A quick accurate method for measuring the microwave dielectric properties of small tissue samples.
A resonant cavity perturbation technique has been developed which provides a quick, simple and accurate method of measuring the microwave dielectric properties of small, easily prepared samples of tissues, tissue-simulating materials and biological fluids. The method gives dielectric properties averaged over the sample volume. The measurement accuracy with the apparatus used is +/- 2.2% for relative permittivity and +/- 3.5% for the loss factor for most tissue and biological material samples. With appropriate basic microwave equipment the method can be applied over the 1.5-6 GHz range of frequencies of interest for active and radiometric tissue microwave imaging.


Multi-science decision support for HIV drug resistance treatment.
The complete cascade from genome, proteome, metabolome, and physiome, to health forms multiscale, multiscience systems and crosses many orders of magnitude in temporal and spatial scales. The interactions between these systems create exquisite multitiered networks, with each component in nonlinear contact with many interaction partners. Understanding, quantifying, and handling this complexity is one of the biggest scientific challenges of our time. In this paper we argue that computer science in general, and Grid computing in particular, provide the language needed to study and understand these systems, and discuss a case study in decision support for HIV drug resistance treatment within the European ViroLab project.


The impact of socioeconomic disparities on the use of upfront autologous stem cell transplantation for mantle cell lymphoma.
Using the National Cancer Database, we identified 10,290 patients with newly diagnosed mantle cell lymphoma (MCL) treated with chemotherapy with or without upfront autologous stem cell transplantation (ASCT). Only 17% of patients underwent ASCT. Patients who underwent ASCT were younger and more likely to have lower comorbidity scores, private insurance, higher income and education, and treatment received at an academic facility. On multivariable analysis, age, comorbidity index, insurance type, the transition of care, facility type, distance to facility, and diagnosis year were predictive for ASCT use. ASCT use was associated with improved 5-year overall survival in younger (82% vs. 64%, p < .001) and older (70% vs. 40%, p < .001) patients, which was retained in the matched propensity score and 12-month analyses. Female gender, the diagnosis year ≥2009, private insurance, higher income, and education were associated with superior survival, whereas Black race and higher comorbidities predicted inferior survival.


Deformable registration of PET/CT and ultrasound for disease-targeted focal prostate brachytherapy.
We propose a deformable registration algorithm for prostate-specific membrane antigen (PSMA) PET/CT and transrectal ultrasound (TRUS) fusion. Accurate registration of PSMA PET to intraoperative TRUS will allow physicians to customize dose planning based on the regions involved. The inputs to the registration algorithm are the PET/CT and TRUS volumes as well as the prostate segmentations. PET/CT and TRUS volumes are first rigidly registered by maximizing the overlap between the segmented prostate binary masks. Three-dimensional anatomical landmarks are then automatically extracted from the boundary as well as within the prostate. Then, a deformable registration is performed using a regularized thin plate spline where the landmark localization error is optimized between the extracted landmarks that are in correspondence. The proposed algorithm was evaluated on 25 prostate cancer patients treated with low-dose-rate brachytherapy. We registered the postimplant CT to TRUS using the proposed algorithm and computed target registration errors (TREs) by comparing implanted seed locations. Our approach outperforms state-of-the-art methods, with significantly lower ( mean ± standard deviation ) TRE of 1.96 ± 1.29 mm while being computationally efficient (mean computation time of 38 s). The proposed landmark-based PET/CT-TRUS deformable registration algorithm is simple, computationally efficient, and capable of producing quality registration of the prostate boundary as well as the internal gland.


Internal metal sequestration and its ecotoxicological relevance: a review.
Organisms are able to control metal concentrations in certain tissues of their body to minimize damage of reactive forms of essential and nonessential metals and to control selective utilization of essential metals. These physiological aspects of organisms are not accounted for when assessing the risk of metals in the environment. The Critical Body Residue (CBR) approach relates toxicity to bioaccumulation and biomagnification and might at first sight provide a more accurate estimation of effects than the external concentration. When expressing CBRs on total internal concentrations, the capacity of organisms to sequester metals in forms that are not biologically reactive is neglected. The predictability of toxic effects will increase when knowledge on metal compartmentalization within the organisms' body is taken into account. Insight in metal compartmentalization sheds light on the different accumulation strategies organisms can follow upon metal exposure. Using a fractionation procedure to isolate metal-rich granules and tissue fragments from intracellular and cytosolic fractions, the internal compartmentalization of metals can be approximated. In this paper, current knowledge regarding metal compartmentalization in organisms is summarized, and metal fractions are identified that are indicators of toxicity. Guidance is provided on future improvement of models, such as the Biotic Ligand Model (BLM), for risk assessment of metal stress to biota.


