Temporospatial tissue interactions regulating the regeneration of the enamel knot in the developing mouse tooth.
The enamel knot (EK), which is a transient signaling center in the tooth germ, regulates both the differential growth of the dental epithelium and the tooth shape. In this study, the regeneration of the EK was evaluated. The EK regions were removed from the E14 and E16 dental epithelia, and the remaining epithelia were recombined with their original dental mesenchymes. All these tooth germs could develop into calcified teeth after being transplanted into the kidney capsule for 3 weeks. One primary EK was regenerated earlier, and two or three secondary EKs were regenerated later in culture. When simply recombined without removing the EK, the tooth germ, which had four secondary EKs and four cuspal areas of the dental papilla, generated one primary EK first and subsequent secondary EKs. These results indicate that the patterning of the EK in all tooth germs always starts from a primary EK independent of the direct epithelial or mesenchymal control. This suggests that neither the dental epithelium nor the dental mesenchyme can dictate the pattern or number of the EK formation, but the interaction between the dental epithelium and the dental mesenchyme is essential for the regeneration and patterning of the EKs.


The patient-centered medical home for chronic illness: is it ready for prime time?
Robert Berenson and colleagues caution that the patient-centered medical home (PCMH) faces many challenges. Its successful adoption will depend on its being precisely defined and demonstration that it is cost saving and scalable across varied clinical settings. Until these issues are addressed in current and upcoming pilot programs, caution about the PCMH's role in the care of people with chronic illnesses is warranted.


Development and validation of 4 different rat models of uncontrolled hemorrhage.
Hemorrhage is the leading cause of death in military trauma and second leading cause of death in civilian trauma. Although many well-established animal models of hemorrhage exist in the trauma and anticoagulant literature, few focus on directly quantitating blood loss. To establish and validate a reproducible rodent model of uncontrolled hemorrhage to serve as the foundation for developing therapies for noncompressible torso trauma. We developed and evaluated 4 different hemorrhage models using male Sprague-Dawley rats (6 rats/model), aged 10 to 14 weeks and weighing 330 to 460 g, at the Department of Surgery, Northwestern University. We used tail-cut (4 cm), liver punch biopsy (12 mm), liver laceration (3.0 × 1.5 cm), and spleen transection models. All animals underwent invasive hemodynamic monitoring. Blood loss, expressed as a percentage of total blood volume (TBV), mean arterial pressure, and heart rate, which were recorded at 2- to 5-minute intervals. The tail-cut model resulted in a mean (SD) TBV loss of 15.4% (6.0%) with hemodynamics consistent with class I hemorrhagic shock. The liver punch biopsy model resulted in a mean (SD) TBV loss of 16.7% (3.3%) with hemodynamics consistent with class I hemorrhagic shock. The liver laceration model resulted in a mean (SD) TBV loss of 19.8% (3.0%) with hemodynamics consistent with class II hemorrhagic shock. The spleen transection model resulted in the greatest blood loss (P < .01), with a mean (SD) TBV loss of 27.9% (3.4%) and hemodynamics consistent with class II hemorrhagic shock. The liver laceration and punch biopsy models resulted in most of the blood loss within the first 2 minutes, whereas the spleen transection and tail-cut models resulted in a steady loss during 10 minutes. The liver laceration and spleen transection models resulted in the greatest degree of hemodynamic instability (mean [SD] arterial pressure decreases of 25 [1] and 41 [11] mm Hg, respectively). One-hour survival was 100% in all 4 models. We established and validated the reproducibility of 4 different rat models of uncontrolled hemorrhage. These models provide a foundation to design novel nonsurgical therapies to control hemorrhage, and the different degrees of hemorrhagic shock produced from these models allow for flexibility in experimental design.


A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors.
AC-7700, a novel combretastatin A-4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC-7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early-stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2-0.5 cm3, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm3. At its MTD, AC-7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC-7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor-alpha production, AC-7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC-7700 is a novel antivascular agent that may have potent activity against advanced-stage cancer in the clinical setting.


Inactivation Kinetics of Coxiella burnetii During High-Temperature Short-Time Pasteurization of Milk.
The Gram-negative, obligate intracellular bacterium Coxiella burnetii is the causative organism of the zoonosis Q fever and is known for its resistance toward various intra- and extracellular stressors. Infected ruminants such as cattle, sheep, and goats can shed the pathogen in their milk. Pasteurization of raw milk was introduced for the inactivation of C. burnetii and other milk-borne pathogens. Legal regulations for the pasteurization of milk are mostly based on recommendations of the Codex Alimentarius. As described there, C. burnetii is considered as the most heat-resistant non-spore-forming bacterial pathogen in milk and has to be reduced by at least 5 log10-steps during the pasteurization process. However, the corresponding inactivation data for C. burnetii originate from experiments performed more than 60 years ago. Recent scientific findings and the technological progress of modern pasteurization equipment indicate that C. burnetii is potentially more effectively inactivated during pasteurization than demanded in the Codex Alimentarius. In the present study, ultra-high heat-treated milk was inoculated with different C. burnetii field isolates and subsequently heat-treated in a pilot-plant pasteurizer. Kinetic inactivation data in terms of D- and z-values were determined and used for the calculation of heat-dependent log reduction. With regard to the mandatory 5 log10-step reduction of the pathogen, the efficacy of the established heat treatment regime was confirmed, and, in addition, a reduction of the pasteurization temperature seems feasible.


Interleukin 1 and its relationship to endotoxin tolerance.
Endotoxin (lipopolysaccharide [LPS])-induced cytokine release has been implicated in the pathogenesis of sepsis. Sublethal doses of LPS induce tolerance to a septic insult. This study evaluated pretreatment with interleukin 1 (IL-1) against an LPS challenge and examined its relationship to endotoxin tolerance. C3H/HeN mice (N = 100) were injected intraperitoneally with phosphate-buffered saline (control group), IL-1 (200 micrograms/kg), or LPS (1 mg/kg) for 3 days. On day 5, peritoneal macrophages were harvested and assayed for antimicrobial activity (superoxide anion production and Candida albicans phagocytosis). Serum cytokine levels and survival after an LPS challenge on day 5 were also assessed. Pretreatment with IL-1 or LPS significantly increased superoxide anion production, C albicans phagocytosis, and survival compared with pretreatment with phosphate-buffered solution. Interleukin 6 levels significantly decreased in the IL-1 and LPS groups. Peak levels of tumor necrosis factor significantly decreased only in the LPS group. Thus, pretreatment with IL-1 or low doses of LPS may exert protective effects by decreasing levels of interleukin 6 while increasing antimicrobial activity. Mice pretreated with IL-1 were protected from endotoxin despite elevated peak levels of tumor necrosis factor, suggesting a different mechanism for endotoxin tolerance than for tolerance to tumor necrosis factor.


Evolutionary genomics of Staphylococcus aureus reveals insights into the origin and molecular basis of ruminant host adaptation.
Phenotypic biotyping has traditionally been used to differentiate bacteria occupying distinct ecological niches such as host species. For example, the capacity of Staphylococcus aureus from sheep to coagulate ruminant plasma, reported over 60 years ago, led to the description of small ruminant and bovine S. aureus ecovars. The great majority of small ruminant isolates are represented by a single, widespread clonal complex (CC133) of S. aureus, but its evolutionary origin and the molecular basis for its host tropism remain unknown. Here, we provide evidence that the CC133 clone evolved as the result of a human to ruminant host jump followed by adaptive genome diversification. Comparative whole-genome sequencing revealed molecular evidence for host adaptation including gene decay and diversification of proteins involved in host-pathogen interactions. Importantly, several novel mobile genetic elements encoding virulence proteins with attenuated or enhanced activity in ruminants were widely distributed in CC133 isolates, suggesting a key role in its host-specific interactions. To investigate this further, we examined the activity of a novel staphylococcal pathogenicity island (SaPIov2) found in the great majority of CC133 isolates which encodes a variant of the chromosomally encoded von Willebrand-binding protein (vWbp(Sov2)), previously demonstrated to have coagulase activity for human plasma. Remarkably, we discovered that SaPIov2 confers the ability to coagulate ruminant plasma suggesting an important role in ruminant disease pathogenesis and revealing the origin of a defining phenotype of the classical S. aureus biotyping scheme. Taken together, these data provide broad new insights into the origin and molecular basis of S. aureus ruminant host specificity.


Mobility and potential bioavailability of antimony in contaminated soils: Short-term impact on microbial community and soil biochemical functioning.
Antimony (Sb) and its compounds are emerging priority pollutants which pose a serious threat to the environment. The aim of this study was to evaluate the short-term fate of antimonate added to different soils (S1 and S2) with respect to its mobility and impact on soil microbial communities and soil biochemical functioning. To this end, S1 (sandy clay loam, pH 8.2) and S2 (loamy coarse sand, pH 4.9) soils were spiked with 100 and 1000 mg Sb(V) kg-1 soil and left in contact for three months. Sequential extractions carried out after this contact time indicated a higher percentage of labile antimony in the Sb-spiked S1 soils than S2 (e.g. ~13 and 4% in S1 and S2 treated with 1000 mg Sb(V) kg-1 respectively), while the opposite was found for residual (hardly bioavailable) Sb. Also, a reduced number of culturable heterotrophic bacteria was recorded in Sb-spiked S1 soil (compared to the unpolluted S1), while an increased one was found in S2. Heterotrophic fungi followed the opposite trend. Actinomycetes and heat-resistant aerobic bacterial spores showed a variable trend depending on the soil type and Sb(V) treatment. The Biolog community level physiological profile indicated a reduced metabolic activity potential of microbial communities from the Sb-spiked S1 soils (e.g. <50% for Sb-1000 compared to the unpolluted S1), while an increase was recorded for those extracted from the Sb-spiked S2 soils (e.g. >2-fold for Sb-1000). The soil dehydrogenase activity followed the same trend. High-throughput 16S rRNA amplicon sequencing analysis revealed that Sb did not influence the bacterial α-diversity in both soils, while significantly affected the composition of the respective soil bacterial communities. Several phyla (e.g. Nitrosospira Nitrososphaeraceae, Adheribacter) were found positively correlated with the concentration of water-soluble Sb in soil. Overall, the results obtained suggest that the risk assessment in soils polluted with antimony should be a priority especially for alkaline soils where the high mobility of the anionic Sb(OH)6- species can pose, at least in the short-term, a serious threat for soil microbial abundance, diversity and functionality, soil fertility and eventually human health.


