Verbal repetition skill in language impaired children: evidence of inefficient lexical processing?
Speeded verbal repetition of spoken words in simple and primed conditions was used to examine lexical processing deficits in children with specific language impairment (SLI). During simple verbal repetition, children with SLI (n = 18) were slower at repeating abstract verbs compared to concrete verbs. This same effect was not observed for nouns. Age matched typically developing (TD) children (n = 18) showed no effect of concreteness for either verbs or nouns. During primed verbal repetition the children heard prime-target word pairs (e.g., lion-tiger) on each trial. Semantically related primes speeded verbal repetition for the TD but not SLI group, suggesting inefficient spreading activation within lexical semantics for children with SLI. Phonologically related primes (e.g., tiny) slowed verbal repetition of the target (e.g., tiger) in both groups, suggesting children with SLI were similar to their age-matched peers in lexical phonological competition. The results are generally supportive of graded deficits in lexical processing skill in SLI consistent with connectionist accounts, and approaches to therapy that combine semantic and phonological dimensions at the word level.


The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A.
The asialoglycoprotein receptor (ASGPR) binds with high affinity factor VIII (FVIII) through its N-linked oligosaccharides. However, its contribution to the wide inter-individual variation of infused FVIII pharmacokinetics (PK) in hemophilia A (HA) is unknown. To investigate the variability in FVIII PK outcomes in relation to genetic variation in the ASGR2, encoding the ASGPR2 subunit. Thirty-two HA patients with FVIII:C ≤2 IU/dL underwent 66 single-dose FVIII PK studies. PK parameters were evaluated in relation to ASGR2 5' untranslated region (5'UTR) polymorphisms, which were investigated by recombinant and white blood cell reverse transcription-polymerase chain reaction approaches. The 5'UTR polymorphisms determine a frequent and conserved haplotype (HT1) in a regulatory region. The HT1 homozygotes may differ in the amounts of alternatively spliced mRNA transcripts and thus ASGPR2 isoforms. Compared with the other ASGR2 genotypes, the c.-95TT homozygotes (n = 9), showed threefold longer Alpha HL (3.60 hours, 95% confidence interval: 1.44-5.76, p = 0.006), and the c.-95TC heterozygotes (n = 17) showed 25% shorter mean residence time (MRT; 18.5 hours, 15.0-22.0, p = 0.038) and 32% shorter Beta HL (13.5 hours, 10.9-16.0, p = 0.016). These differences were confirmed in patients (n = 27) undergoing PK studies (n = 54) with full-length FVIII only. In different linear regression models, the contribution of the ASGR2 genotypes remained significant after adjustment by ABO genotypes and von Willebrand factor (VWF) antigen levels, and explained 14% (MRT), 15 to 18% (Beta HL), and 22% (Alpha HL) of parameter variability. Infused FVIII distribution was modulated by frequent ASGR2 genotypes, independently from and together with ABO and VWF antigen levels, which has potential implications for genetically tailored substitutive treatment in HA.


The 1996 welfare law: key elements and reauthorization issues affecting children.
The Personal Responsibility and Work Opportunity Reconciliation Act of 1996 changed the social policy landscape for children in many ways. It replaced the prior welfare program with block grants to the states entitled Temporary Assistance for Needy Families, and modified a broad array of other programs and initiatives affecting low-income children. This article describes the key themes dominating the debate over welfare reform in 1996, specifically: Increased state discretion in program design, leading to more variability in states' eligibility requirements and services provided to low-income families; More stringent work requirements even for parents of very young children; Time limits on the use of federal funds for cash assistance, and a strong focus on caseload reduction; Increased emphasis on parental responsibility, with stronger child support requirements; and Increased emphasis on reducing out-of-wedlock births, including bonuses to states with the largest reductions, and special requirements for unmarried teen parents who seek welfare. Although child well-being received little attention during the congressional debates in 1996, the authors conclude with the hope that improving child outcomes and child well-being will emerge as a key theme when the law is reauthorized in 2002.


[Morphological analysis of acetabulum bony curved surface].
By using the reverse engineering (RE) technology, the mesh surface model of acetabulum was reconstructed by triangulation. Based on this kind of model, the local morphological analysis (LMA) and global morphological analysis (GMA) could be processed. The fitting minimal quadric surface method was applied to calculate the curvature of any point on the acetabulum bony surface, the local morphological character of its surface could be acquired, and its global surface character could be determined by GMA. The results showed that the acetabulum bony surface is elliptical surface, and its three eigenvalues (lambda1, lambda2, lambda3) relations on the three axes (x, y, z) are as follows: lambda1 is short than lambda2 and lambda3, lambda2 is close to lambda3.


Movement of the cleft maxilla in infants relative to the frontal bone. A roentgen stereophotogrammetric study with the aid of metallic implants.
Four implants (tantalum balls 0.5 mm in diameter) were inserted in the frontal bone, and three implants (tantalum pins 1.5 x 0.5 mm) were inserted in each lateral segment of the cleft maxilla of ten infants aged 13 to 42 months. Motion of the maxillary segments was studied relative to the frontal bone by means of roentgen stereophotogrammetry during observation periods from 371 to 868 days. The results were presented by means of computer drawings of the implant triangles projected on the three cardinal planes. With this technique, movement of the maxillary segments could be visualized with a high degree of accuracy. No pattern of movement related to time or type of surgery, to type of cleft (UCLP/BCLP), or to cleft or non-cleft segment could be found.


[Spinal anesthesia and multiple sclerosis].
Spinal anaesthesia was performed in 9 patients with multiple sclerosis for 14 surgical procedures: urological surgery 13 times and plastic surgery once. No complication was observed. except for a transient exacerbation in one case. Spinal anaesthesia appeared to be an innocuous procedure in multiple sclerosis as no neurotoxicity was observed. Exacerbation of multiple sclerosis was similar to that seen with general anaesthesia. Moreover, spinal anaesthesia improved the operating conditions by relieving bladder spasticity; it was also often asked for by patients who feared the loss of consciousness of general anaesthesia.


Lipopolysaccharide treatment stimulates Pocillopora coral genotype-specific immune responses but does not alter coral-associated bacteria communities.
Corals are comprised of a coral host and associated microbes whose interactions are mediated by the coral innate immune system. The diversity of immune factors identified in the Pocillopora damicornis genome suggests that immunity is linked to maintaining microbial symbioses while also being able to detect pathogens. However, it is unclear which immune factors respond to specific microbe-associated molecular patterns and how these immune reactions simultaneously affect coral-associated bacteria. To investigate this, fragments of P. damicornis and P. acuta colonies from Taiwan were subjected to lipopolysaccharide (LPS) treatment to stimulate immune responses and measure bacteria community shifts. RNA-seq revealed genotype-specific immune responses to LPS involving the upregulation of immune receptors, transcription factors, and pore-forming toxins. Bacteria 16S sequencing revealed significantly different bacteria communities between coral genotypes but no differences in bacteria communities were caused by LPS. Our findings confirm that Pocillopora corals activate conserved immune factors in response to LPS and identify transcription factors coordinating Pocillopora corals' immune responses. Additionally, the strong effect of coral genotype on gene expression and bacteria communities highlights the importance of coral genotype in the investigation of coral host-microbe interactions.


[Quantitative abnormalities in nystagmus induced by caloric stimulation in multiple sclerosis].
Vestibular nystagmus induced by caloric stimulation (20 degrees and 44 degrees C) was evaluated in terms of duration, frequency and slow phase velocity in 80 patients suffering from clinically defined multiple sclerosis. Criteria of abnormality were established with reference to 3 confidence levels from normative data of a 15-subject control group. Abnormal data representative of vestibular hypo- and hyperreflexia were found ranging between 27 and 53% depending on different parameters and diagnostic criteria. Significant differences in occurrence of nystagmus abnormalities became evident by analyzing 6 different windows of the vestibular response. Different distributions of hypo- and hyperreflexia were observed in relation to the time-course of the normal cumulative response curve, as well as to different stimulus temperatures. For each subject the abnormal data of the 2 stimulated ears X 2 caloric stimulations X 6 analysis windows were cumulated, yielding an overall outcome of pathological results in 66% to 90% of the patients, depending on the different diagnostic criteria.


Neoadjuvant FOLFIRINOX followed by Chemoradiotherapy for Middle and Lower Rectal Cancer.
Neoadjuvant concomitant chemoradiotherapy followed by surgical resection is the standard of care in the treatment of rectal cancer. We are investigating the value of adding combination chemotherapy oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX) before neoadjuvant chemoradiotherapy. Forty-one patients with middle and lower rectal cancer were included. FOLFORINOX were given every 2 weeks over 2 months (4 cycles) followed by concomitant chemoradiotherapy (CRT). Surgery was done 6-8 weeks after CRT and then adjuvant 4 months of FOLFOX or XELOX were given. The primary end point was sphincter preservation rate. All patients received the four cycles of neoadjuvant chemotherapy FOLFORINOX, 38 patients completed CRT and only 29 patients underwent surgery. 32 patients were available for assessment (29 patients who underwent surgery and three patients who refuse surgery because of no evidence of disease by endoscopy, imaging and biopsy). Sphincter preservation was achieved in twenty-one patients (51.2%). Pathological complete response rate was 24.1%. After a median follow up of 24 months. Median PFS was 20 months and 2-years PFS was 62.3%. The median overall survival of all patients was not reached, while 2-years OS was 76.5%. Neoadjuvant FOLFIRINOX followed by CRT for middle and lower rectal cancer is feasible, tolerable with satisfactory sphincter preservation rate. <br />.