Tinnitus Treatment with Oxytocin: A Pilot Study.
Tinnitus is the perception of sound in the absence of an external stimulus. It is a frequent condition for which there is as yet no pharmacological treatment approved. Auditory and non-auditory pathways are involved in tinnitus' pathophysiology. Oxytocin is a neurohormone and eventual neurotransmitter that plays a complex role in social cognition and behavior. To evaluate the potential of oxytocin as a tinnitus treatment. Two studies were performed. Study 1 was a long-term open pilot study, while study 2 investigated short-term effects with a double-blinded placebo-controlled cross-over study. Ambulatory ENT care. In study 1, 15 patients were investigated over a 10-week period in an open pilot study. In study 2, 16 patients were included in a placebo-controlled crossover trial to investigate short-term effects following a single dose. For the long-term study (study 1), analysis of variance revealed a significant decrease in tinnitus sensation, both for the Tinnitus Handicap Inventory and Clinical Global Impression (CGI). Also, the short-term effects in study 2 revealed a significant reduction of tinnitus because of the oxytocin nasal spray as measured with the Visual Analog Scale and the CGI Scale. These preliminary studies demonstrated that oxytocin may represent a helpful tool for treating tinnitus and further larger controlled studies are warranted.


The course of lower cranial nerves within the neck: a cadaveric dissection study.
To evaluate the course of lower cranial nerves (CNs) within the neck in relation to surrounding structures and anatomic landmarks via a cadaveric dissection study. A total of 70 neck dissections (31 bilateral, 8 unilateral) were performed on 39 adult fresh cadavers [mean (SD) age: 38.5 (11.2) years, 29 male, 10 female] to identify the course of lower CNs [spinal accessory nerve (SAN), vagus nerve and hypoglossal nerve] within the neck in relation to surrounding structures [internal jugular vein (IJV), common carotid artery (CCA)] and distance to anatomical landmarks (cricoid cartilage, hyoid bone, digastric muscle). SAN travelled most commonly anterior to IJV (51.4%) at the level of jugular foramen, while travelling lateral to IJV at the post belly of digastric (55.7%) and inferior to digastric muscle (90%) in most neck dissections. Vagus nerve travelled lateral to CCA in majority (94.3%) of dissections, while medial (2.9%), posterolateral (1.4%) and posterior (1.4%) positions were also noted. Average distance of hypoglossal nerve was 27.7 (9.7) mm to carotid bifurcation, 9.3 (3.9) mm to hyoid bone, and 54.7 (18.0) mm to the inferior border of cricoid cartilage. In conclusion, our findings indicate that anatomic variations are not rare in the course of lower CNs within the neck in relation to adjacent structures, and awareness of these variations together with knowledge of distance to certain anatomic landmarks may help the surgeon to identify lower CNs during neck surgery and prevent potential nerve injuries.


Quantifying brain iron deposition in patients with Parkinson's disease using quantitative susceptibility mapping, R2 and R2.
To evaluate the sensitivity and specificity of quantitative magnetic resonance (MR) iron mapping including R2, R2* and magnetic susceptibility to differentiate patients with Parkinson's disease (PD) from healthy controls. Thirty (30) healthy controls (HC) (64±7years old) and 20 patients with idiopathic PD (66±8years old) were studied using a 3T MR imaging scanner. R2 maps were generated from GRASE sequence while R2*, and quantitative susceptibility mapping (QSM) were obtained from a conventional multi-echo gradient-echo sequence. R2, R2* and relative susceptibility (Δχ) values of structures in the basal ganglia were measured for each patient and control. An analysis of sensitivity and specificity and unpaired t-test was applied to the two groups. A significant difference (p<0.05) was found for R2 and ∆χ values in the substantia nigra as a whole and in the pars compacta for PD patients. The R2* values were different significantly (p<0.05) only on the substantia nigra pars compacta. QSM presented the highest sensitivity and specificity to differentiate the two populations. The QSM map was the most sensitive quantitative technique for detecting a significant increase of iron for PD. The highest significant difference between controls and patients was found in the substantia nigra pars compacta using QSM.


Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy.
The treatment of painful diabetic polyneuropathy (DPN) is often inadequate and frequently limited by the systemic adverse effects of medications, necessitating the evaluation of novel treatments. To evaluate the effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in painful diabetic polyneuropathy. Open-label, flexible-dosing, 3-week study with a 5-week extension. Outpatient clinics and clinical research centers.Patients Volunteer sample of 56 patients with clinically defined painful diabetic polyneuropathy of longer than 3 months' duration. Intervention The 5% lidocaine patch, with a maximum of 4 patches daily for 18 hours. Change in mean daily pain diary ratings from baseline to week 3. Secondary end points included assessments of safety, tolerability, and quality of life. Patients with painful diabetic polyneuropathy showed significant improvements in pain and quality-of-life outcome measures during a 3-week treatment period. These benefits were maintained in a subgroup of patients treated for an additional 5 weeks, during which taper of concomitant analgesic therapy was permitted. Adverse events were minimal, and systemic accumulation of lidocaine did not occur. Up to four 5% lidocaine patches for up to 18 h/d are well tolerated in patients with painful diabetic polyneuropathy, significantly improve pain and quality-of-life ratings, and may allow tapering of concomitant analgesic therapy. Given the open-label design of this trial, a randomized controlled trial is necessary to confirm these results.