Clinical efficacy of piracetam in treatment of breath-holding spells.
To evaluate the efficacy of piracetam therapy, 76 children with breath-holding spells admitted to the Outpatient Clinic of Dicle University Medical Faculty Paediatrics Department and Bakirköy State Hospital, Paediatrics Department between 1988 and 1990 and 1991 and 1996, respectively, were included in this placebo-controlled trial. Diagnosis of breath-holding spells was made for all cases by medical history, pediatric physical examination, electroencephalogram, and laboratory findings. Placebo or piracetam as suspension was administered to patients on a randomized basis; piracetam was administered to children in suspension 40 mg/kg/day in 2 divided doses for a period of 2 months. Of the 76 children enrolled, 39 received piracetam and 37 received placebo. Overall, control of breath-holding spells was observed in 92.3% of the patients in the group taking piracetam as compared with 29.7% in the group taking placebo (P < .05). No differences between the 2 groups in adverse events or side effects were observed. Complete blood count, biochemical profile, and urine analysis taken before and after treatment revealed no change from beginning to end and no difference between the 2 groups. It is suggested that piracetam is a safe and effective drug, with an incidence of side effects no different from that of placebo, for the treatment of breath-holding spells.


Development and Psychometric Assessment of Novel Item Banks for Hereditary Retinal Diseases.
This study develops psychometrically valid item banks across 10 areas of quality of life (QoL) specific to people with hereditary retinal diseases, which will enable clinicians and researchers to explore the impact of hereditary retinal diseases across all aspects of QoL. The purpose of this study was to assess the psychometric properties of hereditary retinal disease QoL item banks using Rasch analysis and demonstrate the effectiveness of a computerized adaptive testing (CAT) system in obtaining precise measurement of QoL using only a few items. The hereditary retinal disease item banks were answered by 233 participants (median age, 58 years; range, 18 to 94 years; female participants, 59%). The hereditary retinal disease item banks cover 10 QoL domains: activity limitation, mobility, emotional, social, convenience, economic, health concerns, visual symptoms, ocular comfort symptoms, and general symptoms. Rasch analysis assessed the psychometric properties of the 10 item banks and provided item calibrations for the development of CAT. Computerized adaptive testing simulations were performed to calculate the average number of items required to gain precise measurement of each QoL domain. The convenience, economic, visual symptoms, and the social domains formed unidimensional scales. However, the activity limitation and health concerns domains demonstrated multidimensionality and required major modifications to resolve this, which resulted in four new QoL domains, namely, reading, driving, lighting, and concerns about the disease progression. In total, 10 item banks underwent CAT simulation testing, which indicated that 8 to 12 items were required to gain precise measurement of each QoL domain. We have developed 10 psychometrically valid item banks to measure the QoL domains relevant to people with hereditary retinal diseases. On average, only 5 and 10 items were required to gain measurement at moderate and high precision, respectively.


Intelligence and education: causal perceptions drive analytic processes and therefore conclusions.
Educational attainment is associated with many life outcomes, including income, occupation and many health and lifestyle variables. Many researchers use it as a control variable in epidemiological and other social scientific studies, often without specifying exactly what environmental effects or set of personal characteristics is being controlled. Other researchers assume that genetically influenced intelligence drives educational attainment, and think that intelligence is the appropriate control variable. Researchers' different and often unstated causal assumptions can lead to very different analytical approaches and thus to very different results and interpretations. We document several examples of this important variation in the treatment of education and intelligence and their association. We recommend greater clarity in stating underlying assumptions and developing analytical approaches and greater objectivity in interpreting results. We discuss implications for study designs.


Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia.
Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), the putative site of the hypothalamic circadian pacemaker, to determine the nature and degree of pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheimer disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick disease and 2 had severe hippocampal sclerosis. Comparisons were made with a control group composed of 13 age-matched patients with no clinical or pathological evidence of dementia or other CNS disorders. To determine the pathologic involvement within the SCN, human hypothalami were stained with: Nissl, Bielchowsky silver, thioflavin S and specific antibodies directed against vasopressin (VP), neurotensin (NT), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neurofibrillary tangle formation. Only rare diffuse plaques were noted. The pathologic changes within the SCN were less severe than in the other brain regions. Morphometric analysis was accomplished using a stereological approach to sample the average total number of positively stained neurons and astrocytes in 10 different 0.1mm2 microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrease in vasopressin (9.75 vs 16.7, p < 0.001) and neurotensin (6.82 vs 9.63, p < 0.002) neurons, as well as a corresponding increase in the GFAP-stained astrocyte/Nissl-stained neuron ratio (0.54 vs 0.10, p < 0.009). These studies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable indicator of disease-related pathology within the SCN. Taken collectively, our data support the hypothesis that damage to the SCN may be an underlying anatomical substrate for the clinically observed changes in circadian rhythmicity that have been observed in Alzheimer patients.


Health-Related Quality of Life, Pain and Sleep in Patients with HIV Depending on the Clinical Situation: A Cross-Sectional Pilot Study.
Introduction: Health-related quality of life (HRQL), pain and sleep have been described as relevant traits in patients with human immunodeficiency virus (HIV). The aim of this study is to describe and evaluate HRQL, pain and sleep and their interdependence in HIV-positive patients. Methods: A cross-sectional study on HIV-infected patients was conducted. A set of five different questionnaires was used: two questionnaires addressing HRQL (Short Form 36 [SF-36] Health Survey and Medical Outcomes Study Short Form 30 [MOS-SF 30]), one on pain (McGill Pain Questionnaire) and one on sleep (Pittsburgh Sleep Quality Index [PSQI]). We also collected the sociodemographic and clinical characteristics of patients. Results: The sample included 109 patients (age: 46.08 ± 10.49 years; 68.8% male). The pain experience was independent of HRQL and sleep. Relationships among HRQL, pain and sleep associated to sociodemographic and clinical factors were not detected (p > 0.05). Patients with CDC category A showed moderate to high correlations among HRQL, pain and sleep. In CDC B-type patients, a moderate correlation was observed between pain and mental health. In CDC C patients, moderate correlations were observed between HRQL and sleep and pain and sleep, with no correlations between HRQL and pain. Conclusions: HRQL, pain and sleep are differently correlated in HIV patients depending on their clinical stage. Neither the nadir of CD4-T cells nor the current count of CD4-T cells was found to be related with HRQL, pain or sleep.


Feasibility Study of an Educational Intervention to Improve Water Intake in Adolescent Soccer Players: A Two-Arm, Non-Randomized Controlled Cluster Trial.
This study aimed to assess the feasibility of an educational intervention on hydration behavior in adolescent soccer players. A pilot study of a two-arm, non-randomized controlled cluster trial was conducted. A total of 316 players aged 13-16 agreed to participate. The response variables were the players' participation in the intervention, their perception of the knowledge acquired, the usefulness and the overall assessment of the intervention. Hydration patterns and acquisition of knowledge on hydration behavior were also assessed. The intervention involved two elements: posters and a web app. A total of 259 adolescents completed the study (intervention group (IG) = 131; control group (CG) = 128). 80.6% of the players responded to the survey assessing the feasibility of the intervention. The mean number of correct answers regarding behavior was significantly higher in the IG (3.54; SD = 1.162) than in the CG (2.64; SD = 1.174) (p < 0.001). The water consumption pattern at all the clubs was ad libitum. Of the players, 10% did not drink any water at all during the game. In conclusion, this intervention has been shown to be feasible for implementation with adolescent soccer players. It suggests that hydration guidelines should be informed by personal factors and that ad libitum water consumption should be avoided.


Interplay of Fracture and Martensite Transformation in Microstructures: A Coupled Problem.
We are witnessing a tremendous transition towards a society powered by net-zero carbon emission energy, with a corresponding escalating reliance on functional materials (FM). In recent years, the application of FM in multiphysics environments has brought new challenges to the mechanics and materials research communities. The underlying mechanism in FM, which governs several fundamental characteristics, is known as martensitic phase transformation (MPT). When it comes to the application of FM in the multiphysics context, a thorough understanding of the interplay between MPT and fracture plays a crucial role in FM design and application. In the present work, a coupled problem of crack nucleation and propagation and multivariant stress-induced MPT in elastic materials is presented using a finite element method based on Khachaturyan's microelasticity theory. The problem is established based on a phase-field (PF) approach, which includes the Ginzburg-Landau equations with advanced thermodynamic potential and the variational formulation of Griffith's theory. Therefore, the model consists of a coupled system of the Ginzburg-Landau equations and the static elasticity equation, and it characterizes evolution of distributions of austenite and two martensitic variants as well as crack growth in terms of corresponding order parameters. The numerical results show that crack growth does not begin until MPT has grown almost completely through the microstructure. Subsequent to the initial formation of the martensite variants, the initial crack propagates in such a way that its path mainly depends on the feature of martensite variant formations, the orientation and direction upon which the martensite plates are aligned, and the stress concentration between martensite plates. In addition, crack propagation behavior and martensite variant evaluations for different lattice orientation angles are presented and discussed in-detail.