Development, validation and analysis of a human profurin 3D model using comparative modeling and molecular dynamics simulations.
The emergence of new viruses can lead to the outbreak of pandemics as occurred at the end of 2019 with the coronavirus disease (or COVID-19). The fastest way to effectively control viral infections is to develop broad-spectrum antivirals that can fight at least an entire class of viruses. Profurin, the furin precursor propeptide, is responsible for the autoactivation step which is crucial for the maturation of several viral substrates. This role makes the study of furin and profurin interactions interesting for the development of new potential broad-spectrum antivirals for the treatment against several human viral diseases. Since there is no 3D model of profurin published in the literature or deposited in a database, this work reports the development, validation and analysis of a profurin 3D model using comparative modeling and molecular dynamics. The model is available in ModelArchive at https://www.modelarchive.org/doi/10.5452/ma-ct8l7. The usage of this model will make possible further studies of molecular docking and MD simulations of the profurin-furin system, in the design of new potential broad-spectrum antivirals for the treatment against several human viral diseases.Communicated by Ramaswamy H. Sarma.


Rationality in medicine.
Kant taught that, 'Where we find . . . illusions and fallacies . . . , there seems to be required a . . . code of mental legislation . . . founded upon the nature of reason and the objects of its exercise . . . which no fallacy will be able to withstand or escape from . . . ' I address, critically, the Flexnerian and EBM conceptions of scientific medicine and Groopman's ideas about errors of reasoning in the practice of medicine; I underscore the need for theory of medicine, founded on reason and governing cognition about and in the practice of medicine; and I sketch the dawn of rationality in medicine.


Effects of Initial Water Content on Microstructure and Mechanical Properties of Lean Clay Soil Stabilized by Compound Calcium-Based Stabilizer.
Initial water content significantly affects the efficiency of soil stabilization. In this study, the effects of initial water content on the compressibility, strength, microstructure, and composition of a lean clay soil stabilized by compound calcium-based stabilizer were investigated by static compaction test, unconfined compression test, optical microscope observations, environment scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction. The results indicate that as the initial water content increases in the range studied, both the compaction energy and the maximum compaction force decrease linearly and there are less soil aggregates or agglomerations, and a smaller proportion of large pores in the compacted mixture structure. In addition, for specimens cured with or without external water supply and under different compaction degrees, the variation law of the unconfined compressive strength with initial water content is different and the highest strength value is obtained at various initial water contents. With the increase of initial water content, the percentage of the oxygen element tends to increase in the reaction products of the calcium-based stabilizer, whereas the primary mineral composition of the soil-stabilizer mixture did not change notably.


Novel 1,3-diketone modified fullerenes for organic photovoltaic cells.
The feasibility of novel 1,3-diketone modified C60s (compound 1 and 2) was studied as acceptor materials in organic photovoltaic cells (OPVC). 1,3-Diketone modified fullerenes were synthesized by the addition reaction of 1,3-bis(5'-hexylthiophen-2'-yl)propane-1,3-dione with C60 in the presence of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene). From this procedure two products can be prepared, which are mono- (1) and di-substituted compound (2) in the yield of 40% and 17%, respectively. OPVCs fabricated by using the mixture of P3HT and compound 1 as an active layer showed excellent power conversion efficiency of about 3.42% after annealed at 160 degrees C for 15 min and we believe that substantial improvements can be realized by nano-structured heterojunction. It was demonstrated that 1,3-diketone modified C60 (compound 1) was one of the promising candidates for acceptor materials for OPVCs.


The Safety and Efficacy of Cryotherapy in the Prevention of Paclitaxel-Induced Neuropathy: A Systematic Review.
The chemotherapeutic agent paclitaxel has significantly enhanced the treatment of various types of cancer. However, the quality of life of cancer patients is often impacted by the painful and dose-restrictive paclitaxel side effect known as paclitaxel-induced peripheral neuropathy (PIPN). A non-pharmacological method called cryotherapy has shown promise in alleviating PIPN-related symptoms. In this systematic review, we aimed to evaluate the safety and effectiveness of cryotherapy in preventing PIPN. The review analyzed four randomized controlled trials (RCTs) involving individuals treated with paclitaxel for breast and gynecological cancer. Cryotherapy showed success in lowering PIPN symptoms in several studies, as judged by various outcome measures, although the findings varied. The safety profile of cryotherapy was typically good, with minimal side effects. However, methodological variations and small sample sizes in the studies analyzed limit drawing definitive conclusions from them. To obtain conclusive evidence, studies with standardized techniques and larger sample sizes are required. Further research is necessary to understand cryotherapy's potential mechanisms and long-term effects. This review highlights the potential of cryotherapy in the management of PIPN, explains how it works, and suggests future research topics to improve its application.


Toward molecular recognition: three-point halogen bonding in the solid state and in solution.
A well-defined three-point interaction based solely on halogen bonding is presented. X-ray structural analyses of tridentate halogen bond donors (halogen-based Lewis acids) with a carefully chosen triamine illustrate the ideal geometric fit of the Lewis acidic axes of the former with the Lewis basic centers of the latter. Titration experiments reveal that the corresponding binding constant is about 3 orders of magnitude higher than that with a comparable monodentate amine. Other, less perfectly fitting multidentate amines also bind markedly weaker. Multipoint interactions like the one presented herein are the basis of molecular recognition, and we expect this principle to further establish halogen bonding as a reliable tool for solution-phase applications.


Associative representational plasticity in the auditory cortex: a synthesis of two disciplines.
Historically, sensory systems have been largely ignored as potential loci of information storage in the neurobiology of learning and memory. They continued to be relegated to the role of "sensory analyzers" despite consistent findings of associatively induced enhancement of responses in primary sensory cortices to behaviorally important signal stimuli, such as conditioned stimuli (CS), during classical conditioning. This disregard may have been promoted by the fact that the brain was interrogated using only one or two stimuli, e.g., a CS(+) sometimes with a CS(-), providing little insight into the specificity of neural plasticity. This review describes a novel approach that synthesizes the basic experimental designs of the experimental psychology of learning with that of sensory neurophysiology. By probing the brain with a large stimulus set before and after learning, this unified method has revealed that associative processes produce highly specific changes in the receptive fields of cells in the primary auditory cortex (A1). This associative representational plasticity (ARP) selectively facilitates responses to tonal CSs at the expense of other frequencies, producing tuning shifts toward and to the CS and expanded representation of CS frequencies in the tonotopic map of A1. ARPs have the major characteristics of associative memory: They are highly specific, discriminative, rapidly acquired, exhibit consolidation over hours and days, and can be retained indefinitely. Evidence to date suggests that ARPs encode the level of acquired behavioral importance of stimuli. The nucleus basalis cholinergic system is sufficient both for the induction of ARPs and the induction of specific auditory memory. Investigation of ARPs has attracted workers with diverse backgrounds, often resulting in behavioral approaches that yield data that are difficult to interpret. The advantages of studying associative representational plasticity are emphasized, as is the need for greater behavioral sophistication.


Serum cholesterol, other risk factors, and cardiovascular disease in a Japanese cohort.
The relationship of serum cholesterol and other risk factors to cardiovascular disease was investigated in a 16-year cohort of 16,711 residents of Hiroshima and Nagasaki. Examined in detail were the relationship of serum cholesterol, and the joint relationships of serum cholesterol, systolic blood pressure, diastolic blood pressure, and other risk factors to coronary heart disease (CHD), cerebral infarction (CI), and cerebral hemorrhage (CH). Baseline and biennially collected risk factor data were analyzed. The latter type of measurement permitted separate investigation of both the short-term and long-term effects of cholesterol measurements. In both types of analyses, both serum cholesterol and blood pressure showed strong associations with CHD incidence. In particular, there were strong associations with short-term and delayed CHD incidence. Furthermore, the association of cholesterol with short-term CHD incidence could not be explained by its association with delayed CHD incidence, or vice versa. Multivariate analyses that also included several other risk factors (smoking habits, clinical diagnosis of diabetes mellitus, left ventricular hypertrophy or strain on electrocardiogram, relative body weight, hematocrit, and proteinuria) for which data were available showed such risk factors to be of lesser, but generally non-negligible, importance in this population. In the case of CH and CI, serum cholesterol was found to be weakly or not at all related to incidence of either disease while blood pressure remained a strong correlate. For CI some suggestion of a statistical interaction between blood pressure and serum cholesterol was found. Discussed are implications for theories of disease pathogenesis for CHD, CI and CH.


Novel therapeutic targets for acute pancreatitis and associated multiple organ dysfunction syndrome.
Acute pancreatitis is a common clinical condition. The exact mechanisms by which diverse etiological factors induce an attack are unclear but once the disease process is initiated, common inflammatory and repair pathways are invoked. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction; if marked, this leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicemia, severe burns and trauma. Potentially, there is a therapeutic window between symptom onset and the development of distant organ damage in acute pancreatitis, when anti-inflammatory therapy may be of use. Recent studies conducted by us and other investigators have established the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, CINC/GRO-alpha, MCP-1, PAF, IL-10, CD40L, C5a, ICAM-1, and Substance P in acute pancreatitis and the resultant MODS. It is reasonable to speculate that elucidation of the key mediators in acute pancreatitis coupled with the discovery of specific inhibitors will make it possible to develop a clinically effective anti-inflammatory therapy.


