevalence of epilepsy was 62%. Incidence of epilepsy was predominant in patients with hemiplegic and tetraplegic palsies: 70.6% and 66.1%, respectively. First seizure occurred during the first year of life in 74.2% of patients with epilepsy. Generalized and partial were the predominant types of epilepsy (61.3% and 27.4%, respectively). Thirty-three (53.2%) of 62 patients were seizure free for at least 1 year. Neonatal seizures and family history of epilepsy were associated with a higher incidence of epilepsy. epilepsy in cerebral palsy can be predicted if seizures occur in the first year of life, in neonatal period and if there is family history of epilepsy.


Competing Gap Opening Mechanisms of Monolayer Graphene and Graphene Nanoribbons on Strong Topological Insulators.
Graphene is a promising material for designing next-generation electronic and valleytronic devices, which often demand the opening of a bandgap in the otherwise gapless pristine graphene. To date, several conceptually different mechanisms have been extensively exploited to induce bandgaps in graphene, including spin-orbit coupling and inversion symmetry breaking for monolayer graphene, and quantum confinement for graphene nanoribbons (GNRs). Here, we present a multiscale study of the competing gap opening mechanisms in a graphene overlayer and GNRs proximity-coupled to topological insulators (TIs). We obtain sizable graphene bandgaps even without inversion symmetry breaking and identify the Kekulé lattice distortions caused by the TI substrates to be the dominant gap opening mechanism. Furthermore, Kekulé distorted armchair GNRs display intriguing nonmonotonous gap dependence on the nanoribbon width, resulting from the coexistence of quantum confinement, edge passivation, and Kekulé distortions. The present study offers viable new approaches for tunable bandgap engineering in graphene and GNRs.


Introducing women's health in the higher education curriculum: An innovative experience in advancing women's health.
This article was migrated. The article was marked as recommended. Women go through several stages and changes throughout their life time. Hence, their health needs differ according to their life stage. More importantly, women are perceived as the decision-makers for the source of health care for their families. The object of this project is to integrate women's health into higher education curriculum with the aim of empowering women with the knowledge they need to take control of their own health through making informed health decisions, and to seek appropriate and timely care and managing the processes of illness and wellness. I designed an undergraduate course in women's health that addresses the main health issues across the life span of women from local and global perspectives.I developed a stepwise process, or framework, for including women's health course in the undergraduate curriculum of the Royal University for Women in the Kingdom of Bahrain. The course was offered as an elective module pertaining to 3 credits and comprising 3hours of teaching per week. This pioneer experience of introducing women's health to non-medical university students is innovative and supports the notion of "Healthy women hold up a healthy world". Informed women ensure future informed health decisions. This experience will be evaluated and reflected upon with the hope of expanding it to other universities.


Layer-by-Layer (LBL) Self-Assembled Biohybrid Nanomaterials for Efficient Antibacterial Applications.
Although antibiotics have been widely used in clinical applications to treat pathogenic infections at present, the problem of drug-resistance associated with abuse of antibiotics is becoming a potential threat to human beings. We report a biohybrid nanomaterial consisting of antibiotics, enzyme, polymers, hyaluronic acid (HA), and mesoporous silica nanoparticles (MSNs), which exhibits efficient in vitro and in vivo antibacterial activity with good biocompatibility and negligible hemolytic side effect. Herein, biocompatible layer-by-layer (LBL) coated MSNs are designed and crafted to release encapsulated antibiotics, e.g., amoxicillin (AMO), upon triggering with hyaluronidase, produced by various pathogenic Staphylococcus aureus (S. aureus). The LBL coating process comprises lysozyme (Lys), HA, and 1,2-ethanediamine (EDA)-modified polyglycerol methacrylate (PGMA). The Lys and cationic polymers provided multivalent interactions between MSN-Lys-HA-PGMA and bacterial membrane and accordingly immobilized the nanoparticles to facilitate the synergistic effect of these antibacterial agents. Loading process was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and X-ray diffraction spectroscopy (XRD). The minimal inhibition concentration (MIC) of MSN-Lys-HA-PGMA treated to antibiotic resistant bacteria is much lower than that of isodose Lys and AMO. Especially, MSN-Lys-HA-PGMA exhibited good inhibition for pathogens in bacteria-infected wounds in vivo. Therefore, this type of new biohybrid nanomaterials showed great potential as novel antibacterial agents.


[IgG subclasses and their clinical significance].
IgG are the most common isotype of Ig and include four subclasses which differ from one another in the following ways: their initial amino acid sequence, their physical and chemical properties and the different serum concentrations reached with age. Every subclass has a specific biological function: the response to proteic antigens is prevalently mediated by IgG1 and IgG3, while IgG2 mediates the response to polysaccharide antigens. It is still unclear whether IgG4 are protective or sensitising antibodies; IgG1 and IgG3 also have a major ability to bind to the cells that mediate the immune response, while only IgG4 activate the complement using an alternative route. Although low levels of IgG subclasses may be temporary, deficiencies are often associated with various diseases: 1) recidivating bacterial infections involving the respiratory and digestive tracts, primarily sustained by capsulated or pyogenic microorganisms; 2) IgA deficiency; 3) absence of immune response following vaccination; 4) allergic or autoimmune diseases; 5) diseases of the CNS. IgG subclass deficiencies must therefore be looked for every time these diseases are diagnosed, also because subjects may benefit from gammaglobulin replacement therapy.