Melatonin supplementation in patients with complete tetraplegia and poor sleep.
People with complete tetraplegia have interrupted melatonin production and commonly report poor sleep. Whether the two are related is unclear. This pilot study investigated whether nightly supplementation of 3 mg melatonin would improve objective and subjective sleep in tetraplegia. Five participants with motor and sensory complete tetraplegia ingested 3 mg melatonin (capsule) two hours prior to usual sleep time for two weeks. Full portable sleep studies were conducted in participants' homes on the night before commencing melatonin supplementation (baseline) and on the last night of the supplementation period. Endogenous melatonin levels were determined by assaying saliva samples collected the night of (just prior to sleep) and morning after (upon awakening) each sleep study. Prior to each sleep study measures of state sleepiness and sleep behaviour were collected. The results showed that 3 mg of melatonin increased salivary melatonin from near zero levels at baseline in all but one participant. A delay in time to Rapid Eye Movement sleep, and an increase in stage 2 sleep were observed along with improved subjective sleep experience with a reduction in time to fall asleep, improved quality of sleep and fewer awakenings during the night reported. Daytime sleepiness increased however. A randomised, placebo controlled trial with a larger sample is required to further explore and confirm these findings.


Bacterial polymerase and yeast polymerase II use similar mechanisms for transcription through nucleosomes.
We have previously shown that nucleosomes act as a strong barrier to yeast RNA polymerase II (Pol II) in vitro and that transcription through the nucleosome results in the loss of an H2A/H2B dimer. Here, we demonstrate that Escherichia coli RNA polymerase (RNAP), which never encounters chromatin in vivo, behaves similarly to Pol II in all aspects of transcription through the nucleosome in vitro. The nucleosome-specific pausing pattern of RNAP is comparable with that of Pol II. At physiological ionic strength or lower, the nucleosome blocks RNAP progression along the template, but this barrier can be relieved at higher ionic strength. Transcription through the nucleosome by RNAP results in the loss of an H2A/H2B dimer, and the histones that remain in the hexasome retain their original positions on the DNA. The results were similar for elongation complexes that were assembled from components (oligonucleotides and RNAP) and elongation complexes obtained by initiation from the promoter. The data suggest that eukaryotic Pol II and E. coli RNAP utilize very similar mechanisms for transcription through the nucleosome. Thus, bacterial RNAP can be used as a suitable model system to study general aspects of chromatin transcription by Pol II. Furthermore, the data argue that the general elongation properties of polymerases may determine the mechanism used for transcription through the nucleosome.


Multi-tissue transcriptomic study reveals the main role of liver in the chicken adaptive response to a switch in dietary energy source through the transcriptional regulation of lipogenesis.
Because the cost of cereals is unstable and represents a large part of production charges for meat-type chicken, there is an urge to formulate alternative diets from more cost-effective feedstuff. We have recently shown that meat-type chicken source is prone to adapt to dietary starch substitution with fat and fiber. The aim of this study was to better understand the molecular mechanisms of this adaptation to changes in dietary energy sources through the fine characterization of transcriptomic changes occurring in three major metabolic tissues - liver, adipose tissue and muscle - as well as in circulating blood cells. We revealed the fine-tuned regulation of many hepatic genes encoding key enzymes driving glycogenesis and de novo fatty acid synthesis pathways and of some genes participating in oxidation. Among the genes expressed upon consumption of a high-fat, high-fiber diet, we highlighted CPT1A, which encodes a key enzyme in the regulation of fatty acid oxidation. Conversely, the repression of lipogenic genes by the high-fat diet was clearly associated with the down-regulation of SREBF1 transcripts but was not associated with the transcript regulation of MLXIPL and NR1H3, which are both transcription factors. This result suggests a pivotal role for SREBF1 in lipogenesis regulation in response to a decrease in dietary starch and an increase in dietary PUFA. Other prospective regulators of de novo hepatic lipogenesis were suggested, such as PPARD, JUN, TADA2A and KAT2B, the last two genes belonging to the lysine acetyl transferase (KAT) complex family regulating histone and non-histone protein acetylation. Hepatic glycogenic genes were also down-regulated in chickens fed a high-fat, high-fiber diet compared to those in chickens fed a starch-based diet. No significant dietary-associated variations in gene expression profiles was observed in the other studied tissues, suggesting that the liver mainly contributed to the adaptation of birds to changes in energy source and nutrients in their diets, at least at the transcriptional level. Moreover, we showed that PUFA deposition observed in the different tissues may not rely on transcriptional changes. We showed the major role of the liver, at the gene expression level, in the adaptive response of chicken to dietary starch substitution with fat and fiber.


Association of high blood pressure with renal insufficiency: role of albuminuria, from NHANES, 1999-2006.
The relationship between hypertension and kidney disease is complicated. Clinical trials found intense blood pressure control was not associated with alterations in glomerular filtration rate (GFR) in all patients but did slow the rate of GFR decline among those with a higher baseline proteinuria. However, the underlying mechanism has been unclear. We tested the hypothesis that the association between high blood pressure and renal function is modified by albuminuria status by conducting analyses in a cross-sectional study with 12,440 adult participants without known kidney diseases, diabetes or cardiovascular diseases, participating in the National Health and Nutrition Examination Survey (NHANES) 1999-2006. 1226 out of 12440 were found to have unknown high blood pressure and 4494 were found to have reduced renal function. Overall, a moderate association was found between high blood pressure and renal function insufficiency in all participants analyzed. However, among participants with albuminuria, the prevalence of moderate-severe renal insufficiency substantially and progressively increased from normal subjects to prehypertensive and undiagnosed hypertensive subjects (1.43%, 3.44%, 10.96%, respectively, P for trend<0.0001); on the other hand, the prevalence of undiagnosed hypertension was also significantly higher among subjects with moderate-severe renal insufficiency than those with mild renal insufficiency (35.54% Vs 19.09%, P value <0.05), supporting an association between hypertension and renal function damage. In contrast, no association between hypertension and renal insufficiency was observed among those without albuminuria in this population. Similar findings were observed when the CKD-EPI equation was used. The association between high blood pressure and reduced renal function could be dependent upon the albuminuria status. This finding may provide a possible explanation for results observed in clinical trials of intensive blood pressure control. Further studies are warranted to confirm our findings.


Molecular Dynamics Study of the Swelling of Poly(methyl methacrylate) in Supercritical Carbon Dioxide.
The swelling of a poly (methyl methacrylate) in supercritical carbon dioxide was studied by means of full atomistic classical molecular dynamics simulation. In order to characterize the polymer swelling, we calculated various properties related to the density, structure, and dynamics of polymer chains as a function of the simulation time, temperature, and pressure. In addition, we compared the properties of the macromolecular chains in supercritical CO2 with the properties of the corresponding bulk system at the same temperature and atmospheric pressure. It was shown that diffusion of CO2 molecules into the polymer led to a significant increase in the chain mobility and distances between them. Analysis of diffusion coefficients of CO2 molecules inside and outside the poly(methyl methacrylate) sample has shown that carbon dioxide actively interacts with the functional groups of poly (methyl methacrylate). Joint analysis of the radial distribution functions obtained from classical molecular dynamics and of the averaging interatomic distances from Car-Parrinello molecular dynamics allows us to make a conclusion about the possibility of formation of weak hydrogen bonds between the carbon dioxide oxygen atom and the hydrogen atoms of the polymer methyl groups.


Evaluating Individual Radiosensitivity for the Prediction of Acute Toxicities of Chemoradiotherapy in Esophageal Cancer Patients.
In this work, individual radiosensitivity was evaluated using DNA damage response and chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) for the prediction of acute toxicities of chemoradiotherapy (CRT) in esophageal cancer patients. Eighteen patients with esophageal cancer were enrolled in this prospective study. Prescribed doses were 60 Gy in 11 patients and 50 Gy in seven patients. Patients received 2 Gy radiotherapy five days a week. PBLs were obtained during treatment just before and 15 min after 2 Gy radiation therapy on the days when the cumulative dose reached 2, 20, 40 Gy and 50 or 60 Gy. PBLs were also obtained four weeks and six months after radiotherapy in all and 13 patients, respectively. Dicentric and ring chromosomes in PBLs were counted to evaluate the number of CAs. Gamma-H2AX foci per cell were scored to assess DNA double-strand breaks. We analyzed the association between these factors and adverse events. The number of γ-H2AX foci before radiotherapy showed no significant increase during CRT, while their increment was significantly reduced with the accumulation of radiation dose. The mean number of CAs increased during CRT up to 1.04 per metaphase, and gradually decreased to approximately 60% six months after CRT. Five patients showed grade 3 toxicities during or after CRT (overreactors: OR), while 13 had grade 2 or less toxicities (non-overreactors: NOR). The number of CAs was significantly higher in the OR group than in the NOR group at a cumulative dose of 20 Gy (mean value: 0.63 vs. 0.34, P = 0.02), 40 Gy (mean value: 0.90 vs. 0.52, P = 0.04), and the final day of radiotherapy (mean value: 1.49 vs. 0.84, P = 0.005). These findings suggest that number of CAs could be an index for predicting acute toxicities of CRT for esophageal cancer.