Sequential treatment with lamivudine and interferon-alpha monotherapies in hepatitis B e antigen-negative Chinese patients and its suppression of lamivudine-resistant mutations.
To assess the efficacy of sequential treatment with lamivudine and interferon-alpha monotherapies in Chinese patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. One hundred and sixty-two patients with HBeAg-negative chronic hepatitis B were included in this study. Ninety-eight were treated with lamivudine alone (100 mg per day) for 48 weeks (group B). Sixty-four were treated with lamivudine alone (100 mg per day) for 20 weeks, then combined with interferon-alpha-2b (5 million units three times per week) for 4 weeks and then treated for another 24 weeks with interferon-alpha-2b alone (5 million units three times per week) (group A). All patients were followed for an additional 24 weeks. After 48 weeks of treatment, the percentage of patients with normalization of alanine aminotransferase (ALT) levels or hepatitis B virus (HBV) DNA levels below 1000 copies/mL was not significantly different between the lamivudine monotherapy group (55.10% and 55.10%, respectively) and the sequential treatment group (59.36% and 56.25%, respectively). The percentage of patients with normalized ALT levels was significantly higher in group A (53%) than in group B (36%) at week 72 (P<0.05). The percentage of patients with lamivudine-resistant mutations was significantly higher with lamivudine monotherapy (22.45%) than with sequential therapy (P<0.05). Sequential treatment of chronic hepatitis B with lamivudine and interferon-alpha monotherapies is as effective as lamivudine-alone treatment in Chinese patients. However, sequential treatment can significantly suppress the emergence of lamivudine-resistant mutations.


Linking clinical quality indicators to research evidence - a case study in asthma management for children.
Clinical quality indicators are used to monitor the performance of healthcare services and should wherever possible be based on research evidence. Little is known however about the extent to which indicators in common use are based on research. The objective of this study is to measure the extent to which clinical quality indicators used in asthma management in children with outcome measurements can be linked to results in randomised controlled clinical trial (RCT) reports. This work is part of a broader research program to trial methods that improve the efficiency and accuracy of indicator development. National-level indicators for asthma management in children were extracted from the National Quality Measures Clearinghouse database and the National Institute for Health and Care Excellence quality standards by two independent appraisers. Outcome measures were extracted from all published English language RCT reports for asthma management in children below the age of 12 published between 2005 and 2014. The two sets were then linked by manually mapping both to a common set of Unified Medical Language System (UMLS) concepts. The analysis identified 39 indicators and 562 full text RCTs dealing with asthma management in children. About 95% (37/39) of the indicators could be linked to RCT outcome measures. It is possible to identify relevant RCT reports for the majority of indicators used to assess the quality of asthma management in childhood. The methods reported here could be automated to more generally support assessment of candidate indicators against the research evidence.


Fatal peripheral T-cell lymphoma following intramuscular tuberculosis of the forearm.
Intramuscular tuberculosis (TB) is a rare disease, and lymphoma may occur following a bout of TB. We report on an unusual presentation of peripheral T-cell lymphoma that occurred after an infiltrative lesion of intramuscular TB of the forearm in an immunocompetent host. To our knowledge, this is the first case where TB of a muscle presenting as an infiltrative lesion instead of an abscess developed into peripheral T-cell lymphoma.


Sports Injury Surveillance Systems: A Review of Methods and Data Quality.
Data from sports injury surveillance systems are a prerequisite to the development and evaluation of injury prevention strategies. This review aimed to identify ongoing sports injury surveillance systems and determine whether there are gaps in our understanding of injuries in certain sport settings. A secondary aim was to determine which of the included surveillance systems have evaluated the quality of their data, a key factor in determining their usefulness. A systematic search was carried out to identify (1) publications presenting methodological details of sports injury surveillance systems within clubs and organisations; and (2) publications describing quality evaluations and the quality of data from these systems. Data extracted included methodological details of the surveillance systems, methods used to evaluate data quality, and results of these evaluations. Following literature search and review, a total of 15 sports injury surveillance systems were identified. Data relevant to each aim were summarised descriptively. Most systems were found to exist within professional and elite sports. Publications concerning data quality were identified for seven (47%) systems. Validation of system data through comparison with alternate sources has been undertaken for only four systems (27%). This review identified a shortage of ongoing injury surveillance data from amateur and community sport settings and limited information about the quality of data in professional and elite settings. More surveillance systems are needed across a range of sport settings, as are standards for data quality reporting. These efforts will enable better monitoring of sports injury trends and the development of sports safety strategies.


Hypothalamic neuronal networks and feeding-related peptides involved in the regulation of feeding.
The hypothalamus is a region of the brain that plays a critical role in feeding regulation. It has been revealed by various physiological experiments that the feeding-regulating center is confined to the ventromedial hypothalamus, lateral hypothalamus (LH) and arcuate nucleus (ARC). Many kinds of neurons in these areas of the hypothalamus express factors such as melanin-concentrating hormone (MCH), neuropeptide Y (NPY), proopiomelanocortin (POMC), orexin (OX) and ghrelin, which have been implicated in feeding regulation. In tissues of the periphery, two critical factors involved in feeding regulation, leptin and ghrelin, have been identified. Both hormone peptides are secreted mainly from adipose and stomach tissue, respectively, and are considered to function via their receptors mainly through several hypothalamic nuclei that play important roles in the regulation of appetite. The present review looks mainly at the functional significance of feeding-regulation factors, such as those described above, and the humoral and neuronal interactions among these compounds in the hypothalamus by drawing on published reports of morphological and physiological analyses. Immunohistochemical and in situ hybridization experiments indicate that both leptin and ghrelin receptors are distributed in the hypothalamus and that there are reciprocal interactions between MCH and OX neurons in the LH. Morphological and physiological studies on single living cells isolated from fresh rat hypothalamus or with receptor agonist and antagonist combined with immunohistochemisry clearly demonstrate that both leptin and OX reciprocally regulate NPY- and POMC-containing neurons in the ARC and that ghrelin may regulate feeding status independently through direct OX and NPY pathways. In this way, cross-talking systems in the hypothalamus play a role in determining feeding states.


Suicidal mercury injection into the upper limb: a case study.
We report a rare case of self-injection of mercury into the subcutaneous tissue of the upper limb. A multi-disciplinary management approach was adopted including cooperation between toxicologists, orthopaedic surgeons, radiologists and environment safety personnel. Surgical removal of mercury under radiological screening and systemic intoxication treated by chelating agents, namely dimercaprol and succimer. Serial serum and urine mercury levels showed an initial rise despite surgical removal and returned to normal after a prolonged period of time. Safety precautions were taken during surgery to avoid inadvertent intoxication of staff. Contamination of the operation theatre was monitored by the amount of mercury vapour released into the air. All personnels involved in the management of the patient did not show any evidence of mercury intoxication.


Housing and health inequalities: a synthesis of systematic reviews of interventions aimed at different pathways linking housing and health.
Housing and neighbourhood conditions are widely acknowledged to be important social determinants of health, through three main pathways: (1) internal housing conditions, (2) area characteristics and (3) housing tenure. We conducted a systematic overview of systematic reviews of intervention studies to provide an overview of the evidence on the impact of housing and neighbourhood interventions on health and health inequalities. There is relatively strong evidence for interventions aimed at improving area characteristics and compelling evidence for warmth and energy efficiency interventions targeted at vulnerable individuals. However, the health impacts of area-level internal housing improvement interventions are as yet unclear. We found no reviews of interventions aimed at altering housing tenure. This remains an important area for further research and potentially new evidence syntheses.


Recommendations for an update of 2003 European regulatory requirements for registration of drugs to be used in the treatment of RA.
Since 2003, the European Medicines Agency (EMA) document, 'Points to consider on clinical investigation of medicinal products other than NSAIDs (nonsteroidal anti-inflammatory drugs) for the treatment of rheumatoid arthritis' has provided guidance for the clinical development of both biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs). In the last few years, several new products have been developed or are in development for the treatment of RA, which offer significant efficacy with regard to disease control, including prevention of structural damage and disability. Concurrently, novel insights have been gained with respect to the assessment of disease activity, joint damage and disability. New treatment strategies have been established which relate to early therapy, tight control and rapid switching of medication. Accordingly, several new EULAR/ACR recommendations have been or are being developed. Several important additions and changes are needed in the 2003 guidance to incorporate the current scientific knowledge into clinical trial design for the development of future products. Under the auspices of the Group for the Respect of Ethics and Excellence in Science (GREES), a group of experts in the field of RA and clinical trial design met to provide a consensus recommendation for an update to the 2003 EMA guidance document.


Enzyme solid-state support assays: a surface plasmon resonance and mass spectrometry coupled study of immobilized insulin degrading enzyme.
Solid-support based assays offer several advantages that are not normally available in solution. Enzymes that are anchored on gold surfaces can interact with several different molecules, opening the way to high throughput array format based assays. In this scenario, surface plasmon resonance (SPR) and mass spectrometry (MS) investigations have often been applied to analyze the interaction between immobilized enzyme and its substrate molecules in a tag-free environment. Here, we propose a SPR-MS combined experimental approach aimed at studying insulin degrading enzyme (IDE) immobilized onto gold surfaces and its ability to interact with insulin. The latter is delivered by a microfluidic system to the IDE functionalized surface and the activity of the immobilized enzyme is verified by atmospheric pressure/matrix assisted laser desorption ionization (AP/MALDI) MS analysis. The SPR experiments allow the calculation of the kinetic constants involved for the interaction between immobilized IDE and insulin molecules and evidence of IDE conformational change upon insulin binding is also obtained.


Integrated, molecular engineering approaches to develop prostate cancer gene therapy.
Gene therapy is a translational science, with the ultimate goal of cancer gene therapy research being to develop effective and safe treatments for patients. In the new millennium, it is imperative to tailor a therapeutic strategy for a particular disease, based on clinical management issues. The desirable regulatory features and therapeutic strategies need to be fully considered before proceeding with molecular engineering of the gene delivery vector. Issues, such as cell-targeted expression, in vivo monitoring of gene delivery and expression, therapeutic strategies, and vector selection that targets the particular disease stage should be addressed. During the validation phase of the study, an objective evaluation in relevant animal models should determine whether the vector meets the desired specifications. Meeting the predetermined criteria should propel the product towards the clinical phase of evaluation. This review will present the conceptual framework that has been applied to developing an integrated and targeted gene therapy for prostate cancer.