Disruption of E-cadherin-mediated cell adhesion systems in gastric cancers in young patients.
The aim of this study was to elucidate the pathogenetic backgrounds of early-onset gastric cancers. Mutations of the E-cadherin and beta-catenin genes were analyzed by subjecting microdissected cancer cells and corresponding non-cancerous epithelial cells obtained from 9 gastric cancer patients under 35 years old to polymerase chain reaction-single strand conformation polymorphism analysis. Somatic, but no germline, E-cadherin gene mutations were detected in 6 (67%) of the patients. The cancer cells of 2 patients were exon 9-deleted E-cadherin molecule-immunoreactive. Neither somatic nor germline mutations in exon 3 of the beta-catenin gene were observed in any patient. One patient lacked beta-catenin immunoreactivity and the cancer cells of 6 others showed cytoplasmic beta-catenin immunoreactivity. The E-cadherin-mediated cell adhesion system in the cancer cells of all the patients examined appeared to be disrupted, indicating that somatically acquired dysfunction of this system plays an important role in early-onset diffuse-type gastric cancers. Helicobacter pylori infection was observed in 6 (67%) of our 9 patients, an incidence higher than the average in young Japanese individuals. Thus, early-onset gastric cancers may be attributable to environmental factors such as Helicobacter pylori infection.


Biocatalytic reductive aminations with NAD(P)H-dependent enzymes: enzyme discovery, engineering and synthetic applications.
Chiral amines are pivotal building blocks for the pharmaceutical industry. Asymmetric reductive amination is one of the most efficient and atom economic methodologies for the synthesis of optically active amines. Among the various strategies available, NAD(P)H-dependent amine dehydrogenases (AmDHs) and imine reductases (IREDs) are robust enzymes that are available from various sources and capable of utilizing a broad range of substrates with high activities and stereoselectivities. AmDHs and IREDs operate via similar mechanisms, both involving a carbinolamine intermediate followed by hydride transfer from the co-factor. In addition, both groups catalyze the formation of primary and secondary amines utilizing both organic and inorganic amine donors. In this review, we discuss advances in developing AmDHs and IREDs as biocatalysts and focus on evolutionary history, substrate scope and applications of the enzymes to provide an outlook on emerging industrial biotechnologies of chiral amine production.


Genotyping of the Duffy blood group among Plasmodium knowlesi-infected patients in Malaysia.
The Duffy blood group is of major interest in clinical medicine as it plays an important role in Plasmodium knowlesi and Plasmodium vivax infection. In the present study, the distribution of Duffy blood group genotypes and allelic frequencies among P. knowlesi infected patients as well as healthy individuals in Peninsular Malaysia were determined. The blood group of 60 healthy blood donors and 51 P. knowlesi malaria patients were genotyped using allele specific polymerase chain reaction (ASP-PCR). The data was analyzed using Fisher's exact test in order to assess the significance of the variables. Our results show a high proportion of the FY*A/FY*A genotype (>85% for both groups) and a high frequency of the FY*A allele (>90% for both groups). The FY*A/FY*A genotype was the most predominant genotype in both infected and healthy blood samples. The genotype frequency did not differ significantly between the donor blood and the malaria patient groups. Also, there was no significant correlation between susceptibility to P. knowlesi infection with any Duffy blood genotype.


Ethnic differences in the monthly variation of preeclampsia among Bedouin and Jewish parturients in the Negev.
To assess seasonal patterns and monthly variations in the incidence of preeclampsia in the Jewish and Bedouin population in Israel, assuming that ethnicity and environmental factors may have a role in the causal mechanism. A retrospective population-based study comparing all singleton pregnancies of patients with and without preeclampsia was performed. The study included all deliveries between and including 1988 and 2007. For each month, the percentage of births complicated by preeclampsia was calculated. The relative risks of preeclampsia by month of delivery were estimated as odds ratios, using the month of August as the reference category. During the study period, 203,461 deliveries took place, of which 8,421 (4.1%) were complicated with preeclampsia (either mild or severe). Significantly higher incidence of preeclampsia was demonstrated in the Jewish population: 4.7% (n = 4,783 deliveries) versus 3.6% in the Bedouin population (n = 3,683), (p < 0.001). A similar U shaped trend in the incidence of preeclampsia was noted in both populations: the incidence was highest in the winter months and reached its nadir in August, with subsequent increase through the fall months (p < 0.001). Using August as the reference month, odds ratios were 1.32 (95% CI 1.19-1.48) for January, 1.38 (95% CI 1.24-1.54) for February and 1.33 (95% CI 1.19-1.48) for March. Time series analysis demonstrated a difference in the behavior of the 2 populations. Whereas the Jewish population had demonstrated a Gregorian-month cycle, the Bedouin population had demonstrated a lunar-month cycle. Preeclampsia is significantly more common in the Jewish population. However, both populations demonstrate the same seasonal pattern, with higher incidence of preeclampsia in the winter months. Our findings suggest that climate and environmental exposure may have an important role in the pathophysiology of preeclampsia.