Rates of Epidural Blood Patch following Lumbar Puncture Comparing Atraumatic versus Bevel-Tip Needles Stratified for Body Mass Index.
Postdural puncture headache, a known complication of lumbar puncture, typically resolves with conservative management. Symptoms persist in a minority of patients, necessitating an epidural blood patch. One method of decreasing rates of postdural puncture headache is using atraumatic, pencil-point needles rather than bevel-tip needles. To the best of our knowledge, this is the first study comparing epidural blood patch rates between pencil- and bevel-tip needles with a subgroup analysis based on body mass index. This single-institution retrospective study identified 4435 patients with a recorded body mass index who underwent a lumbar puncture with a 22-ga pencil-tip Whitacre needle, a 20-ga bevel-tip Quincke needle, or a 22-ga Quincke needle. The groups were stratified by body mass index. We compared epidural blood patch rates between 22-ga pencil-tip Whitacre needles versus 22-ga Quincke needles and 22-ga Quincke needles versus 20-ga bevel-tip Quincke needles using the Fischer exact test and χ2 test. Postdural puncture headache necessitating an epidural blood patch was statistically more likely using a 22-ga Quincke needle in all patients (P < .001) and overweight (P = .03) and obese (P < .001) populations compared with using a 22-ga pencil-tip Whitacre needle. In the normal body mass index population, there was no statistically significant difference in epidural blood patch rates when using a 22-ga pencil-tip Whitacre needle compared with a 22-ga Quincke needle (P = .12). There was no significant difference in epidural blood patch rates when comparing a 22-ga Quincke needle versus a 20-ga bevel-tip Quincke needle in healthy (P = .70), overweight (P = .69), or obese populations (P = .44). Using a 22-ga pencil-tip Whitacre needle resulted in lower epidural blood patch rates compared with a 22-ga Quincke needle in all patients. Subgroup analysis demonstrated a statistically significant difference in epidural blood patch rates in overweight and obese populations, but not in patients with a normal body mass index.


Development of a Pipeline for Adverse Drug Reaction Identification in Clinical Notes: Word Embedding Models and String Matching.
Knowledge about adverse drug reactions (ADRs) in the population is limited because of underreporting, which hampers surveillance and assessment of drug safety. Therefore, gathering accurate information that can be retrieved from clinical notes about the incidence of ADRs is of great relevance. However, manual labeling of these notes is time-consuming, and automatization can improve the use of free-text clinical notes for the identification of ADRs. Furthermore, tools for language processing in languages other than English are not widely available. The aim of this study is to design and evaluate a method for automatic extraction of medication and Adverse Drug Reaction Identification in Clinical Notes (ADRIN). Dutch free-text clinical notes (N=277,398) and medication registrations (N=499,435) from the Cardiology Centers of the Netherlands database were used. All clinical notes were used to develop word embedding models. Vector representations of word embedding models and string matching with a medical dictionary (Medical Dictionary for Regulatory Activities [MedDRA]) were used for identification of ADRs and medication in a test set of clinical notes that were manually labeled. Several settings, including search area and punctuation, could be adjusted in the prototype to evaluate the optimal version of the prototype. The ADRIN method was evaluated using a test set of 988 clinical notes written on the stop date of a drug. Multiple versions of the prototype were evaluated for a variety of tasks. Binary classification of ADR presence achieved the highest accuracy of 0.84. Reduced search area and inclusion of punctuation improved performance, whereas incorporation of the MedDRA did not improve the performance of the pipeline. The ADRIN method and prototype are effective in recognizing ADRs in Dutch clinical notes from cardiac diagnostic screening centers. Surprisingly, incorporation of the MedDRA did not result in improved identification on top of word embedding models. The implementation of the ADRIN tool may help increase the identification of ADRs, resulting in better care and saving substantial health care costs.


Effect of Star Topology Versus Linear Polymers on Antifungal Activity and Mammalian Cell Toxicity.
The global increase in invasive fungal infections and the emergence of drug-resistant strains demand the urgent development of novel antifungal drugs. In this context, synthetic polymers with diverse compositions, mimicking natural antimicrobial peptides, have shown promising potential for combating fungal infections. This study investigates how altering polymer end-groups and topology from linear to branched star-like structures affects their efficacy against Candida spp., including clinical isolates. Additionally, the polymers' biocompatibility is accessed with murine embryonic fibroblasts and red blood cells in vitro. Notably, a low-molecular weight star polymer outperforms both its linear polymeric counterparts and amphotericin B (AmpB) in terms of an improved therapeutic index and reduced haemolytic activity, despite a higher minimum inhibitory concentration against Candida albicans (C. albicans) SC5314 (16-32 µg mL-1 vs 1 µg mL-1 for AmpB). These findings demonstrate the potential of synthetic polymers with diverse topologies as promising candidates for antifungal applications.


De novo analysis of receptor binding affinity data of benzodiazepines.
The receptor binding affinity data of a series of 39 benzodiazepines (BDZ) have been analyzed by means of the Free-Wilson model The comparison of th individual group contributions shows the primary importance of the presence of a carbonyl group at position 2 and of a nitrogen atom at position 4 of the diazepine ring for an optimum receptor binding. The great difference between group contributions of BDZ having different absolute configurations with respect to the chiral carbon atom at position 3 of the diazepine ring is discussed in terms of BDZ-receptor interactions.


Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus.
Alpha-1 antitrypsin (AAT) has been shown to reduce pro-inflammatory markers and protect pancreatic islets from autoimmune responses in recent studies. Our aim was to evaluate its safety and tolerability in three different doses, in a pediatric population with recent onset type 1 diabetes mellitus (T1DM). A 37-wk prospective, open-label, phase I/II interventional trial, comprised of 24 recently diagnosed subjects (12 males; age 12.9 ± 2.4 yr), who received 18 infusions of 40, 60, or 80 mg/kg/dose high-purity, liquid, ready to use AAT over 28 wk (Glassia(®) ; Kamada Ltd., Ness Ziona, Israel). safety and tolerability; secondary outcomes: glycemic control, C-peptide reserve, and autoantibody levels. Possible responders were defined as individuals with peak C-peptide that declined less than 7.5% below baseline. No serious adverse events, diabetic ketoacidosis (DKA), or severe hypoglycemic episodes were reported. Adverse events were dose-independent and transient. Glycemic control parameters improved during the study in all groups, independent of dosage. Hemoglobin A1c (HbA1c) decreased from 8.43 to 7.09% (mean, p < 0.001). At the end of the study, 18 subjects (75%) had a peak C-peptide ≥0.2 pmol/mL. Eight subjects (33.3%) were considered possible responders and were characterized by shorter duration of T1DM at screening (54.5 ± 34.3 vs. 95.9 ± 45.7 d, p = 0.036) and greater decrease in their HbA1c during the study period (-2.94 ± 1.55 vs.-0.95 ± 1.83%, p = 0.016). AAT treatment was safe and well tolerated in pediatric subjects with recently diagnosed autoimmune diabetes. Placebo-controlled studies with larger cohorts and dose range are warranted in order to assess efficacy in maintaining pancreatic beta cell reserve and glycemic control.


Selection in Hereford cattle. II. Expected and realized response.
Data from 14 inbred lines and 14 linecross groups of Hereford cattle at the San Juan Basin Research Center, Hesperus, were used to evaluate expected and realized response in birth and weaning traits and postweaning traits in males and females over a 28-yr period. There were large differences in the means and variances of the performance traits among the inbreds and linecrosses, with the inbreds showing inbreeding depression and greater variability among lines, while the linecrosses manifested within-breed heterosis. Except for gain from weaning to 12 mo, in females, genetic progress was expected in all traits studied, mainly due to sire selection. Regressions of annual trait means on years indicated positive phenotypic trends in the inbreds for heart girth circumference at birth, adjusted weaning weight (adjusted for inbreeding), weaning score, final weight, feed consumption and the yearling weights and gains in females. Changes were negative for other traits. In the linecross group phenotypic trends were positive in all traits except heart girth circumference, weaning age, initial test weight and feed efficiency. Estimated genetic progress per generation due to within-line selection was negative in most of the traits in the inbreds but was considerably positive for the linecrosses for most of the traits. As expected, between-line selection yielded greater genetic improvement in the inbred than in the linecross population. The different patterns of response in the two populations are attributed to high rates and levels of inbreeding. Although variable, the actual progress was below prediction in most of the traits studied.


Assessment of gamma dose rates from terrestrial exposure in Serbia and Montenegro.
The gamma dose rates due to naturally occuring terrestrial radionuclides ((226)Ra, (232)Th and (40)K) were calculated based on their activities in soil samples, determined by gamma-ray spectrometry. A total of 140 soil samples from 21 different regions of Serbia and Montenegro were collected. The gamma dose rates ranged from 7.40 to 29.7 nGy h(-1) for (226)Ra, from 12.9 to 46.5 nGy h(-1) for (232)Th and from 12.5 to 37.1 nGy h(-1) for (40)K. The total absorbed gamma dose rate due to these radionuclides varied from 34.5 to 97.6 nGy h(-1) with mean of 66.8 nGy h(-1). Assuming a 20% occupancy factor, the corresponding annual effective dose varied from 4.23 x 10(-5) to 11.9 x 10(-5) Sv with mean of 8.19 x 10(-5) Sv, i.e. the dose was lower than world wide average value. According to the values of external hazard index (mean: 0.39) obtained in this study, the radiation hazard was found to be insignificant for population living in the investigated area.