Advanced interferometric profile measurements through refractive media.
Optical profilers are valuable tools for the characterization of microelectromechanical systems (MEMSs). They use phase sifting interferometry (PSI) or vertical scanning interferometry to measure the topography of microscale structures with nanometer resolution. However, for many emerging MEMS applications, the sample needs to be imaged while placed in a liquid or in a package with a glass window. The increased refractive index of the transparent medium degrades the interference image contrast and prevents any measurement of the sample. We report on the modification of a Veeco NT1100 optical profiler to enable PSI measurements through refractive media. This approach can be applied to any other optical profiler with PSI capability. The modification consists in replacing the original illumination source with a custom-built narrow linewidth source, which increases the coherence length of the light and the contrast of the interference image. We present measurements taken with the modified configuration on samples covered with 3 mm water or 500 mum glass, and we compare them to measurements of uncovered samples. We show that the measurement precision is only slightly reduced by the water and glass, and that it is still sufficiently high for typical MEMS applications. The described method can be readily used for measuring through other types and thicknesses of refractive materials.


A dynamic analytical model for impact evaluation of percutaneous implants.
The ongoing need for a clinically effective noninvasive technique for monitoring implant stability has led to a number of testing methods based on the concept of resonant frequency. Resonant frequency measurements are an indirect measure of the bone-implant interface integrity and do not provide any specific measures of the physical properties of the interface itself. In this study, an analytical model has been developed to interpret the measurement results of an impact testing method based on the Periotest handpiece. Model results are compared to a variety of in vitro tests to verify model predictions and to gain an understanding of the parameters influencing the measurements. Model simulations are then used to predict how changes in the supporting stiffness properties, material loss around the neck of the implant, and the presence of an implant flange will affect the measurements. The developed analytical model, in conjunction with the impact measurements, allows direct estimation of the bone properties that support implants. Model simulations show the impact testing technique to be sensitive to bone loss and stiffness changes that would correspond to poorly integrated implants (ones which may be in danger of failing). Similarly, for implants with very stiff support, little useful quantitative data can be obtained about the bone supporting the implant, as the stiffness of the other components of the system dominate the response. However, such implants are generally considered healthy.


Evaluation of changes in effluent quality from industrial complexes on the Korean nationwide scale using a self-organizing map.
One of the major issues related to the environment in the 21st century is sustainable development. The innovative economic growth policy has supported relatively successful economic development, but poor environmental conservation efforts, have consequently resulted in serious water quality pollution issues. Hence, assessments of water quality and health are fundamental processes towards conserving and restoring aquatic ecosystems. In this study, we characterized spatial and temporal changes in water quality (specifically physico-chemical variables plus priority and non-priority pollutants) of discharges from industrial complexes on a national scale in Korea. The data were provided by the Water Quality Monitoring Program operated by the Ministry of Environment, Korea and were measured from 1989 to 2008 on a monthly basis at 61 effluent monitoring sites located at industrial complexes. Analysis of monthly and annual changes in water quality, using the seasonal Mann-Kendall test, indicated an improvement in water quality, which was inferred from a continuous increase in dissolved oxygen and decrease in other water quality factors. A Self-Organizing Map, which is an unsupervised artificial neural network, also indicated an improvement of effluent water quality, by showing spatial and temporal differences in the effluent water quality as well as in the occurrence of priority pollutants. Finally, our results suggested that continued long-term monitoring is necessary to establish plans and policies for wastewater management and health assessment.


Global Mapping of Metalloproteomes.
Metalloproteins play diverse and critical functions in all living systems, and their dysfunctional forms are closely related to many human diseases. The development of methods that enable comprehensive mapping of metalloproteome is of great interest to help elucidate crucial roles of metalloproteins in both physiology and pathology, as well as to discover new metalloproteins. We herein briefly review recent progress in the field of metalloproteomics and provide future outlooks.


Mutation in the ap2-6 allele causes recognition of a cryptic splice site.
Mutations in the homeotic gene APETALA2 of Arabidopsis thaliana cause severe developmental alterations, most prominently homeotic floral organ replacements from petals to carpels and petals to stamens in the outer two floral whorls. To date, ten different alleles have been identified conferring phenotypes of various degrees. Of these ten alleles, only three have been characterized at the sequence level. The identification of the sequence alteration in the ap2-6 allele is reported here. In ap2-6 a single G.C to A.T transition occurred at the 3' end of intron 6 (position 1342) which leads to a dinucleotide loss at the mRNA level. This change is consistent with the G.C to A.T transition destroying a conserved dinucleotide motif (AG) required for proper splice recognition and with the resulting recognition of the next available downstream AG dinucleotide which in AP2 is immediately adjacent to the authentic 3' splice site. The dinucleotide loss will cause a frameshift, the translation of three incorrect amino acids and a premature stop codon resulting in a truncation of the AP2 sequence within the AP2-R2 domain. Such a truncation is predicted to impact severely on the function of AP2 and is consistent with the observed phenotype.


What makes an endurance athlete world-class? Not simply a physiological conundrum.
Inter-individual variation in endurance performance capacity is a characteristic, not only of the general population, but also in trained athletes. The ability of sport scientists to predict which athletes amongst an elite group will become world-class is limited. We do not fully understand the interactions between biological factors, training, recovery and competitive performance. Assessment methods and interpretation of results do not take into account the facts that most research is not done on elite athletes and performances of world-class endurance athletes cannot be attributed to aerobic capacity alone. Many lines of evidence suggest that there is a limit to adaptation in aerobic capacity. Recent advances in molecular biology and genetics should be harnessed by exercise biologists in conjunction with previously used physiological, histological and biochemical techniques to study elite athletes and their responses to different training and recovery regimens. Technological advances should be harnessed to study world-class athletes to determine optimal training and competition strategies. In summary, it is likely that multiple factors are essential contributors to world-class endurance performance and that it is only by using a multidisciplinary approach that we will come closer to solving the conundrum: 'What makes an endurance athlete world class?'


Update of Standard Practices for New Method Validation in Forensic Toxicology.
International agreement concerning validation guidelines is important to obtain quality forensic bioanalytical research and routine applications as it all starts with the reporting of reliable analytical data. Standards for fundamental validation parameters are provided in guidelines as those from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the German speaking Gesellschaft fur Toxikologie und Forensische Chemie (GTFCH) and the Scientific Working Group of Forensic Toxicology (SWGTOX). These validation parameters include selectivity, matrix effects, method limits, calibration, accuracy and stability, as well as other parameters such as carryover, dilution integrity and incurred sample reanalysis. It is, however, not easy for laboratories to implement these guidelines into practice as these international guidelines remain nonbinding protocols, that depend on the applied analytical technique, and that need to be updated according the analyst's method requirements and the application type. In this manuscript, a review of the current guidelines and literature concerning bioanalytical validation parameters in a forensic context is given and discussed. In addition, suggestions for the experimental set-up, the pros and cons of statistical approaches and adequate acceptance criteria for the validation of bioanalytical applications are given.


[Studies on the relationship between blood type and personality in foreign countries].
"Typing by blood", which was proposed by popular psychologists, has been very prevalent since the beginning of the 1970s. In Japan, there is little information concerning the studies of "blood type and personality" in foreign countries. In foreign countries, the studies of relationship between blood type and disease began in the 1920s. These studies caught the attention of some psychologists in the 1960s. It is thought that there is no relationship between "typing by blood" in Japan and "blood type and personality" in foreign countries. The present study deals with the history of the studies of "blood type and personality" in foreign countries and discusses relationship between "typing by blood" and "blood type and personality".


An incidental finding of Gitelman's syndrome.
Gitelman's syndrome is characterised by hypokalaemia, hypomagnesaemia and tetany. This rare disorder is not well described in the literature, probably due to its similarity with Bartter's syndrome. We describe the symptoms and treatment of a young patient whom we consider to have Gitelman's syndrome.


HbM methaemoglobinaemia as a rare case of early neonatal benign cyanosis.
Early neonatal central cyanosis that is unrelated to cardiopulmonary causes, alerts clinicians to possibility of methaemoglobinaemia. Congenital methaemoglobinaemia due to haemoglobin M is an autosomal dominant disorder characterised by lifelong cyanosis. We report a case presentation and review of diagnostic pitfalls of a newborn who presented with central cyanosis; investigations revealed a low methaemoglobin reductase (2.2 IU/g Hb), with normal maternal levels (9.1 IU/g Hb). Therefore, haemoglobinopathy investigations were completed on the mother and her baby, which showed an α-globin variant in both. The maternal α2 globin gene sequencing showed heterozygosity for haemoglobin M Boston (α58 His → Tyr).


An Investigation of Protective Effects of Litium Borate on Blood and Histopathological Parameters in Acute Cadmium-Induced Rats.
This study was carried out to determine the protective effects of lithium borate (LTB) on blood parameters and histopathological findings in experimentally induced acute cadmium (Cd) toxicity in rats. Twenty-eight male Wistar albino rats were used, weighing 200-220 g, and they were randomly divided into four groups, including one control and the following three experimental groups: a Cd group (0.025 mmol/kg), a LTB group (15 mg/kg/day orally for 5 days), and a LTB + Cd group (15 mg/kg/day orally for 5 days and Cd 0.025 mmol/kg by intraperitoneal injection on the fifth day). All the rats in the study were anesthetized with ketamine at the end of the sixth day, blood was taken from their hearts, and then the rats were decapitated. The values in the control and LTB group were usually close to each other. White blood cell (WBC), neutrophil %, and C-reactive protein (CRP) levels increased in the Cd and LTB + Cd groups while lymphocyte and monocyte levels decreased in a statistically significant manner, in comparison to the other groups. It was determined that the levels of red blood cells (RBCs), hematocrit (Htc), and hemoglobin (Hb) did not change in the groups. The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the Cd and LTB + Cd groups significantly increased, in comparison to the other groups, while the glucose, alkaline phosphatase (ALP), albumin (ALB), and total protein (TP) levels decreased. According to histopathological findings in the control and LTB groups, the liver and kidney tissues were found to have normal histological structures. In the Cd group, severe necrotic hemorrhagic hepatitis, mild steatosis, and mononuclear cell infiltration were detected in the liver. In the LTB + Cd group, degeneration and mild mononuclear cell infiltration were found in the liver. Regarding the kidney tissue in the Cd group, severe intertubular hyperemia in both kidney cortex and medulla, as well as degeneration and necrosis in the tubulus epithelium, was observed. In the LTB + Cd group, mild interstitial hyperemia and mononuclear cell infiltration was detected. Resultantly, it can be said that LTB at this dose has non-toxic effects and some beneficial effects for liver and kidney damage caused by acute Cd toxicity.