Phytoalexins of leguminous plants.
The production of phytoalexins by various plants belonging to the family Leguminosae is reviewed. Many of the plants involved and/ or products derived from them are currently being consumed by humans. Most of the compounds that have been characterized were found to be toxic to certain microorganisms and hence they may be potential hazards for humans. The induction, chemical and physical characteristics, and other available information on these compounds are presented along with pertinent references. The lack of complete information on many of the phytoalexins reported suggests the need for further and continuing research in this area.


Effect of pregnancy on resistance to Listeria monocytogenes and Toxoplasma gondii infections in mice.
Studies of the effect of pregnancy on the capacity of mice to resist Listeria monocytogenes and Toxoplasma gondii infection revealed significantly diminished resistance of pregnant mice to infection by both agents as measured by mortality. The development of immunity to listeria was assessed by studying the kinetics of listeria growth in the livers and spleens of virgin and pregnant mice infected intravenously with a sublethal dose of listeria. In both virgin and pregnant mice there was a rise in the number of listeria colony-forming units per organ during the first 3 days after infection. Thereafter, there was a decline in colony-forming units in these organs in virgin mice but a persistence of listeria in spleens and livers of pregnant mice. Paradoxically, during the first 3 days after infection, listeria counts in spleens of virgin mice were significantly higher than those in pregnant mice. Nonspecific resistance to listeria conferred by chronic infection with T. gondii was significantly diminished in pregnant mice when measured by mortality and quantitative cultures of listeria in livers and spleens. These studies demonstrate a remarkably decreased resistance of pregnant mice to two intracellular organisms and a diminished capacity of pregnant mice to develop immunity to listeria. This decrease in resistance may play an important role in congenital transmission of these organisms.


The orbicularis oculi response after hemispheral damage.
The corneal and blink reflexes were evaluated in 20 normal subjects and in 30 patients with motor deficits secondary to unilateral hemispheral lesions of vascular origin. In the normal population there were no differences between subjects below and subjects above 50 years of age. In the patients the reflex evoked by electrical stimulation of the cornea of the clinically affected side was depressed in 24 out of 30 cases. The depression mainly affected the afferent branch of the circuit, which triggers both homolateral and contralateral orbicularis oculi discharge (afferent abnormality). In three cases the depression was exerted concomitantly on the efferent branch (afferent and efferent abnormality) and only in one case was it limited to the efferent branch (efferent abnormality). The late R2 component of the blink reflex was depressed in 15 out of 30 patients. The early R1 component was slightly facilitated on the affected side. The changes of the corneal reflex and of the R2 component of blink reflex were similar, but the blink reflex had a greater safety factor. The patients with an abnormal corneal reflex had more extensive damage than had the patients with normal corneal response, as shown by computer tomography, but the site of the lesion was comparable in the two groups. Conduction through the brain stem circuits mediating the orbicularis oculi response is normally under pyramidal facilitatory influences while facial motoneurons are subjected to pyramidal inhibition. After pyramidal damage the transmission of impulses in the brain stem was slowed down, ultimately to a degree that abolished the reflex. Removal of pyramidal inhibition on facial motoneurons is probably the basis of the slight facilitation of the R1 component of the blink reflex.


[Comparison of the results of clinico-epidemiological examination of retarded children-orphans and retarded children brought up in the family].
A group of mentally retarded children (n = 881) aged 8 to 14 years, identified as a result of a clinico-epidemiological screening, were examined. The results obtained were compared in two groups. Group 1 (n = 272 or 30.9%) included orphans and children who remained without their parents' care since infancy and group II (n = 609 or 69.1%) included children brought up in complete or incomplete families. The differences were established in the degree of mental retardation, in its complication by additional psychopathological symptomatology, in the share of some complicating syndromes and the time of their origin, in the times of the diagnosis establishment and sending to specialized institutions, in the quality and timeliness of the assistance rendered, and in some other indicators. The importance of the problem of psychic deprivation in mental retardation is emphasized.


Infinite flag varieties and conjugacy theorems.
We study the orbit of a highest-weight vector in an integrable highest-weight module of the group G associated to a Kac-Moody algebra [unk](A). We obtain applications to the geometric structure of the associated flag varieties and to the algebraic structure of [unk](A). In particular, we prove conjugacy theorems for Cartan and Borel subalgebras of [unk](A), so that the Cartan matrix A is an invariant of [unk](A).