The predictive value of semaphorins 3 expression in biopsies for biochemical recurrence of patients with low- and intermediate-risk prostate cancer.
The class-3 semaphorins (Sema3A-F, Sema3s) are initially identified to play an important role in axonal guidance and cell migration. Our previous studies showed that Sema3s are also involved in the lymph node metastasis of prostate cancer, and are likely to modulate the behavior of prostate cancer with a pro-tumoral or an anti-tumoral effect, depending on their subtypes. However, no study has critically investigated the value of Sema3s expression in preoperative biopsy samples for the prediction of biochemical recurrence (BCR) after radical prostatectomy. In this study, we evaluated Sema3s expression by immunohistochemistry on 198 prostate biopsies with low- and intermediate-risk localized prostate cancer. The median follow-up was 42 months (range, 6-60) for all patients. Our results showed that Sema3A (OR: 0.19, P<0.001), Sema3B (OR: 0.38, P=0.003), Sema3E (OR: 0.39, P=0.007), and Sema3C (OR: 2.31, P=0.014) staining were independent predictors of BCR on multivariable analysis. Sema3A, 3B, 3C and 3E expression demonstrated potential values in predicting BCR upon survival analysis (P=0.001, P=0.003, P=0.029, P=0.037, respectively, Log-rank test). Our findings suggested that Sema3A, 3B, 3C, and 3E immunostaining in prostate biopsies, as supplements to clinicopathological parameters, could be used for predicting BCR in low- and intermediate-risk prostate cancer patients after radical prostatectomy. Specially, concurrent Sema3C-positive and Sema3A-negative, 3B-negative, 3E-negative staining is associated with an adverse prognosis. Further prospective studies in larger patient populations are needed to validate the current observations.


Intravenous lidocaine: an adjunct for nitrous oxide thiopental anesthesia.
Although lidocaine is commonly accepted as an anti-arrhythmic drug, it can also be used intravenously as an anesthetic agent. The author focuses on how lidocaine can be used as an integral part of the anesthetic itself for patients with cardiac arrhythmias, particularly premature ventricular contractions.


Evolutionary ecology of Datura stramonium: genetic variation and costs for tolerance to defoliation.
The incorporation of plant tolerance after damage as a new alternative to cope with herbivory, as opposed to resistance, opened new avenues for our understanding of coevolution between plants and herbivores. Although genetic variation on tolerance to defoliation has been detected in some species, few studies have been undertaken with nonagricultural species. In this study, we explore in the annual weed Datura stramonium the existence of genetic variation for tolerance and fitness costs of tolerance. To determine which fitness-related trait was responsible for possible differences in tolerance, growth rate, total flower and fruit production, and the number of seeds per fruit were recorded. Inbred line replicates of D. stramonium from a population of Mexico City were exposed to four defoliation levels (0%, 10%, 30%, and 70%). Our results from a greenhouse experiment using controlled genetic material (inbred lines) indicated that significant genetic variation for tolerance was detected across defoliation environments. Defoliation reduced plant fitness from 15% to 25% in the highest levels of defoliation. Differences on tolerance among inbred lines were accounted by a differential reduction in the proportion of matured fruits across defoliation levels (up to 20%). Within defoliation levels, significant genetic variation in plant fitness suggests that tolerance could be selected. The correlation between fitness values of inbred lines in two environments (with and without damage) was positive (rg = 0.77), but not significant, suggesting absence of fitness costs for tolerance. The finding of genetic variation on tolerance might be either due to differences among inbred lines in their capability to overcome foliar damage through compensation or due to costs incurred by inducing secondary metabolites. Our results indicate the potential for norms of reaction to be selected under a gradient of herbivory pressure and highlights the importance of dissecting induced from compensatory responses when searching for potential causes of genetic variation on tolerance.


Alternative splicing of Xenopus alphafast-tropomyosin pre-mRNA during development: identification of determining sequences.
The Xenopus alphafast-tropomyosin gene contains in its central part a set of mutually exclusive exons, designated 6A and 6B, which are incorporated into mRNA encoding, respectively, nonmuscle and muscle tropomyosins. In this study, we show that usage of both exons is strictly regulated during development, exon 6A being used in the oocyte and nonmuscle tissues of the embryo, while exon 6B is used in muscle tissues. An approach of transient embryo transgenesis was developed to study the mechanisms involved in the splice site choice during development. We demonstrate that a-tropomyosin minigenes driven by tissue-specific promoters that target gene expression in nonmuscle and muscle tissues recapitulate the splicing pattern of the endogenous gene. A mutational analysis showed that regulation occurred at both exons 6A and 6B in muscle and nonmuscle tissues. In this context, we have identified an element located in the intron downstream of 6A that participates in the recognition of the weak 5' splice site of exon 6A and the repression of exon 6B in nonmuscle cells.


Assessing combined methylation-sensitive high resolution melting and pyrosequencing for the analysis of heterogeneous DNA methylation.
Heterogeneous DNA methylation leads to difficulties in accurate detection and quantification of methylation. Methylation-sensitive high resolution melting (MS-HRM) is unique among regularly used methods for DNA methylation analysis in that heterogeneous methylation can be readily identified, although not quantified, by inspection of the melting curves. Bisulfite pyrosequencing has been used to estimate the level of heterogeneous methylation by quantifying methylation levels present at individual CpG dinucleotides. Sequentially combining the two methodologies using MS-HRM to screen the amplification products prior to bisulfite pyrosequencing would be advantageous. This would not only replace the quality control step using agarose gel analysis prior to the pyrosequencing step but would also provide important qualitative information in its own right. We chose to analyze DAPK1 as it is an important tumor suppressor gene frequently heterogeneously methylated in a number of malignancies, including chronic lymphocytic leukemia (CLL). A region of the DAPK1 promoter was analyzed in ten CLL samples by MS-HRM. By using a biotinylated primer, bisulfite pyrosequencing could be used to directly analyze the samples. MS-HRM revealed the presence of various extents of heterogeneous DAPK1 methylation in all CLL samples. Further analysis of the biotinylated MS-HRM products by bisulfite pyrosequencing provided quantitative information for each CpG dinucleotide analyzed, and confirmed the presence of heterogeneous DNA methylation. Whereas each method could be used individually, MS-HRM and bisulfite pyrosequencing provided complementary information for the assessment of heterogeneous methylation.


Estimated dietary intake and major food sources of polyphenols in the Polish arm of the HAPIEE study.
The aim of this study was to estimate the intake of known individual polyphenols and their major dietary sources in the Polish arm of the HAPIEE (Health, Alcohol and Psychosocial factors In Eastern Europe) study. A total of 10,477 random sample (45-69 y) of urban population of Krakow, Poland, completed a validated 148-item food frequency questionnaire. Polyphenol intake was calculated by matching food consumption data with the recently developed Phenol-Explorer database. The mean intake of polyphenols was 1756.5 ± 695.8 mg/d (median = 1662.5 mg/d). The main polyphenol groups were flavonoids (897 mg/d) and phenolic acids (800 mg/d). A total of 347 polyphenols from 19 polyphenol subclasses were found. The individual compounds with the highest intakes were isomers of chlorogenic acid (i.e., 5-caffeoylquinic acid and 4-caffeoylquinic acid) among hydroxycinnamic acids (average intake 150 mg/d), that largely originated from coffee, and compounds belonging to the catechin chemical family (i.e., [+]-gallocatechin, [-]-epigallocatechin 3-O-gallate, and [-]-epicatechin) among flavanols (average intake 50 mg/d), that mostly originated from tea and cocoa products. The current study provides the most updated data for individual polyphenols intake in the diet of a well-established nutritional cohort. These findings will be useful to assess potential beneficial role on health of specific foods with high polyphenol content and characterize the effects of individual phenolic compounds.


Impact of ozone exposure on the phagocytic activity of human surfactant protein A (SP-A) and SP-A variants.
Surfactant protein A (SP-A) enhances phagocytosis of Pseudomonas aeruginosa. SP-A1 and SP-A2 encode human (h) SP-A; SP-A2 products enhance phagocytosis more than SP-A1. Oxidation can affect SP-A function. We hypothesized that in vivo and in vitro ozone-induced oxidation of SP-A (as assessed by its carbonylation level) negatively affects its function in phagocytosis (as assessed by bacteria cell association). To test this, we used P. aeruginosa, rat alveolar macrophages (AMs), hSP-As with varying levels of in vivo (natural) oxidation, and ozone-exposed SP-A2 (1A, 1A0) and SP-A1 (6A2, 6A4) variants. SP-A oxidation levels (carbonylation) were measured; AMs were incubated with bacteria in the presence of SP-A, and the phagocytic index was calculated. We found: 1) the phagocytic activity of hSP-A is reduced with increasing levels of in vivo SP-A carbonylation; 2) in vitro ozone exposure of hSP-A decreases its function in a dose-dependent manner as well as its ability to enhance phagocytosis of either gram-negative or gram-positive bacteria; 3) the activity of both SP-A1 and SP-A2 decreases in response to in vitro ozone exposure of proteins with SP-A2 being affected more than SP-A1. We conclude that both in vivo and in vitro oxidative modifications of SP-A by carbonylation reduce its ability to enhance phagocytosis of bacteria and that the activity of SP-A2 is affected more by in vitro ozone-induced oxidation. We speculate that functional differences between SP-A1 and SP-A2 exist in vivo and that the redox status of the lung microenvironment differentially affects function of SP-A1 and SP-A2.


Adsorption properties versus oxidation states of rutile TiO2(110).
Using density functional theory we have studied the adsorption properties of different atoms and molecules deposited on a stoichiometric, reduced, and oxidized rutile TiO(2)(110) surface. Depending on the oxidation state of the surface, electrons can flow from or to the substrate and, therefore, negatively or positively charged species are expected. In particular, we have found that a charge transfer process from or to the surface always occurs for highly electronegative or highly electropositive species, respectively. For atoms or molecules with intermediate electron affinity, the direction of the charge flow depends on the oxidation state of the rutile surface and on the adsorption site. Generally, the charging effect leads to more stable complexes. However, the increase in the binding energy of the adsorbates is highly dependent on the electronic states of the surface prior to the adsorption event. In this work we have analyzed in details these mechanisms and we have also established a direct correlation between the enhanced binding energy of the adsorbates and the induced gap states.