Astaxanthin Induces the Nrf2/HO-1 Antioxidant Pathway in Human Umbilical Vein Endothelial Cells by Generating Trace Amounts of ROS.
Astaxanthin is a powerful antioxidant that possesses potent protective effects against various human diseases and physiological disorders. However, the mechanisms underlying its antioxidant functions in cells are not fully understood. In the present study, the effects of astaxanthin on reactive oxygen species (ROS) production and antioxidant enzyme activity, as well as mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K)/Akt, and the nuclear factor erythroid 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) pathways in human umbilical vein endothelial cells (HUVECs), were examined. It was shown that astaxanthin (0.1, 1, and 10 μM) induced ROS production by 9.35%, 14.8%, and 18.06% compared to control, respectively, in HUVECs. In addition, astaxanthin increased the mRNA levels of phase II enzymes HO-1 and also promoted GSH-Px enzyme activity. Furthermore, we observed ERK phosphorylation, nuclear translocation of Nrf-2, and activation of antioxidant response element-driven luciferase activity upon astaxanthin treatment. Knockdown of Nrf-2 by small interfering RNA inhibited HO-1 mRNA expression by 60%, indicating that the Nrf-2/ARE signaling pathway is activated by astaxanthin. Our results suggest that astaxanthin activates the Nrf-2/HO-1 antioxidant pathway by generating small amounts of ROS.


Flexible Nd:YAG laser palliation of obstructive tracheal metastatic malignancies.
Flexible Nd:YAG endoscopic laser surgery may become an effective new modality for palliation in patients with obstructive endotracheal metastatic malignancies. We report the results of the treatment of two patients with severely obstructing intraluminal tracheal metastatic melanoma and medullary thyroid carcinoma, using the neodymium-YAG laser via the flexible fiberoptic bronchoscope. Both patients complained of significant dyspnea, orthopnea, cough, and hemoptysis and were not candidates for rigid bronchoscopy because of underlying medical contraindications and anatomical problems. Multiple treatment sessions were used with treatment intervals of 1 to 2 weeks. All treatments were performed in the operating room under sedation, without intubation, with topical lidocaine and standard superior laryngeal nerve block. Successful relief of airway obstruction with complete regression of the endotracheal masses was achieved and no recurrences were seen after 9 months' follow-up. Flexible Nd:YAG laser bronchoscopy offered an alternative for the relief of obstructing endotracheal or bronchial malignancies in patients in whom the rigid bronchoscope could not be passed. it seemed to prolong survival in selected cases, and provided definite improvement in quality of life.


[Motility disorders of the esophagus in progressive systemic scleroderma. Pathophysiology, diagnosis and therapy].
Gastrointestinal manifestations of collagen diseases are frequent. In progressive systemic sclerosis esophageal involvement is found in 60% of cases and is thus the main gastrointestinal complication. Atrophy of the smooth muscle and fibrotic degeneration of the distal esophagus result in progressive motility disorders which may cause severe reflux esophagitis with typical consequences, such as stenosis and strictures. Manometry and cinematography are basic diagnostic procedures. Esophagoscopy and long-term pH-monitoring are most useful for evaluating the degree of esophageal involvement. The severity of sclerodermatous motility disorders should be classified according to a modification of the Garrett scale, which is particularly recommended for determining the further prognosis and therapeutic approach. Esophageal involvement of grades I and II should be treated conservatively, whereas grade III is a clear indication for surgical therapy. The original Nissen type of fundoplication or distal gastric resection with Roux-en-Y anastonosis are the methods of choice.


Carbon stable isotope composition of modern and archaeological Cornelian cherry fruit stones: a pilot study.
The carbon stable isotope content of Cornelian cherry stones collected from wild tree stands in Serbia, SE Europe, was measured using elemental analyser-isotope ratio mass spectrometry, with the aim of recording natural carbon isotope composition of the fruit stones and its possible variation. The results show a significant variation in the carbon isotope values; we identified several environmental factors that, along with a number of other possible determinants, likely contributed to this variation. The obtained data are compared with the measurement of carbon isotope content of an archaeological specimen of Cornelian cherry stone discovered at the Neolithic site of Vinča (ca. 5600-4500 BC) in Serbia. Notwithstanding the limitedness of the data and the complexity surrounding carbon fractionation and the isotopic variation, it is suggested that the differences/similarities in carbon isotope ratios between modern and archaeological Cornelian cherry stones, when measured for much larger assemblages, could potentially offer a glimpse into growing conditions of Cornelian cherry trees in the past.


Non-Conventional Methods for Gelation of Alginate.
This review presents and critically evaluates recent advances in non-conventional gelation method of native alginate. A special focus is given to the following three methods: cryotropic gelation, non-solvent induced phase separation and carbon dioxide induced gelation. A few other gelation approaches are also briefly reviewed. Results are discussed in the context of subsequent freeze and supercritical drying. The methods are selected so as to provide the readers with a range of novel tools and tactics of pore engineering for alginate and other anionic polysaccharides.


[Stability of hpt marker gene in transgenic rice in different food matrices and under varying food-processing conditions].
To estimate the likelihood of horizontal gene transfer from transgenic rice to bacteria of the food chain and human gut, the stability of s86 transgenic rice hpt gene in different food matrices and under varying food-processing conditions was studied. Degradation of DNA was monitored by fragment -multiplex polymerase chain reaction. Integrity of hpt gene in various food samples was tested. A PCR system for the hpt gene of genetically modified rice has been established to detect fragments ranging between 236bp and 910bp. Detection of hpt and rbcl gene fragments was carried out in various food-processed samples by this PCR system. The data showed that the fragments up to 500 bp were detected in rice and congee, while the fragment length more than 236bp was not detected in crispy rice and popcorn-like rice. These results suggested that there are significant differences in DNA degradation by different food-processing methods. The likelihood of the large hpt gene fragments transfer from transgenic rice processed food to bacteria is reduced by food process.


Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d.
Cyclin(-D-)-dependent kinase (Cdk) inhibitors of the Ink4 family specifically bind to Cdk4 and Cdk6, but not to other Cdks. Ink4c and Ink4d mRNAs are maximally and periodically expressed during the G(2)/M phase of the cell division cycle, but the abundance of their encoded proteins is regulated through distinct mechanisms. Both proteins undergo polyubiquitination, but the half life of p18(Ink4c) (approximately 10 hours) is much longer than that of p19(Ink4d) (approximately 2.5 hours). Lysines 46 and 112 are preferred sites of ubiquitin conjugation in p18(Ink4c), although substitution of these and other lysine residues with arginine, particularly in combination, triggers protein misfolding and accelerates p18(Ink4c) degradation. When tethered to either catalytically active or inactive Cdk4 or Cdk6, polyubiquitination of p18(Ink4c) is inhibited, and the protein is further stabilized. Conversely, in competing with p18(Ink4c) for binding to Cdks, cyclin D1 accelerates p18(Ink4c) turnover. In direct contrast, polyubiquitination of p19(Ink4d) is induced by its association with Cdks, whereas cyclin D1 overexpression retards p19(Ink4d) degradation. Although it has been generally assumed that p18(Ink4c) and p19(Ink4d) are biochemically similar Cdk inhibitors, the major differences in their stability and turnover are likely key to understanding their distinct biological functions.


Laser Phototherapy (660 nm) Can Be Beneficial for Reducing Gingival Inflammation in Prosthodontics.
Among the new technologies developed, low power lasers have enabled new approaches to provide conservative treatment. Low power lasers act at cellular level, resulting in reduced pain, modulating inflammation, and improved tissue healing. Clinical application of the low power laser requires specific knowledge concerning laser interaction with biological tissue so that the correct irradiation protocol can be established. The present case report describes the clinical steps involved in an indirect composite resin restoration performed in a 31-year-old patient, in whom low power laser was used for soft tissue biomodulation. Laser therapy was applied with a semiconductor laser 660 nm, spot size of 0.028 cm(2), energy density of 35.7 J/cm(2), mean power of 100 mW, and energy per point as 1 J, in contact mode, on a total of 2 points (mesial and distal), totaling 2 J of energy. The therapy with low power laser can contribute positively to the success of an indirect restorative treatment.


Oxidative addition at a carbene center: synthesis of an iminoboryl-CAAC adduct.
The reaction of a cyclic (alkyl)(amino)carbene (CAAC) with dichloro- and dibromobis(trimethylsilyl)aminoborane results in the formation of haloiminoborane-CAAC adducts. When the iodo analogue is used, an oxidative addition at the carbene center affords a cationic iminoboryl-CAAC adduct, featuring a boron-nitrogen triple bond. Similar salts are also obtained by halide abstraction from the chloro- and bromoiminoborane-CAAC adducts. The reactivity of all of these compounds towards CO2 is discussed.