Revisiting soil bacterial counting methods: Optimal soil storage and pretreatment methods and comparison of culture-dependent and -independent methods.
Although a number of different methods have been used to quantify soil bacteria, identifying the optimal method(s) for soil bacterial abundance is still in question. No single method exists for undertaking an absolute microbial count using culture-dependent methods (CDMs) or even culture-independent methods (CIMs). This study investigated soil storage and pretreatment methods for optimal bacterial counts. Appropriate storage temperature (4°C) and optimal pretreatment methods (sonication time for 3 min and centrifugation at 1400 g) were necessary to preserve bacterial cell viability and eliminate interference from soil particles. To better estimate soil bacterial numbers under various cellular state and respiration, this study also evaluated three CDMs (i.e., colony forming unit, spotting, and most probable number (MPN) and three CIMs (i.e., flow cytometry (FCM), epifluorescence microscopy (EM) count, and DNA quantitation). Each counting method was tested using 72 soil samples collected from a local arable farm site at three different depths (i.e., 10-20, 90-100, and 180-190 cm). Among all CDMs, MPN was found to be rapid, simple, and reliable. However, the number of bacteria quantified by MPN was 1-2 orders lower than that quantified by CIMs, likely due to the inability of MPN to count anaerobic bacteria. The DNA quantitation method appeared to overestimate soil bacterial numbers, which may be attributed to DNA from dead bacteria and free DNA in the soil matrix. FCM was found to be ineffective in counting soil bacteria as it was difficult to separate the bacterial cells from the soil particles. Dyes used in FCM stained the bacterial DNA and clay particles. The EM count was deemed a highly effective method as it provided information on soil mineral particles, live bacteria, and dead bacteria; however, it was a time-consuming and labor-intensive process. Combining both types of methods was considered the best approach to acquire better information on the characteristics of indigenous soil microorganisms (aerobic versus anaerobic, live versus dead).


Oral health care education and its effect on caregivers' knowledge, attitudes, and practices: A randomized controlled trial.
The population of older people as well as the number of dependent older people is steadily increasing. Those unable to live independently at home are being cared for in a range of settings. Practical training for nurses and auxiliary care staff has frequently been recommended as a way of improving oral health care for functionally dependent elderly. To evaluate an oral health education program for the caretakers of institutionalized elderly. The study was a cluster randomized intervention trial with an elderly home as the unit of randomization. Seven out of 65 elderly homes accommodating a total of 78 caretakers and 462 elderly residents were selected in Bangalore city, India, out of which 3 elderly homes were assigned to the intervention group and 4 to the control group. Oral health knowledge of caretakers was assessed using a pre-tested proforma; later, oral health education was provided to the caretakers of the intervention group. Oral health education was given at the end of 6 months to the caretakers of the control group. Chi-square test, Fisher exact test, and paired proportion test were used for statistical analysis. There was significant improvement in the oral health knowledge of the caretakers from baseline in the interventional group. The results of the present study showed that there was a significant improvement in the oral health knowledge among the caretakers. Educating the caretakers for assisting or enabling residents for maintaining oral hygiene is essential.


sigma-1 receptors protect RGC-5 cells from apoptosis by regulating intracellular calcium, Bax levels, and caspase-3 activation.
sigma-1 Receptor ligands prevent neuronal death associated with glutamate excitotoxicity both in vitro and in vivo. However, the molecular mechanism of the neuroprotective effect remains to be elucidated. The present study was undertaken to determine whether sigma-1 receptor agonists provide neuroprotection by decreasing glutamate-induced calcium mobilization and preventing apoptotic gene expression. Cell death was measured by using a calcein-AM/propidium iodide cell-survival assay. Western blot analysis determined the expression levels of Bax in normal RGC-5 cells. Caspase-3 activation after glutamate treatment was determined with a carboxyfluorescein caspase-3 detection kit. Glutamate-induced intracellular calcium mobilization was measured by using ratiometric calcium imaging. sigma-1 Receptor-overexpressing RGC-5 (RGC-5-S1R) cells had lower glutamate-induced intracellular calcium mobilization than did normal RGC-5 cells, and the sigma-1 receptor ligand (+)-SKF10047 reduced the glutamate calcium response in normal and RGC-5-S1R cells. (+)-SKF10047 protected RGC-5 cells from glutamate-induced cell death, and the RGC-5-S1R cells showed a significant resistance to glutamate-induced apoptosis compared with the control RGC-5 cells. BD1047, a sigma-1 receptor antagonist, blocked the protective effect of (+)-SKF10047. Western blot analysis showed that (+)-SKF10047 inhibited the increase in Bax after glutamate treatments. Glutamate-mediated cell death involved activation of caspase-3, and sigma-1 receptor activation prevented an increase in caspase-3 expression. The results suggest that sigma-1 receptors regulate intracellular calcium levels and prevent activation of proapoptotic genes, thus promoting retinal ganglion cell survival. The sigma-1 ligands appear to be neuroprotective and are a potential target for neuroprotective therapeutics.