Soil tillage erosion estimated by using magnetism of soils--a case study from Bulgaria.
A detailed field and laboratory study on small 0.84-ha test site of agricultural land near Sofia (Bulgaria) has been carried out in order to test the applicability of magnetic methods in soil erosion estimation in the particular case of strongly magnetic parent material. Field measurements of magnetic susceptibility were carried out with grid size of 6 m, resulting in 258 data points. Bulk soil material was gathered from 78 grid points. Natural, non-disturbed soil section was sampled near the agricultural field for reference profile of complete undisturbed soil. Surface susceptibility measurements reveal well-defined maxima down slope which, however, cannot be assigned directly to a certain depth interval, corresponding with susceptibilities along the non-disturbed soil profile. This is caused by the high magnetic susceptibility of the lithogenic coarse-grained magnetic fraction. Non-uniqueness is resolved by using magnetic susceptibility of coarse (1 mm > d > 63 μm) and fine (d < 63 μm) mechanical fractions and the parameter Δχ = 100*(χ (coarse) -χ (fine))/χ (bulk) (%). It shows increased values in the C-horizon of undisturbed soil profile, which corresponds to a certain part of the studied area. After the application of an empirical model to predict the values of magnetic parameter after tillage homogenization and removal of soil material from the surface, the amount of soil loss is estimated.


Sleep disorders in children with Attention-Deficit/Hyperactivity Disorder (ADHD) recorded overnight by video-polysomnography.
To outline specific sleep disturbances in different clinical subsets of Attention Deficit/Hyperactivity Disorder (ADHD) and to confirm, by means of nocturnal video-polysomnography (video-PSG), a variety of sleep disorders in ADHD besides the classically described periodic leg movement disorder (PLMD), restless legs syndrome (RLS) and sleep related breathing disorder (SRBD). Fifty-five ADHD children (47 M, 8F; mean age=8.9 y) were included: 16 had Inattentive and 39 Hyperactive/Impulsive or Combined ADHD subtype. Behavior assessment by Conners and SNAP-IV Scales, a structured sleep interview and a nocturnal video-PSG were administered. Most children/parents reported disturbed, fragmentary sleep at night; complaints were motor restlessness (50%), sleep walking (47.6%), night terrors (38%), confusional arousals (28.5%), snoring (21.4%), and leg discomfort at night associated with RLS (11.9%). There is a significant difference (p value <0.05 or <0.001) in almost all the studied sleep variables between ADHD children and controls. International RLS Rating Scale scoring, Periodic Limb Movements during Sleep (PLMS) and Wake (PLMW) indexes, hyperactivity and opposition scores and ADHD subtype appear related. Different sleep disorders seem to address specific ADHD phenotypes and correlate with severity of symptoms as in sleep related movement disorders occurring in Hyperactive/Impulsive and Combined ADHD subtypes. Besides, an abnormality of the arousal process in slow wave sleep with consequent abnormal prevalence of disorders of arousal possibly enhanced by SRBD has also been detected in 52% of our sample. This study underlines the opportunity to propose and promote the inclusion of sleep studies, possibly by video-PSG, as part of the diagnostic screening for ADHD. This strategy could address the diagnosis and treatment of different specific ADHD phenotypic expressions that might be relevant to children's symptoms and contribute to ADHD severity.


Identifying Key Topics Bearing Negative Sentiment on Twitter: Insights Concerning the 2015-2016 Zika Epidemic.
To understand the public sentiment regarding the Zika virus, social media can be leveraged to understand how positive, negative, and neutral sentiments are expressed in society. Specifically, understanding the characteristics of negative sentiment could help inform federal disease control agencies' efforts to disseminate relevant information to the public about Zika-related issues. The purpose of this study was to analyze the public sentiment concerning Zika using posts on Twitter and determine the qualitative characteristics of positive, negative, and neutral sentiments expressed. Machine learning techniques and algorithms were used to analyze the sentiment of tweets concerning Zika. A supervised machine learning classifier was built to classify tweets into 3 sentiment categories: positive, neutral, and negative. Tweets in each category were then examined using a topic-modeling approach to determine the main topics for each category, with focus on the negative category. A total of 5303 tweets were manually annotated and used to train multiple classifiers. These performed moderately well (F1 score=0.48-0.68) with text-based feature extraction. All 48,734 tweets were then categorized into the sentiment categories. Overall, 10 topics for each sentiment category were identified using topic modeling, with a focus on the negative sentiment category. Our study demonstrates how sentiment expressed within discussions of epidemics on Twitter can be discovered. This allows public health officials to understand public sentiment regarding an epidemic and enables them to address specific elements of negative sentiment in real time. Our negative sentiment classifier was able to identify tweets concerning Zika with 3 broad themes: neural defects,Zika abnormalities, and reports and findings. These broad themes were based on domain expertise and from topics discussed in journals such as Morbidity and Mortality Weekly Report and Vaccine. As the majority of topics in the negative sentiment category concerned symptoms, officials should focus on spreading information about prevention and treatment research.


Growth inhibitory effect of gene-cloned interferons on human myeloblast colonies.
The effect on marrow myeloblast colony formation in blood from nine patients with acute myeloid leukemia was studied by using three recombinant-DNA-derived human leukocyte interferons (IFN alpha 2, IFN alpha-A, and IFN alpha-C). In preliminary experiments, a brief exposure of leukemic marrow cells to IFN alpha resulted in a sharp increase in the IFN-induced enzyme 2-5A synthetase, indicating the expression of IFN cell receptors as well as the ability of leukemia cells to respond metabolically. Dose-response studies showed a dose-dependent suppression of myeloblast colony formation in all experiments using concentrations of 10(2)-10(5) U/ml of the three IFN subtypes. In self-renewal assays derived from the primary cultures that initially contained IFN alpha 2, a "carryover" antiproliferative effect was observed with a dose-dependent decline in secondary growth. In comparison studies of IFN alpha-A and IFN alpha-C, the suppressive effect on primary myeloblast growth was much more pronounced with IFN alpha-C at concentrations of 10(3) U/ml and higher; in self-renewal assays, the antiproliferative effect of IFN alpha-C on secondary growth was no longer observed, whereas that of IFN alpha-A persisted. These three subtypes of gene-cloned IFN have antileukemic properties in vitro, with differences in degree of suppression of primary myeloblast growth and of self-renewal.


A randomized, controlled trial of computerized physiologic trend monitoring in an intensive care unit.
To assess whether the provision of computerized physiologic trend data could improve outcome in newborn infants requiring intensive care. Randomized, controlled trial, with subsidiary questionnaire studies. Tertiary neonatal intensive care unit with 12 intensive care cots. All infants admitted between January 1991 and September 1993 who were < or =32 wks gestation or >32 wks gestation, and ventilated for >4 hrs or asphyxiated. Randomization to one of four groups for first 7 days of life: A) no display of trend data; B) continuous display of trend data; C1) alternating 24-hr display of trend data, starting with display in first 24 hrs; and C2) alternating 24-hr display of trend data, starting with no display in first 24 hrs. The short-term effects of monitoring on patient outcome was judged by volume of colloid given, number of blood gases taken, and by measurement taken from cranial Doppler ultrasound. Medium-term measures included time ventilated, time given supplemental oxygen, death, time to death or discharge, and cranial ultrasound at discharge. Long-term outcome was assessed by neurodevelopmental status at age 1 to 4 yrs of age. Staff and parent questionnaires assessed their respective attitudes to the introduction of this technology. None of the patient outcome measures, short-, medium-, or long-term, demonstrated any significant benefit from the provision of computerized physiologic trend monitoring. Staff questionnaires demonstrated an acceptance of the system and an improved understanding of neonatal physiology as a result of computerized physiologic trends. Parent questionnaires demonstrated increased anxiety caused by the system in 11% of parents, although only 1% of parents continued to have concerns if the system were able to help their child. A randomized, controlled trial was unable to demonstrate any benefit to patients resulting from the introduction of a computerized physiologic trend monitoring system. Benefits of the system have been recognized, however, in subsidiary studies, staff education, and research studies.


Classifying diabetic foot surgery: toward a rational definition.
The purpose of this manuscript was to describe a classification of diabetic foot surgery performed in the absence of critical limb ischaemia. The basis of this classification is centered on three fundamental variables which are present in the assessment of risk and indication: 1) the presence or absence of neuropathy (loss of protective sensation); 2) the presence or absence of an open wound; 3) the presence or absence of acute, limb-threatening infection. The conceptual framework for this classification is to define distinct classes of surgery in an order of theoretically increasing risk for high-level amputation. These classes include: Class I: Elective Diabetic Foot Surgery (procedures performed to treat a painful deformity in a patient without loss of protective sensation); Class II: Prophylactic (Procedure performed to reduce risk of ulceration or reulceration in person with loss of protective sensation but without open wound); Class III: Curative (Procedure performed to assist in healing open wound) and Class IV: Emergent (Procedure performed to limit progression of acute infection). The presence of critical ischaemia in any of these classes of surgery should prompt a vascular evaluation to consider a) the urgency of the procedure being considered and b) possible revascularization prior or temporally concomitant with the procedure. It is our hope that this system begins a dialogue amongst physicians and surgeons which can ultimately facilitate communication, enhance perspective, and improve care.


Repetitive Transcranial Magnetic Stimulation in the Treatment of a Difficult to Treat Condition, Borderline Personality Disorder.
Borderline personality disorder (BPD) is a serious mental disorder characterized by a pervasive pattern of instability in affect regulation and interpersonal relationships, poor self-image and behavioral control, self-injurious behavior, suicidality, and other high-risk behaviors. It is also characterized by a high mortality rate by suicide. The published literature on repetitive transcranial magnetic stimulation (TMS), theta-burst stimulation (TBS), and deep TMS in the treatment of BPD were reviewed. Four clinical studies (2 randomized trials and 2 case studies) with limited sample sizes found that TMS and TBS were safe and potentially effective in the reduction of symptoms of BPD. Given the limited clinical evidence for efficacy on the basis of the results of these studies, future controlled studies involving larger samples and optimal stimulus parameters should be designed to confirm the short-term and long-term safety and efficacy of repetitive TMS and TBS in the treatment of BPD.