Cut marks on bone surfaces: influences on variation in the form of traces of ancient behaviour.
Although we know that our lineage has been producing sharp-edged tools for over 2.6 Myr, our knowledge of what they were doing with these tools is far less complete. Studies of these sharp-edged stone tools show that they were most probably used as cutting implements. However, the only substantial evidence of this is the presence of cut marks on the bones of animals found in association with stone tools in ancient deposits. Numerous studies have aimed to quantify the frequency and placement of these marks. At present there is little consensus on the meaning of these marks and how the frequency relates to specific behaviours in the past. Here we investigate the possibility that mechanical properties associated with edges of stone tools as well as the properties of bones themselves may contribute to the overall morphology of these marks and ultimately their placement in the archaeological record. Standardized tests of rock mechanics (Young's modulus and Vickers hardness) indicate that the hardness of tool edges significantly affects cut-mark morphology. In addition, we show that indentation hardness of bones also impacts the overall morphology of cut marks. Our results show that rock type and bone portions influence the shape and prevalence of cut marks on animal bones.


Multi-scale modeling of intensive macroalgae cultivation and marine nitrogen sequestration.
Multi-scale macroalgae growth models are required for the efficient design of sustainable, economically viable, and environmentally safe farms. Here, we develop a multi-scale model for Ulva sp. macroalgae growth and nitrogen sequestration in an intensive cultivation farm, regulated by temperature, light, and nutrients. The model incorporates a range of scales by incorporating spatial effects in two steps: light extinction at the reactor scale (1 m) and nutrient absorption at the farm scale (1 km). The model was validated on real data from an experimental reactor installed in the sea. Biomass production rates, chemical compositions, and nitrogen removal were simulated under different seasons, levels of dilution in the environment and water-exchange rate in the reactor. This multi-scale model provides an important tool for environmental authorities and seaweed farmers who desire to upscale to large bioremediation and/or macroalgae biomass production farms, thus promoting the marine sustainable development and the macroalgae-based bioeconomy.


The development of the inner layer of backfat in fetal and young pigs.
The development of the innermost layer of backfat was studied histologically and histochemically in fetuses from Yorkshire sows at 45, 60, 65, 75, 85, 90, 105, 110, and 112 d of gestation. Samples were also obtained from fetuses at 110 d of gestation from Ossabaw sows and from sows selected for high (obese) or low (lead) backfat thickness. Fetuses from some sows were decapitated at 45 d of gestation and samples were obtained from these fetuses at 110 d of gestation. The inner layer develops before 75 d of gestation and has stromal-vascular characteristics that clearly distinguish it from the middle layer of backfat. For instance, a well organized and dense collagen matrix immediately surrounds small fat cell clusters in the inner layer. Most fat cell cluster capillaries (in the inner layer) reacted strongly for ATPase histochemically and are histologically immature. The inner layer morphology and cell size was similar in Ossabaw, obese and lean fetuses. The number of PAS (Periodic Acid Schiff) positive cells were dependent on fetal strain. The number was highest in obese fetuses and lowest in Ossabaws. Comparison of decapitated fetuses and weight-matched controls indicated that the inner layer was most affected by decapitation. A decreased organization and amount of collagen was associated with larger fat cell clusters in decapitated fetuses, and most fat cell cluster capillaries reacted little for ATPase histochemically and were histologically mature. The range in inner-layer fat cell diameter was wider in decapitated fetuses (11 to 55 micron) than in control fetuses (11 to 30 micron). These results demonstrate that the characteristics of the inner layer are clearly different from the other layers and that the amount and organization of collagen was inversely associated with the size of fat cell clusters and fat cells and with the maturity of the adipocyte-associated capillaries.


Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease.
Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors complement activation and inflammation may trigger and sustain endothelial dysfunction. We sought to assess the association between endothelial function, high sensitivity C-reactive protein (hs-CRP) and markers of complement activation in patients with either stable or unstable coronary artery disease. We prospectively recruited 78 patients, 35 patients with stable angina pectoris (SAP) and 43 patients with unstable angina pectoris (UAP). Endothelial function was assessed as brachial artery reactivity (BAR). Hs-CRP, C3a, C5a and C1-Inhibitor (C1 inh.) were measured enzymatically. Patients with UAP showed higher median levels of hs-CRP and C3a compared to patients with SAP, while BAR was not significantly different between patient groups. In UAP patients, hs-CRP was significantly correlated with cholesterol (r=0.27, p<0.02), C3a (r=0.32, p<0.001) and C1 INH.(r=0.41, p<0.003), but not with flow mediated dilatation (r=0.09, P=0.41). Hs-CRP and C1 INH.were found to be independent predictors of UAP in a backward stepwise logistic regression model. We conclude that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP.


Tobacco constituents, flavorants, and paper permeability of factory-made and roll-your-own cigarettes on the Australian market.
Roll-your-own (RYO) tobacco is a popular choice in Australia, with some people who smoke finding these products more attractive than factory-made cigarettes (FMC). Differences in visual and tactile properties and in the feel and taste of the smoke may contribute to this attractiveness. These differences may be driven by variation in tobacco constituents and wrapping paper permeability. However, to date, there has been no comparison of RYO and FMC products on the Australian market. Chemical constituents, pH, flavorants and paper permeability were compared in unburned RYO tobacco and tobacco from FMC. RYO and FMC products from matched brands were compared, as were products from the most popular FMC and RYO brands on the Australian market in 2018. RYO tobacco had higher moisture and humectant content (glycerol and propylene glycol) than FMC tobacco. RYO tobacco also had higher amounts of total and reducing sugars and lower nicotine when comparing the most popular brands. RYO papers were less permeable than FMC papers. Both RYO and FMC tobacco contained many chemicals identified as flavorants, including fourteen with known potential health risks. For most measured constituents and flavorants, RYO tobaccos had more in common with other RYO than FMC, with the commonalities remaining even when matched brands were compared. Higher levels of moisture, humectants and sugars in Australian RYO tobacco compared to FMC may be increasing attractiveness of RYO by reducing the harsh taste of the smoke and increasing the moist feel of the tobacco. While price is the main factor driving the use of RYO tobacco, some people who smoke find these products more attractive. This study has shown that Australian RYO tobacco contains higher amounts of glycerol, propylene glycol and sugars than FMC. These chemicals may be improving the taste of the tobacco, as well as creating a moist feel that is falsely perceived as indicating that the tobacco is 'fresh' and 'less chemically.' Ironically, it may be that higher amounts of some added chemicals in RYO contribute to false perceptions of a more natural and less harmful product.


Global hearing health care: new findings and perspectives.
In 2015, approximately half a billion people had disabling hearing loss, about 6·8% of the world's population. These numbers are substantially higher than estimates published before 2013, and point to the growing importance of hearing loss and global hearing health care. In this Review, we describe the burden of hearing loss and offer our and others' recommendations for halting and then reversing the continuing increases in this burden. Low-cost possibilities exist for prevention of hearing loss, as do unprecedented opportunities to reduce the generally high treatment costs. These possibilities and opportunities could and should be exploited. Additionally, a comprehensive worldwide initiative like VISION 2020 but for hearing could provide a focus for support and also enable and facilitate the increased efforts that are needed to reduce the burden. Success would produce major personal and societal gains, including gains that would help to fulfil the "healthy lives" and "disability inclusive" goals in the UN's new 2030 Agenda for Sustainable Development.


Healthcare waste management: qualitative and quantitative appraisal of nurses in a tertiary care hospital of India.
The nurse's role in healthcare waste management is crucial. (1) To appraise nurses quantitatively and qualitatively regarding healthcare waste management; (2) to elicit the determinants of knowledge and attitudes of healthcare waste management. A cross-sectional study was undertaken at a tertiary care hospital of Mangalore, India. Self-administered pretested questionnaire and "nonparticipatory observation" were used for quantitative and qualitative appraisals. Percentage knowledge score was calculated based on their total knowledge score. Nurses' knowledge was categorized as excellent (>70%), good (50-70%), and poor (<50%). Chi square test was applied to judge the association of study variables with their attitudes and knowledge. Out of 100 nurses 47 had excellent knowledge (>70% score). Most (86%) expressed the need of refresher training. No study variable displayed significant association (P > 0.05) with knowledge. Apt segregation practices were followed except in casualty. Patients and entourages misinterpreted the colored containers. Nurses' knowledge and healthcare waste management practices were not satisfactory. There is a need of refresher trainings at optimum intervals to ensure sustainability and further improvement. Educating patients and their entourages and display of segregation information board in local language are recommended.


A PTEN-like phosphatase with a novel substrate specificity.
We show that a novel PTEN-like phosphatase (PLIP) exhibits a unique preference for phosphatidylinositol 5-phosphate (PI(5)P) as a substrate in vitro. PI(5)P is the least characterized member of the phosphoinositide (PI) family of lipid signaling molecules. Recent studies suggest a role for PI(5)P in a variety of cellular events, such as tumor suppression, and in response to bacterial invasion. Determining the means by which PI(5)P levels are regulated is therefore key to understanding these cellular processes. PLIP is highly enriched in testis tissue and, similar to other PI phosphatases, exhibits poor activity against several proteinaceous substrates. Despite a recent report suggesting a role for PI(5)P in the regulation of Akt, the overexpression of wild-type or catalytically inactive PLIP in Chinese hamster ovary-insulin receptor cells or a dsRNA-mediated knockdown of PLIP mRNA levels in Drosophila S2 cells does not alter Akt activity or phosphorylation. The unique in vitro catalytic activity and detailed biochemical and kinetic analyses reported here will be of great value in our continued efforts to identify in vivo substrate(s) for this highly conserved phosphatase.


Antibiotic treatment of patients with mucosal thickening in the paranasal sinuses, and validation of cut-off points in sinus CT.
We compared the efficacy of penicillin V and amoxycillin treatment with placebo in 70 adult patients from Norwegian family practice with a clinical diagnosis of acute sinusitis and mucosal thickening on CT, but without fluid level or total opacification. The study was randomized and double-blind. Three different outcomes were evaluated; subjective status after 10 days of treatment, difference in clinical score between day 0 and day 10, and duration of the illness episode. Amoxycillin and penicillin V gave no better response to treatment than placebo, evaluated by all three outcome measures. The median duration of the sinusitis episode was 10 days in the amoxycillin- and placebo groups and 13 days in the penicillin-V group. In patients with a clinical diagnosis of acute sinusitis, fluid level and total opacification on CT are good criteria to differentiate between groups of patients that need or do not need antibiotic treatment.