Sinus infection due to Eikenella corrodens.
Eikenella corrodens is a gram-negative rod that has been identified as a cause of endocarditis, osteomyelitis, pneumonia, cellulitis, and other infections. Because it is difficult to grow unless it is incubated in 10% carbon dioxide and because it may be overgrown by other organisms, it can be overlooked as a sinus pathogen. This is a report of the isolation of E corrodens from the sinuses of three patients with sinusitis. Three important features of infection with E corrodens, which are illustrated by these cases, are as follows: (1) the indolence of E corrodens infections; (2) the unusual susceptibility pattern of E corrodens; and (3) the fact that E corrodens is often isolated in mixed culture. The purulent contents of sinus cavities should be cultured in aerobic, anaerobic, and 10% carbon dioxide atmospheres.


Verbal memory, learning, and executive functioning among adolescent inhalant and cannabis users.
Inhalant use is a common form of drug misuse among young adolescents. However, very little is known about how chronic inhalant misuse affects cognition. Several studies have examined cognitive deficits among inhalant users, but no study has thoroughly addressed the confounding issues frequently associated with inhalant users (e.g., polysubstance use). The aim of the current study was to examine possible deficits in memory, learning, and executive components of memory (interference susceptibility) among young, regular inhalant users relative to a statistically equivalent drug-using control group (primarily cannabis users) and a community control group. Three groups of 21 young people (aged 13-24 years) were recruited: an inhalant- using group, a drug-using control group, and a community control group. The inhalant and drug-using controls were matched at the group level on demographic, clinical, and substance use measures. All three groups were statistically equivalent on age, sex, and education. The Rey Auditory Verbal Learning Test was used to assess memory, learning, and interference susceptibility. Community controls performed significantly better than both drug-using groups, while inhalant users were more susceptible to proactive interference relative to drug-using controls. Difficulty in successful proactive interference resolution demonstrated by the inhalant group may relate to inhalant-specific deficits in executive functioning. These findings raise important questions regarding the hypothesized toxicity of inhalants and of substance-specific cognitive deficits among regular adolescent substance users. Future studies should consider using more specific, experimental probes of cognitive functioning to identify potentially subtle changes among substance-using adolescents.


Saccharin and other sweeteners: mutagenic properties.
Saccharin preparations commonly distributed as artificial sweeteners exhibited mutagenic activity in bacterial tests. When administered orally to mice, mutagenic activity was demonstrable in the urines of these animals as well as in a host-mediated assay. Highly purified saccharin was not mutagenic in the direct assay, but the urines of mice to which this material had been administered exhibited mutagenic effects on one tester strain (Salmonella typhimurium TA100). Two other sweeteners, neohesperidin dihydrochalcone and xylitol, had no detectable mutagenic activity in any of these assays using his- Salmonella typhimurium strains TA100 or TA98.


Antibody Targets and Properties for Complement-Fixation Against the Circumsporozoite Protein in Malaria Immunity.
The Plasmodium falciparum circumsporozoite protein (CSP) forms the basis of leading subunit malaria vaccine candidates. However, the mechanisms and specific targets of immunity are poorly defined. Recent findings suggest that antibody-mediated complement-fixation and activation play an important role in immunity. Here, we investigated the regions of CSP targeted by functional complement-fixing antibodies and the antibody properties associated with this activity. We quantified IgG, IgM, and functional complement-fixing antibody responses to different regions of CSP among Kenyan adults naturally exposed to malaria (n=102) and using a series of rabbit vaccination studies. Individuals who acquired functional complement-fixing antibodies had higher IgG, IgM and IgG1 and IgG3 to CSP. Acquired complement-fixing antibodies targeted the N-terminal, central-repeat, and C-terminal regions of CSP, and positive responders had greater antibody breadth compared to those who were negative for complement-fixing antibodies (p<0.05). Using rabbit vaccinations as a model, we confirmed that IgG specific to the central-repeat and non-repeat regions of CSP could effectively fix complement. However, vaccination with near full length CSP in rabbits poorly induced antibodies to the N-terminal region compared to naturally-acquired immunity in humans. Poor induction of N-terminal antibodies was also observed in a vaccination study performed in mice. IgG and IgM to all three regions of CSP play a role in mediating complement-fixation, which has important implications for malaria vaccine development.


MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells.
Cancer pathogenesis is restricted by stresses that compromise cell division and survival. In this study, we identify miR-708, a little studied member of a set of microRNAs that have been implicated in stress control, as an important tumor suppressor in renal cell carcinoma (RCC). miR-708 expression was attenuated widely in human RCC specimens. Restoration of miR-708 expression in RCC cell lines decreased cell growth, clonability, invasion, and migration and elicited a dramatic increase in apoptosis. Moreover, intratumoral delivery of miR-708 was sufficient to trigger in vivo regression of established tumors in murine xenograft models of human RCC. Investigation of the targets of miR-708 identified the inhibitor of apoptosis protein survivin as important. siRNA-mediated knockdown of survivin partially phenocopied miR-708 overexpression suggesting that the proapoptotic role of miR-708 may be mediated primarily through survivin regulation. Additionally, we identified the E-cadherin regulators ZEB2 and BMI1 as likely miR-708 targets. Taken together, our findings define a major tumor suppressive role for miR-708, which may offer an attractive new target for prognostic and therapeutic intervention in RCC.