Traumatic extremity arterial injury in children: epidemiology, diagnostics, treatment and prognostic value of Mangled Extremity Severity Score.
Traumatic paediatric arterial injuries are a great challenge due to low incidence and specific characteristics of paediatric anatomy and physiology. The aim of the present study was to investigate their epidemiology, diagnostic and therapeutic options and complications. Furthermore, the prognostic value of the Mangled Extremity Severity Score (MESS) was evaluated. In a retrospective clinical study 44 children aged 9.0 +/- 3.2 years treated for traumatic extremity arterial lesions in our Level I trauma center between 1971 and 2006 were enrolled. Exclusion criteria were age > 14, venous and iatrogenic vascular injury. Demographic data, mechanism of injury, severity of arterial lesions (by Vollmar and MESS), diagnostic and therapeutic management, complications and outcome were evaluated. The most commonly injured vessel was the femoral artery (25%) followed by the brachial artery (22.7%). The mechanism of injury was penetrating (31.8%), isolated severe blunt extremity trauma (29.6%), multiple trauma (25%) and humeral supracondylar fractures (13.6%). In 63.6% no specific vascular diagnostic procedure was performed in favour of emergency surgery. Surgical reconstructive strategies were preferred (68.2%). A MESS < 7 was associated with initial (p < 0.05) and definite limb salvage (p < 0.001) of the lower extremity. Traumatic paediatric vascular injuries are very rare. The most common situations of vascular lesions in childhood were penetrating injuries and fractures of the extremities either as isolated injuries or in multiply injured patients. In paediatric patients, the MESS could serve as a basis for decision making for limb salvage or amputation.


Chemotherapy for advanced gastric cancer: review and update of current practices.
No standard adjuvant or palliative chemotherapy regimen has been internationally approved for patients with advanced gastric cancer. Adjuvant chemoradiotherapy is administered prior to surgery and is used in the Unitied States, and intensified chemotherapy is administered prior to and after surgery and is used in Europe. Limited D1 dissections are also frequently performed in the United States and Europe. In Korea, patients undergoing D2 resection appear to benefit from postoperative adjuvant chemotherapy using S-1 or capecitabine plus oxaliplatin. Fluoropyrimidine, platinum, taxane, epirubicin, and irinotecan may be employed alone or in combination as a first-line therapy in a palliative chemotherapy regimen. In Asia, an orally administered fluoropyrimidine, such as capecitabine or S-1, is favored over the continuous infusion of 5-fluorouracil because of its convenience. Trastuzumab has been integrated into the current standard chemotherapy for human epidermal growth factor receptor 2-overexpressing gastric cancers. There is currently no standard regimen for secondary palliative chemotherapy. Clinical studies of several targeted therapies are ongoing.


Passive immunity in prevention and treatment of infectious diseases.
Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.


Toxigenic cutaneous diphtheria in a returned traveller.
Diphtheria is rarely reported in Australia. A case of cutaneous diphtheria was reported to the South Australian Department for Health and Ageing in April 2013 in an Australian-born 18-year-old female following travel in India. The case presented with a skin ulcer on her toe. Toxigenic Corynebacterium diphtheriae was isolated from a swab of the lesion. The case was treated with antibiotics. The public health response included infection control advice, assessing the case and household contacts for organism carriage and providing antimicrobial chemoprophylaxis to contacts. Although cutaneous diphtheria is not included as part of the Australian communicable disease surveillance case definition, this may be an oversight as international evidence demonstrates that it is a source of organism transmission and can potentially result in outbreaks among susceptible populations. This formed the rationale for the public health response to this particular case. The protocol for the public health management of diphtheria in South Australia has since been revised to include cutaneous lesions caused by the toxigenic strain of the organism as part of the surveillance case definition.


Galectin-7 induction by EHMT2 inhibition enhances immunity in MSS colorectal cancer.
Despite immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high (MSI), it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. An in vitro CRISPR screen was performed using co-culture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 upregulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a co-transcriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.


Neuromodulation of the median nerve in carpal tunnel syndrome, a single-blind, randomized controlled study.
: This study aimed to evaluate the efficacy of pulsed radiofrequency applied using transcutaneous electrodes in carpal tunnel syndrome (CTS). : After randomization, the patients received two cycles of noninvasive pulsed radiofrequency (NiPRF), once weekly, or splinting (the control group) for three months. Clinical evaluations were recorded at baseline and weeks 4 and 8. The Boston Carpal Tunnel Syndrome Questionnaire (BCTQ) was used to determine the functional status and symptom severity. : Sixty-two patients were followed up for three months. There was no difference between the groups in the BCTQ scores before and after treatment. The NiPRF group found a significant difference between the BCTQ measurements at all time intervals (paired sample t-test; P < 0.001). In the splint group, there was a significant difference only between the basal-1st month and basal-3rd month (paired samples t-test; P < 0.001). The main effect of the time variable was statistically significant (ANOVA; P < 0.001), but the group variable was not. There was no correlation between the BCTQ results measured at any time and the electroneuromyelogragphy findings in either group. : NiPRF effectively improves symptoms and functionality in patients with CTS for up to 3 months. Thus, NiPRF can be considered an easy, safe, and useful alternative treatment modality for CTS.


Motor performance: normative data, age dependence and handedness.
Quantitative, apparatus-based assessment of motor performance is a useful tool when addressing questions of therapy evaluation, quality control and early detection of movement disorders. Until now, few such methods have been sufficiently standardised to allow their routine employment in the clinic. Before assessing the impaired performance of patients, the first stage of standardisation is the determination of criteria of normal performance in healthy subjects. We have standardised a multidimensional test battery for motor performance of the upper extremities (Schoppe's "motorische Leistungs-Serie" = MLS). On the basis of the performance of 80 healthy controls, normative algorithms which allow correction of performance with reference to age were calculated. Further, our investigation provided information concerning the complexity of normal motor performance and the question of laterality (handedness). Standardised apparatus-based quantification of performance promises to be a valuable supplement to rating scales in the evaluation of patient motor skills, particularly in the early stages of their illness.


Theory Testing Using Quantitative Predictions of Effect Size.
Traditional Null Hypothesis Testing procedures are poorly adapted to theory testing. The methodology can mislead researchers in several ways, including: (a) a lack of power can result in an erroneous rejection of the theory; (b) the focus on directionality (ordinal tests) rather than more precise quantitative predictions limits the information gained; and (c) the misuse of probability values to indicate effect size. An alternative approach is proposed which involves employing the theory to generate explicit effect size predictions that are compared to the effect size estimates and related confidence intervals to test the theoretical predictions. This procedure is illustrated employing the Transtheoretical Model. Data from a sample (N = 3,967) of smokers from a large New England HMO system were used to test the model. There were a total of 15 predictions evaluated, each involving the relation between Stage of Change and one of the other 15 Transtheoretical Model variables. For each variable, omega-squared and the related confidence interval were calculated and compared to the predicted effect sizes. Eleven of the 15 predictions were confirmed, providing support for the theoretical model. Quantitative predictions represent a much more direct, informative, and strong test of a theory than the traditional test of significance.


Unaffected family members report improvements in daily routine sun protection 2 years following melanoma genetic testing.
Reducing ultraviolet radiation exposure may decrease melanoma risk in the hereditary melanoma setting. It is unknown whether genetic counseling and test reporting of CDKN2A/p16 mutation status promote long-term compliance with photoprotection recommendations, especially in unaffected mutation carriers. This study evaluated changes 2 years following melanoma genetic testing in self-reported practice of sun protection (sunscreen, photoprotective clothing, and ultraviolet radiation avoidance) among 37 members of two CDKN2A/p16 kindreds (10 unaffected carriers, 11 affected carriers, and 16 unaffected noncarriers; response rate = 64.9% of eligible participants). Multivariate profile analysis indicated that all three participant groups reported increased daily routine practice of sun protection 2 years following melanoma genetic testing (P < 0.02), with 96.9% reporting that at least one sun protection behavior was part of their daily routine, up from 78.1% at baseline (P < 0.015). Unaffected carriers (P < 0.024) and unaffected noncarriers (P < 0.027) reported significantly more frequent use of photoprotective clothing. Affected carriers maintained adherence to all sun protection behaviors. Reported sunburns in the past 6 months decreased significantly (P < 0.018). Members of high-risk families reported increased daily routine sun protection and decreased sunburns 2 years following melanoma genetic testing, with no net decline in sun protection following negative test results. Thus, genetic testing and counseling may motivate sustained improvements in prevention behaviors.


Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer.
A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds. Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients). Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.


γ-Oryzanol Enhances Adipocyte Differentiation and Glucose Uptake.
Recent studies show that brown rice improves glucose intolerance and potentially the risk of diabetes, although the underlying molecular mechanisms remain unclear. One of the phytochemicals found in high concentration in brown rice is γ-oryzanol (Orz), a group of ferulic acid esters of phytosterols and triterpene alcohols. Here, we found that Orz stimulated differentiation of 3T3-L1 preadipocytes and increased the protein expression of adipogenic marker genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhanced binding protein alpha (C/EBPα). Moreover, Orz significantly increased the glucose uptake in insulin-resistant cells and translocation of glucose transporter type 4 (GLUT4) from the cytosol to the cell surface. To investigate the mechanism by which Orz stimulated cell differentiation, we examined its effects on cellular signaling of the mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth and proliferation. The Orz treatment increased mTORC1 kinase activity based on phosphorylation of 70-kDa ribosomal S6 kinase 1 (S6K1). The effect of Orz on adipocyte differentiation was dependent on mTORC1 activity because rapamycin blocks cell differentiation in Orz-treated cells. Collectively, our results indicate that Orz stimulates adipocyte differentiation, enhances glucose uptake, and may be associated with cellular signaling mediated by PPAR-γ and mTORC1.