Combined effect of titanium dioxide nanoparticles and glucose on the blood glucose homeostasis in young rats after oral administration.
Titanium dioxide nanoparticles (TiO2 NPs) were usually consumed with a high content of sugar, and children were identified as having the highest exposures due to sweet food preferences. Research on the combined effect of ingested TiO2 NPs and glucose has great significance, particularly in young people. We examined young Sprague-Dawley rats administered TiO2 NPs (0, 2, 10 and 50 mg/kg) orally with and without glucose (1.8 g/kg) for 90 days. Blood glucose homeostasis was assessed by monitoring blood glucose and detecting glycoproteins. Glucose tolerance was also evaluated by the oral glucose tolerance test. The levels of blood glucose-related hormones such as insulin, C-peptide and glucagon were measured. We found that subchronic co-exposure of TiO2 NPs and glucose caused slight imbalance of blood glucose homeostasis in vivo. Mild and temporary hypoglycemia, impaired glucose tolerance and changes of glucose-regulating hormones were shown in the exposure groups. The combined effect of TiO2 NPs and glucose was more apparent than that of TiO2 NPs alone, which may be due to the effects of excess glucose and the interactions between TiO2 NPs and glucose. The antagonistic effect of TiO2 NPs with glucose did exist in the level of glycosylated hemoglobin in female rats. Gender differences were apparent in these effects induced by TiO2 NPs and glucose. Female rats seemed to be more susceptible for blood glucose disorders. Co-exposure of TiO2 NPs and excessive glucose could induce gender-dependent imbalance of blood glucose homeostasis in rats. It may be the reason that these consumers face greater health risks glycosylated hemoglobin.


Active devices based on organic semiconductors for wearable applications.
Plastic electronics is an enabling technology for obtaining active (transistor based) electronic circuits on flexible and/or nonplanar surfaces. For these reasons, it appears as a perfect candidate to promote future developments of wearable electronics toward the concept of fabrics and garments made by functional (in this case, active electronic) yarns. In this paper, a panoramic view of recent achievements and future perspectives is given.


The role of N6-methyladenosine (m6A) in kidney diseases.
Chemical modifications are a specific and efficient way to regulate the function of biological macromolecules. Among them, RNA molecules exhibit a variety of modifications that play important regulatory roles in various biological processes. More than 170 modifications have been identified in RNA molecules, among which the most common internal modifications include N6-methyladenine (m6A), n1-methyladenosine (m1A), 5-methylcytosine (m5C), and 7-methylguanine nucleotide (m7G). The most widely affected RNA modification is m6A, whose writers, readers, and erasers all have regulatory effects on RNA localization, splicing, translation, and degradation. These functions, in turn, affect RNA functionality and disease development. RNA modifications, especially m6A, play a unique role in renal cell carcinoma disease. In this manuscript, we will focus on the biological roles of m6A in renal diseases such as acute kidney injury, chronic kidney disease, lupus nephritis, diabetic kidney disease, and renal cancer.


Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer (HNPCC).
Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominant cancer syndrome that confers an elevated risk of early-onset colorectal cancer (CRC) and increased lifetime risk for other cancers of the endometrium, stomach, small intestine, hepatobiliary system, kidney, ureter, and ovary. Lynch syndrome accounts for up to 3% of all CRC, making it the most common hereditary colorectal cancer syndrome. Germline mutations in methyl-directed mismatch repair (MMR) genes give rise to microsatellite instability (MSI) in tumor DNA. Lynch syndrome is most frequently caused by pathogrenic variants in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Germline mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with Lynch syndrome. Pathogenic vatiants in MSH6 have been reported in approximately 7-10% of families with Lynch syndrome. Pathogenic variants in PMS2 account for fewer than 5% of mutations in families with Lynch syndrome. This unit presents a comprehensive molecular genetic testing strategy for Lynch syndrome including MSI analysis, next generation sequencing (NGS)-based targeted sequence analysis, PCR-based Sanger sequencing and microarray-based comparative genomic hybridization (array-CGH). © 2017 by John Wiley & Sons, Inc.


Experiences of women in a minimal contact pedometer-based intervention: a qualitative study.
Minimal contact pedometer-based interventions are gaining in popularity as a cost-effective method of promoting physical activity. The experiences of women in these interventions, however, have not been adequately studied. This study used focus groups to explore women's experiences in a minimal contact pedometer-based intervention. Participants were women aged 31 to 51 years who completed a 6-week minimal contact pedometer-based intervention. Before the intervention, all participants were inactive or irregularly active. For the intervention, participants wore pedometers, completed weekly logs of daily steps taken, created physical activity goals, and received weekly emails. Email messages contained strategies for increasing physical activity and served as reminders to wear the pedometer and submit the step logs. After the intervention, participants were invited to attend focus groups to discuss their experiences in the intervention. A generic qualitative research approach was used to analyze the data. Wearing the pedometer helped participants set goals and motivated them to increase their physical activity. Submitting step logs made them accountable. They wanted more innovative tips in the emails for increasing physical activity. Our results suggest that the effectiveness of minimal contact interventions may be enhanced by including pedometers, step logs, and email reminders.


Multidisciplinary Approach Towards Hypertensive and Chronic Alcoholic Patient With Intracerebral Bleed.
Intracerebral haemorrhage, the most lethal form of stroke, accounts for almost a third of all strokes. The brain receives and expels blood through blood arteries. Veins or arteries may rupture due to trauma, improper development, or excessive pressure. Blood itself has the potential to harm brain tissue. Here, we discuss the case of a 36-year-old individual who experienced giddiness, two to three seizure episodes, and left extremity weakness. Investigation revealed an intracerebral bleed. Physiotherapy was necessary to enable the patient to carry out his everyday activities comfortably in addition to medical management. The patient's condition was improved with the help of a physiotherapy protocol.


Nosocomial candidemia in a tertiary care hospital in Saudi Arabia.
Demographic information, risk factors, therapy, and outcome for all patients who had candidemia at King Fahad teaching hospital Al-khobar, between January 1995 and January 2000 were retrospectively reviewed. Thirty-two candidemic patients were identified. Candida parapsilosis was the most frequently isolated species (44%), followed by Candida tropicalis (25%), Candida albicans (19%), Candida krusei (6%), Candida glabrata (3%), and Candida guilliermondi (3%). Risk factors included recent broad-spectrum antibiotics use (100%), ICU residency (71%), central venous catheters (66%), recent surgery (56%), total parenteral nutrition (43%), and immunosuppressive therapy (31%). Fluconazole was used before the onset of candidemia in only two patients. The overall mortality rate was 44%. Eight (25%) episodes of candidemia were not diagnosed and treated before the patient's demise. In view of the high mortality rate associated with hematogenous candidiasis, and lack of sensitive and specific laboratory tests necessary for the premortem diagnosis of infection, empirical antifungal therapy is recommended for high-risk patients.


Program assessment framework for a rural palliative supportive service.
Although there are a number of quality frameworks available for evaluating palliative services, it is necessary to adapt these frameworks to models of care designed for the rural context. The purpose of this paper was to describe the development of a program assessment framework for evaluating a rural palliative supportive service as part of a community-based research project designed to enhance the quality of care for patients and families living with life-limiting chronic illness. A review of key documents from electronic databases and grey literature resulted in the identification of general principles for high-quality palliative care in rural contexts. These principles were then adapted to provide an assessment framework for the evaluation of the rural palliative supportive service. This framework was evaluated and refined using a community-based advisory committee guiding the development of the service. The resulting program assessment framework includes 48 criteria organized under seven themes: embedded within community; palliative care is timely, comprehensive, and continuous; access to palliative care education and experts; effective teamwork and communication; family partnerships; policies and services that support rural capacity and values; and systematic approach for measuring and improving outcomes of care. It is important to identify essential elements for assessing the quality of services designed to improve rural palliative care, taking into account the strengths of rural communities and addressing common challenges. The program assessment framework has potential to increase the likelihood of desired outcomes in palliative care provisions in rural settings and requires further validation.


Studies on hypothalamo-pituitary corticoliberin system. I. Localization of corticotropin-releasing factor (CRF)- and neurophysin-immunoreactive neurons in the Mongolian gerbil (Meriones unguiculatus).
The immunohistochemical localization of CRF- and neurophysin-containing neurons in the hypothalamus of the Mongolian gerbil was studied by means of the PAP technique. The CRF-immunoreactive fibers were detected mainly in the outer layer of the median eminence of intact adult male gerbils. The CRF-positive neurons respond to aminoglutethimide (Elipten, Ciba) administration by showing increased immunoreactivity and an increase in the number of stained cell bodies in the parvocellular division of the paraventricular nucleus. Aminoglutethimide treatment results also in an increase in the number of neurophysin-immunoreactive nervous fibers localized in the internal layer of the median eminence. However, CRF-immunoreactive fibers are observed mainly in the outer layer of the median eminence while neurophysin-immunopositive axons are seen predominantly in the internal layer of this region. Since the axons of paraventricular neurons run to the median eminence and their staining ability is changed due to aminoglutethimide, their involvement in the endocrine control of hypophysial ACTH release is postulated.


Kruppel-like factor-9 (KLF9) inhibits glioblastoma stemness through global transcription repression and integrin α6 inhibition.
It is increasingly important to understand the molecular basis for the plasticity of neoplastic cells and their capacity to transition between differentiated and stemlike phenotypes. Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation, and neural development; however, the molecular basis for the diverse contextual functions of KLF9 remains unclear. This study focused on the functions of KLF9 in human glioblastoma stemlike cells. We established for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stemlike cells and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, showed that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation and identify KLF9-regulated molecular targets applicable to cancer therapeutics.