Gains in QTL detection using an ultra-high density SNP map based on population sequencing relative to traditional RFLP/SSR markers.
Huge efforts have been invested in the last two decades to dissect the genetic bases of complex traits including yields of many crop plants, through quantitative trait locus (QTL) analyses. However, almost all the studies were based on linkage maps constructed using low-throughput molecular markers, e.g. restriction fragment length polymorphisms (RFLPs) and simple sequence repeats (SSRs), thus are mostly of low density and not able to provide precise and complete information about the numbers and locations of the genes or QTLs controlling the traits. In this study, we constructed an ultra-high density genetic map based on high quality single nucleotide polymorphisms (SNPs) from low-coverage sequences of a recombinant inbred line (RIL) population of rice, generated using new sequencing technology. The quality of the map was assessed by validating the positions of several cloned genes including GS3 and GW5/qSW5, two major QTLs for grain length and grain width respectively, and OsC1, a qualitative trait locus for pigmentation. In all the cases the loci could be precisely resolved to the bins where the genes are located, indicating high quality and accuracy of the map. The SNP map was used to perform QTL analysis for yield and three yield-component traits, number of tillers per plant, number of grains per panicle and grain weight, using data from field trials conducted over years, in comparison to QTL mapping based on RFLPs/SSRs. The SNP map detected more QTLs especially for grain weight, with precise map locations, demonstrating advantages in detecting power and resolution relative to the RFLP/SSR map. Thus this study provided an example for ultra-high density map construction using sequencing technology. Moreover, the results obtained are helpful for understanding the genetic bases of the yield traits and for fine mapping and cloning of QTLs.


Reproduction life history and hip fractures.
The present study assesses the association between reproduction and hip fractures. We used two surveys on elderly Danish twins of both sexes and the Danish National Register of Patients. In a cross-sectional study of 2045 twins aged 75-98 years in 1995, we studied the association between different aspects of reproduction and hip fractures leading to hospitalization between 1977 and 1994. In a prospective study, 3057 twins aged 66-99 years in 1977 were followed for a total of 29,112 years, and the association between number of children and incidence of hip fractures was investigated. In the cross-sectional study, as well as the prospective study, we found, for both sexes, that having no children was associated with a higher risk of hip fracture compared to having at least one child. When excluding persons without children, we found no effect of number of birth events/children. In the cross-sectional study, we found no effect of birth interval length or age at first birth. For women, we found an effect of age at last birth. No "cost-of-reproduction" in terms of hip fractures was observed. On the contrary, we found that having one or more children was associated with a lower risk of hip fracture.


Direct Determination of Pyrazinamide (PZA) Susceptibility by Sputum Microscopic Observation Drug Susceptibility (MODS) Culture at Neutral pH: the MODS-PZA Assay.
Pyrazinamide (PZA) is considered the pivot drug in all tuberculosis treatment regimens due to its particular action on the persistent forms of Mycobacterium tuberculosis However, no drug susceptibility test (DST) is considered sufficiently reliable for routine application. Although molecular tests are endorsed, their application is limited to known PZA resistance associated mutations. Microbiological DSTs for PZA have been restricted by technical limitations, especially the necessity for an acidic pH. Here, for the first time, MODS culture at neutral pH was evaluated using high PZA concentrations (400 and 800 μg/ml) to determine PZA susceptibility directly from sputum samples. Sputum samples were cultured with PZA for up to 21 days at 37°C. Plate reading was performed at two time points: R1 (mean, 10 days) and R2 (mean, 13 days) for each PZA concentration. A consensus reference test, composed of MGIT-PZA, pncA sequencing, and the classic Wayne test, was used. A total of 182 samples were evaluated. The sensitivity and specificity for 400 μg/ml ranged from 76.9 to 89.7 and from 93.0 to 97.9%, respectively, and for 800 μg/ml ranged from 71.8 to 82.1 and from 95.8 to 98.6%, respectively. Compared to MGIT-PZA, our test showed a similar turnaround time (medians of 10 and 12 days for PZA-sensitive and -resistant isolates, respectively). In conclusion, MODS-PZA is presented as a fast, simple, and low-cost DST that could complement the MODS assay to evaluate resistance to the principal first-line antituberculosis drugs. Further optimization of test conditions would be useful in order to increase its performance.