Polymorphism of the TAP1 gene in Polish patients with psoriasis vulgaris.
Psoriasis vulgaris is a HLA-associated common and persistent inflammatory skin disease of unknown aetiology. The transporters associated with antigen processing (TAP) genes are polymorphic genes located in the HLA class II region and due to their essential involvement in class I antigen presentation might be additional susceptibility genes to psoriasis. To investigate the possible involvement of the TAP1 gene in the pathogenesis of psoriasis, we analysed its polymorphism in 169 Polish patients with psoriasis vulgaris and compared them with 66 healthy controls. The frequency of TAP1*D was significantly increased in the patients, compared to the control group. The TAP alleles were also analysed with respect to the age of onset of psoriasis in the patients but no significant differences were recorded. In conclusion, our data suggest that the TAP1*D allele could lead to genetic susceptibility to psoriasis vulgaris in Poles.


Modifiable Risk factors of Hypertension and Socio-demographic Profile in Oghara, Delta State; Prevalence and Correlates.
Factors associated with the development of hypertension can be categorized into modifiable and non-modifiable risk factors. The modifiable risk factors include obesity, physical inactivity, high salt diet, smoking alcohol consumption and others. This study was aimed to determine the prevalence of modifiable risk factors of hypertension in a rural community; Oghara and to ascertain if any association exists with these risk factors and socio-demographic variables. Descriptive cross-sectional study design was utilized for the study and it was carried out over a period of 6 months (Feburary 2012 to August 2012). Cluster sampling was utilized to select a total of 272 respondents for the study. An interviewer administered questionnaire was used to collect data and data analysis was performed by SPSS version 16.0 (Chicago II, USA). The prevalence of hypertension is 21.0% (57/272), while the prevalence of modifiable risk factors of hypertension such as smoking, alcohol consumption and obesity are 15.8% (43/272), 43.4% (118/272) and 18.8% (51/272) respectively. There is a statistical significant association between hypertension and smoking (P < 0.001), as well as hypertension and alcohol. (P < 0.001), on the other hand socio-demographic variables were significantly associated with smoking (P < 0.001). The study showed high prevalence of modifiable risk factors of hypertension. This underscores the need for preventive efforts to encourage changes in life style pattern in order to reverse the impending epidemic of hypertension and other non-communicable diseases.


The gastric sieve of penaeid shrimp species is a sub-micrometer nutrient filter.
Unlike that of vertebrates, the penaeid shrimp stomach is of ectodermic origin and is thus covered by a cuticle that is sloughed upon molting. It is composed of two chambers, here called the anterior and posterior stomach chambers, ASC and PSC, respectively. The PSC contains a filtration structure variously called a pyloric filter, filter press, gastric filter or gastric sieve (GS), and the last of these will be used here. The GS resembles an elongated, inverted-V, dome-like, chitinous structure with a midline ridge that is integral to the ventral base of the PSC. The dome surface is covered with a carpet-like layer of minute, comb-like setae bearing laterally branching setulae. This carpet serves as a selective filter that excludes large partially digested food particles but allows smaller particles and soluble materials to enter hepatopancreatic ducts that conduct them into the shrimp hepatopancreas (HP), where further digestion and absorption of nutrients takes place. Although the GS function is well known, its exclusion limit for particulate material has not been clearly defined. Using histological and ultra-structure analysis, we show that the GS sieve pore diameter is approximately 0.2-0.7 µm in size, indicating a size exclusion limit of substantially less than 1 µm. Using fluorescent microbeads, we show that particles of 1 µm diameter could not pass through the GS but that particles of 0.1 µm diameter did pass through to accumulate in longitudinal grooves and move on to the HP, where some were internalized by tubule epithelial cells. We found no significant difference in these sizes between the species Penaeus monodon and Penaeus vannamei or between juveniles and adults in P. vannamei This information will be of value for the design of particulate feed ingredients such as nutrients, therapeutic drugs and toxin-absorbing materials that may selectively target the stomach, intestine or HP of cultivated shrimp.


Biomechanical properties and associated collagen composition in vaginal tissue of women with pelvic organ prolapse.
The pelvic tissue of women with pelvic organ prolapse is stiffer than that of controls but there are scant data on the collagen composition that corresponds to these mechanical properties. We evaluated human vaginal wall stiffness using the novel scanning haptic microscope and correlated these measurements to collagen expression in women with and without pelvic organ prolapse. In this simultaneous biomechanical and biochemical assessment we evaluated the usefulness of this measurement technology for pelvic floor disorder research and confirmed an association between mechanical properties and composition. The elastic constant (a measure of stiffness) of vaginal wall tissue was measured with the scanning haptic microscope. Protein expression of collagen types I and III of the same tissues were determined by Western blot. The Student t test was used for comparisons between groups. The anterior and posterior vaginal walls of premenopausal and postmenopausal women with pelvic organ prolapse were significantly stiffer than those of controls (p <0.05). Collagen III protein expression in the anterior vaginal wall in the control group was higher than in menopausal women. Collagen I expression was not significantly different between controls and cases. The scanning haptic microscope produced reliable mechanical measurements in small tissue samples without tissue destruction. Vaginal wall tissues are stiffer in women with pelvic organ prolapse than in controls. This vaginal wall stiffness was associated with lower protein expression of collagen III in the vaginal wall compared to that in asymptomatic controls.


Optimal Objective-Based Experimental Design for Uncertain Dynamical Gene Networks with Experimental Error.
In systems biology, network models are often used to study interactions among cellular components, a salient aim being to develop drugs and therapeutic mechanisms to change the dynamical behavior of the network to avoid undesirable phenotypes. Owing to limited knowledge, model uncertainty is commonplace and network dynamics can be updated in different ways, thereby giving multiple dynamic trajectories, that is, dynamics uncertainty. In this manuscript, we propose an experimental design method that can effectively reduce the dynamics uncertainty and improve performance in an interaction-based network. Both dynamics uncertainty and experimental error are quantified with respect to the modeling objective, herein, therapeutic intervention. The aim of experimental design is to select among a set of candidate experiments the experiment whose outcome, when applied to the network model, maximally reduces the dynamics uncertainty pertinent to the intervention objective.


Evidence for a branched electron transport chain in Trypanosoma brucei.
The flow of electrons the terminal oxidases present in the bloodstream and procyclic trypomastigotes of Trypanosoma brucei LUMP 1026 has been investigated by the use of salicylhydroxamic acid (SHAM) and cyanide. Respiration in bloodstream trypomastigotes was completely inhibited by 0.5 mM SHAM with a Ki below 10 microM. The Ki for SHAM in procyclic trypomastigotes was 70 microM. In procyclic trypomastigotes there are at least three terminal oxidases of which the two major ones are cytochrome aa3 oxidase, sensitive to cyanide inhibition, and alpha-glycerophosphate oxidase (GPO), sensitive to SHAM inhibition. These two oxidases contribute 60 and 30%, respectively, to total cell respiration. Inhibition of the cytochrome system with cyanide causes an increase in the flow of electrons through the GPO system, and inhibition of the GPO system with SHAM stimulates electron flow in the cytochrome system. Succinate oxidation in the mitochondrial fraction is partially inhibited by SHAM and this SHAM-sensitive respiration is not inhibited by antimycin A. The kinetic data of respiration by procyclic trypomastigotes fit a model proposed by Bahr and Bonner to determine the maximum rates of two competing electron transport pathways. It is concluded that the electron transport chain in T. brucei is branched.


Genomic structure and functional characterization of the promoter region of human IkappaB kinase-related kinase IKKi/IKKvarepsilon gene.
The inducible IkappaB kinase (IKKi/IKKepsilon) is a recently described serine-threonine kinase that activates the transcription factors NFkappaB, interferon regulatory factor-3 (IRF3) and CCAAA/enhancer-binding protein (C/EBPdelta). Several inflammatory agents have been shown to induce the expression of the IKKi gene in macrophages and other cell types but the mechanism is unknown. We have found that the IKKi expression was constitutive in human chondrocytes from OA cartilage and a human chondrocytic cell line C28/I2 but was up-regulated by the inflammatory cytokines TNFalpha or IL-1betain an NFkappaB-dependent manner. To understand the constitutive and inducible expression of the IKKi gene we localized the transcription start site (TSS), cloned and sequenced a 2 kb genomic DNA fragment 5' of the TSS and characterized the putative promoter region (PPR), and identified the motifs therein that are required for basal and cytokine-induced IKKi gene promoter activity. We found that IKKi core promoter was TATA-less and by using PCR generated deletion mutants of the PPR we found that the cis-elements responsible for basal transcriptional activity were located between -51 and -100 bp upstream of the TSS while the cytokine response elements were located distally between -501 and -1000 bp upstream of the TSS. The DNA region containing the cytokine response elements had two kappaB sites as the most relevant regulatory motifs. The results of site-directed mutagenesis revealed that the kappaB site located between -833 and -847 bp upstream of the TSS was biologically functional and required for cytokine-induced IKKi promoter activity in human chondrocytes and HeLa cells. The silence of the other kappaB site (-816/-802) was positional, rather than sequence-specific. Over-expression of NFkappaB p65 mimics the TNFalpha-induced activation of the IKKi promoter. Also the gel shift assay suggested that NFkappaB p65 is responsible for activation of the IKKi promoter. These data for the first time characterize the promoter region and provide further insights into the transcriptional regulation of IKKi in human chondrocytes and other cell types.