Growth of silicon nanowires on H-terminated Si {111} surface templates studied by transmission electron microscopy.
We have studied the growth of silicon nanowires (SiNWs) by means of transmission electron microscopy. SiNWs are grown from nanocatalysts via the Vapor-Liquid-Solid (VLS) mechanism using silane (SiH4) gas as a source gas. The nanocatalysts are prepared on a hydrogen (H)-terminated Si surface. We have examined the formation mechanism of nanocatalysts on H-terminated surface and have observed several structural variants of SiNWs. According to the study we have suggested that many structural variations of SiNWs are possible, which modify the structural properties of SiNWs to great extents.


[1-deaminopenicillamine,4-valine]-8-D-arginine-vasopressin, a highly potent inhibitor of the vasopressor response to arginine-vasopressin.
In attempting to design an antagonist of the antidiuretic response to arginine-vasopressin (AVP) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP) was synthesized by the solid-phase method and assayed for antidiuretic, vasopressor, and oxytocic activities. dPVDAVP has an antidiuretic potency of 123 +/- 22 units/mg, one-tenth that of its parent [deamino,4-valine,8-D-arginine]vasopressin (dVDAVP). Like dVDAVP its antidiuretic effect in conscious diabetes insipidus rats is greatly prolonged when compared to AVP. dPVDAVP causes a prolonged inhibition of vasopressor responses to AVP but not to norepinephrine or angiotensin II. It has an antivasopressor pA2 value of 7.82 +/- 0.05 when tested against AVP. Thus the penicillamine substitution at position 1 in dVDAVP increased its antivasopressor activity sixfold (dVDAVP has a pA2 value of 7.03 +/- 0.11). dPVDAVP is thus the most potent vasopressor antagonist yet reported. dPVDAVP was also found to be a potent inhibitor of the in vitro oxytocic response to oxytocin (pA2 value = 7.23 +/- 0.04). dPVDAVP with its potent and specific ability to antagonize the vasopressor effects of AVP should be a useful pharmacological tool with which to explore the possible participation of AVP's potent vasoconstrictor properties in cardiovascular regulation in physiological and pathological states.


[Characterization of aromatic hydrocarbons in heavy gas oil using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry].
An analytical method for separating and identifying the aromatic hydrocarbons in heavy gas oil using comprehensive two-dimensional gas chromatography (GC x GC) coupled to time-of-flight mass spectrometry (TOF MS) was established. The two-dimensional distribution by ring number of the aromatic hydrocarbons was obtained. Besides phenanthrene and methyl-phenanthrene, many other polycyclic aromatic hydrocarbons (PAHs) such as pyrene and benzo [a] anthracene were identified by using the retention times, standard mass spectra or literature reports. The method was successfully applied to the hydrotreating process of heavy gas oil and the hydrotreated products of phenanthrene, pyrene were identified. This method provided technical support for the characterization of aromatic hydrocarbons in heavy gas oil and the investigation of hydrogenation mechanism of polycyclic aromatic hydrocarbons. Compared with the conventional method, gas chromatography coupled to mass spectrometry (GC-MS), the GC x GC-TOF MS method illustrated the obvious advantages for heavy gas oil analysis.


Functional asymmetry in the motor performances of women: neuropsychological effects of depression.
The influence of depression on the cerebral hemispheric motor functioning of 40 right-handed women, half of whom had been classified as depressed, the other half as nondepressed, was examined. The depressed women were also characterized by elevated state and trait anxiety, suggestive of an anxious-depressive state with heightened arousal. A hand dynamometer was used as a standardized measure of hemispheric motor functioning such as hand-grip strength, perseveration, and fatigue. Primary findings indicated that depressed women displayed significantly less perseveration at the left hand than did nondepressed women, but a nonsignificant trend only was noted for less perseveration at the right hand. These results suggest possible differential arousal of the left and right cerebral hemispheres in this sample of anxious-depressed women and are discussed in terms of arousal theory.


Primary rat hepatocytes express cyclin D1 messenger RNA during their growth cycle and during mitogenic transitions induced by transforming growth factor-alpha.
Cyclin D1 messenger RNA expression was investigated in differentiated proliferation-competent primary cultures of adult rat hepatocytes. Periodic expression was observed during the 12-day growth cycle (approximately two population doublings). Upon reaching a quiescent G(o)-state, 4-kb cyclin D1 mRNA levels were undetectable. When G(o) cultures were shifted into defined media without or with 0.2-0.8 nM TGF-alpha, conditions that reinitiate full proliferative transitions synchronously, cyclin D1 mRNA levels were elevated 1.2-4.6-fold, respectively. These findings support the hypothesis that hepatic mitogens stimulate periodic cyclin mRNA expression directly.


In vitro antiplasmodial and cytotoxic activities of sesquiterpene lactones from Vernonia fimbrillifera Less. (Asteraceae).
Due to the in vitro antiplasmodial activity of leaf extracts from Vernonia fimbrillifera Less. (Asteraceae), a bioactivity-guided fractionation was carried out. Three sesquiterpene lactones were isolated, namely 8-(4'-hydroxymethacrylate)-dehydromelitensin (1), onopordopicrin (2) and 8α-[4'-hydroxymethacryloyloxy]-4-epi-sonchucarpolide (3). Their structures were elucidated by spectroscopic methods (1D and 2D NMR and MS analyses) and by comparison with published data. The isolated compounds exhibited antiplasmodial activity with IC50 values ≤ 5 μg/mL. Cytotoxicity of the compounds against a human cancer cell line (HeLa) and a mouse lung epithelial cell line (MLE12) was assessed to determine selectivity. Compound 3 displayed promising selective antiplasmodial activity (SI > 10).


Molecular and cellular mechanisms underlying defective antibody responses.
Primary immune deficiency is caused by genetic mutations that result in immune dysfunction and subsequent susceptibility to infection. Over the last decade there has been a dramatic increase in the number of genetically defined causes of immune deficiency including those which affect B-cell function. This has not only identified critical nonredundant pathways that control the generation of protective antibody responses but also revealed that immunodeficiency and autoimmunity are often closely linked. Here we explore the molecular and cellular mechanisms of these rare monogenic conditions that disrupt antibody production, which also have implications for understanding the causes of more common polygenic immune dysfunction.


Intermittent claudication: symptom severity versus health values.
The objective of this study was to obtain health values from patients with intermittent claudication with five different instruments and to study the construct validity of these measures of health-related quality of life by examining their relation with symptom severity. We included all patients with intermittent claudication who participated in an exercise program of the Department of Internal Medicine at our university hospital (n = 92). Health value instruments included the verbal rating scale, time trade-off, standard gamble, EuroQol, and the Health Utilities Index (Mark III). Symptom-free walking distance was used as a measure of symptom severity. For all instruments the average health values in groups of patients with a symptom-free walking distance < or = 150 m were lower than the average values in patients with a greater walk distance, but the differences for the time trade-off and the standard gamble were small, and only the differences for the verbal rating scale and the EuroQol were statistically significant. At the individual patient level considerable heterogeneity was seen, and the statistical association of the symptom-free walking distance with health values varied from poor to moderate (Spearman rank correlations, 0.03 to 0.48; p values, 0.003 to 0.78). At least for the verbal rating scale and the EuroQol, the results of our study provide evidence of the validity of the various health value instruments in a population of patients with peripheral arterial occlusive disease.


A new simplified comorbidity score as a prognostic factor in non-small-cell lung cancer patients: description and comparison with the Charlson's index.
Treatment of non-small-cell lung cancer (NSCLC) might take into account comorbidities as an important variable. The aim of this study was to generate a new simplified comorbidity score (SCS) and to determine whether or not it improves the possibility of predicting prognosis of NSCLC patients. A two-step methodology was used. Step 1: An SCS was developed and its prognostic value was compared with classical prognostic determinants in the outcome of 735 previously untreated NSCLC patients. Step 2: the SCS reliability as a prognostic determinant was tested in a different population of 136 prospectively accrued NSCLC patients with a formal comparison between SCS and the classical Charlson comorbidity index (CCI). Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The SCS summarised the following variables: tobacco consumption, diabetes mellitus and renal insufficiency (respective weightings 7, 5 and 4), respiratory, neoplastic and cardiovascular comorbidities and alcoholism (weighting=1 for each item). In step 1, aside from classical variables such as age, stage of the disease and performance status, SCS was a statistically significant prognostic variable in univariate analyses. In the Cox model weight loss, stage grouping, performance status and SCS were independent determinants of a poor outcome. There was a trend towards statistical significance for age (P=0.08) and leucocytes count (P=0.06). In Step 2, both SCS and well-known prognostic variables were found as significant determinants in univariate analyses. There was a trend towards a negative prognostic effect for CCI. In multivariate analysis, stage grouping, performance status, histology, leucocytes, lymphocytes, lactate dehydrogenase, CYFRA 21-1 and SCS were independent determinants of a poor prognosis. CCI was removed from the Cox model. In conclusion, the SCS, constructed as an independent prognostic factor in a large NSCLC patient population, is validated in another prospective population and appears more informative than the CCI in predicting NSCLC patient outcome.


Molecular imaging for the diagnosis of high-risk plaque.
Despite advances in our understanding of the pathogenesis of atherosclerosis and new therapeutic modalities, the absence of an adequate method for early detection limits the prevention and treatment of the disease. High-resolution magnetic resonance has recently emerged as one of the most promising techniques for the non-invasive study of atherothrombotic disease, as it can characterize plaque composition and monitor progression. This review of plaque imaging focuses on the most recent technique: "molecular imaging", which uses specific contrast agents targeted to plaque components, and may allow for better stratification of "high-risk" plaque and "high-risk" patients.