Triplex forming oligonucleotides against type α1(I) collagen attenuates liver fibrosis induced by bile duct ligation.
Liver fibrosis is a consequence of chronic liver disorders which lead to the accumulation of extracellular matrix (ECM). Particularly, there is an increased accumulation of collagen in the fibrotic liver. We have therefore used a triplex forming oligonucleotide (TFO) against the type α1(I) collagen and evaluated, whether it can attenuate liver fibrosis induced by common bile duct ligation (CBDL) in rats. There was a significant decrease in hydroxyproline levels and Masson's trichrome staining for collagen in TFO-treated CBDL groups compared to non-treated CBDL group. There was over expression of type α1(I) collagen, α-smooth muscle actin (α-SMA) and TGF-β1 expression in the CBDL group compared to TFO-treated CBDL group. Also, the serum alanine transaminase (ALT) and aspartate transaminase (AST) concentrations were less in the TFO treated group compared to non-treated CBDL group. There was also less neutrophils accumulation in TFO treated CBDL group assayed by myeloperoxidase (MPO) assay. These results suggests that TFO can be used to downregulate type 1 collagen gene expression and can alleviate liver fibrosis induced by common bile duct ligation.


Measurement depth enhancement in terahertz imaging of biological tissues.
We demonstrate the use of a THz penetration-enhancing agent (THz-PEA) to enhance the terahertz (THz) wave penetration depth in tissues. The THz-PEA is a biocompatible material having absorption lower than that of water, and it is easily absorbed into tissues. When using glycerol as a THz-PEA, the peak value of the THz signal which was transmitted through the fresh tissue and reflected by a metal target, was almost doubled compared to that of tissue without glycerol. THz time-of-flight imaging (B-scan) was used to display the sequential glycerol delivery images. Enhancement of the penetration depth was confirmed after an artificial tumor was located below fresh skin. We thus concluded that the THz-PEA technique can potentially be employed to enhance the image contrast of the abnormal lesions below the skin.


Intraoral sebaceous carcinoma: A rare presentation on the tongue and review of the literature.
Intraoral sebaceous carcinoma (SC) is exceedingly rare, especially in the tongue. We reported the clinicopathological and immunohistochemical features of a rare SC case in a 59-year-old male who presented a painful ulcer on the tongue's posterior region. Microscopically, the tumor was composed of atypical basaloid cells with round to oval nuclei and prominent nucleoli arranged in lobes showing prominent sebaceous differentiation and areas of holocrine secretion. Immunohistochemistry showed positivity for pan-cytokeratin AE1/AE3 and epithelial membrane antigen (EMA) and negativity for cytokeratin 7 (CK7). The sebaceous cells were positive for adipophilin and perforin. Wide surgical excision followed by adjuvant chemotherapy and radiotherapy was performed. Careful histopathological analysis of these lesions is crucial to ensure a correct diagnosis. Due to the aggressive behavior of SCs, early diagnosis and treatment are essential to increase the patient's survival time. To the best of our knowledge, this is the second case of SC in the tongue.


Templating photodimerization of coumarins within a water-soluble nano reaction vessel.
An octahedral Pd nanocage serves as a reaction vessel to control photodimerization of coumarins in water. The coumarin derivatives explored in this study react within the Pd nanocage to selectively yield a syn head-head dimer, whereas in water, they yield either a mixture of dimers or a different isomer. The selective dimerization is interpreted to mean that the monomers are preorganized by the cage through weak intermolecular forces. The selectivity obtained within the nanocage is more general and predictable compared to other hosts used previously to control the geometry of photodimerization reactions.


Identification of the most influential factors in the Norwegian guidelines for risk assessment of dispersion of contaminants from sediments.
The Norwegian guidelines for risk assessment of contaminated sediments are used to identify areas of concern where remediation may be needed to meet the governmental long-term goal of clean fjords and harbors along the Norwegian coastline. By a thorough sensitivity analysis, this study identifies the most influential factors and parameters for the Tier 2A model in this risk guideline, which are used to estimate fluxes of contaminants from sediments due to diffusion and bioturbation (F(diff)), resuspension caused by ship traffic (F(skipnorm)), and uptake and predation of benthic biota (F(org)). The sensitivity analysis is run for 36 different scenarios combining 3 different sizes of contaminated area, 3 harbor types, and 3 persistent organic pollutants, namely lindane (γ-hexachlorocyclohexane), benzo[a]pyrene, and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), as well as the metal mercury (Hg). The most influential parameters vary from scenario to scenario, but generally 5 parameters appear to be particularly influential for the fluxes and transport estimated by the Tier 2A model: flux of organic carbon to sediment (OC(sed)), factor for increased diffusion due to bioturbation (a), sediment-water partitioning coefficient (K(d)), benthic biota-water bioconcentration factor (BCF(fisk)), and mass of resuspended fine sediment during arrival or departure of a ship (m(sed)). We also quantify which of the 3 fluxes (F(diff), F(skipnorm), and F(org)) dominate in the different scenarios. Our sensitivity analysis results can be used by authorities, problem owners, consultants, and environmental managers involved in contaminated sediment management to gain insight on the key processes and parameters and to focus their site-specific or laboratory-based measurement efforts on the key parameters and thus increase efficiency and reliability in the contaminated sediment risk assessment.


Short-interval intracortical inhibition in human primary motor cortex: A multi-locus transcranial magnetic stimulation study.
Short-interval intracortical inhibition (SICI) has been studied with paired-pulse transcranial magnetic stimulation (TMS) by administering two pulses at a millisecond-scale interstimulus interval (ISI) to a single cortical target. It has, however, been difficult to study the interaction of nearby cortical targets with paired-pulse TMS. To overcome this limitation, we have developed a multi-locus TMS (mTMS) device, which allows controlling the stimulus location electronically. Here, we applied mTMS to study SICI in primary motor cortex with paired pulses targeted to adjacent locations, aiming to quantify the extent of the cortical region producing SICI in the location of a test stimulus. We varied the location and timing of the conditioning stimulus with respect to a test stimulus targeted to the cortical hotspot of the abductor pollicis brevis (APB) in order to study their effects on motor evoked potentials. We further applied a two-coil protocol with the conditioning stimulus given by an oval coil only to the surroundings of the APB hotspot, to which a subsequent test stimulus was administered with a figure-of-eight coil. The strongest SICI occurred at ISIs below 1 ms and at ISIs around 2.5 ms. These ISIs increased when the conditioning stimulus receded from the APB hotspot. Our two-coil paired-pulse TMS study suggests that SICI at ISIs of 0.5 and 2.5 ms originate from different mechanisms or neuronal elements.


A Polynucleotide Repeat Expansion Causing Temperature-Sensitivity Persists in Wild Irish Accessions of Arabidopsis thaliana.
Triplet repeat expansions underlie several human genetic diseases such as Huntington's disease and Friedreich's ataxia. Although such mutations are primarily known from humans, a triplet expansion associated genetic defect has also been reported at the IIL1 locus in the Bur-0 accession of the model plant Arabidopsis thaliana. The IIL1 triplet expansion is an example of cryptic genetic variation as its phenotypic effects are seen only under genetic or environmental perturbation, with high temperatures resulting in a growth defect. Here we demonstrate that the IIL1 triplet expansion associated growth defect is not a general stress response and is specific to particular environmental perturbations. We also confirm and map genetic modifiers that suppress the effect of IIL1 triplet repeat expansion. By collecting and analyzing accessions from the island of Ireland, we recover the repeat expansion in wild populations suggesting that the repeat expansion has persisted at least 60 years in Ireland. Through genome-wide genotyping, we show that the repeat expansion is present in diverse Irish populations. Our findings indicate that even deleterious alleles can persist in populations if their effect is conditional. Our study demonstrates that analysis of groups of wild populations is a powerful tool for understanding the dynamics of cryptic genetic variation.


Involvement of the endoplasmic reticulum in the assembly and envelopment of African swine fever virus.
African swine fever (ASF) virus is a large enveloped DNA virus assembled in the cytoplasm of cells. In this study, the membrane compartments involved in the envelopment of ASF virus were investigated. A monoclonal antibody recognizing p73, the major structural protein of ASF virus, was generated to analyze the binding of p73 to membranes during the assembly of the virus. Approximately 50% of the intracellular pool of p73 associated with membranes as a peripheral membrane protein. Binding was rapid and complete within 15 min of synthesis. Subcellular membrane fractionation showed that newly synthesized p73 molecules cosedimented with endoplasmic reticulum (ER) membranes and remained associated with the ER during a 2-h chase. A similar distribution on gradients was recorded for p17, a structural membrane protein of ASF virus. The results suggested that the ER was involved in the assembly of ASF virus. A protease protection assay demonstrated a time-dependent envelopment of the membrane bound, but not cytosolic, pool of p73. Envelopment of p73 took place 1 h after binding to membranes and was completed 1 h before the first detection of p73 in virions secreted from cells. Envelopment was unaffected by brefeldin A and monensin, drugs that block membrane transport between the ER and Golgi. Taken together the results provide evidence for the binding of ASF virus structural proteins to a specific membrane compartment and implicate a role for the ER in the assembly and envelopment of ASF virus.


Coparenting Problems with Toddlers Predict Children's Symptoms of Psychological Problems at Age 7.
This study examined whether coparenting during toddlerhood predicts children's later symptoms of attention deficit/hyperactivity disorder, oppositional defiant disorder, affective disorder, and somatic complaints. When children were 2 years old, 108 middle-class nonclinical families were observed in triadic interactions to assess two domains of dyadic coparenting (competitive and cooperative), as well as each parent's individual competitive behavior toward the spouse. Teachers and mothers reported children's symptoms of psychological problems at age 7. Independent of cooperative coparenting and each parents' individual harsh parenting, competitive coparenting predicted children's symptoms of ADHD and ODD. Interactions with child gender indicated that competitive coparenting predicted ADHD symptoms in boys (not in girls) and teacher-reported (not mother-reported) somatic complaints in girls (not in boys). ODD and ADHD symptoms were also predicted by fathers' (not mothers') individual competitive behaviors. The children of parents who were both low in competitive behaviors had the lowest teacher-rated symptoms of affective disorder.


Cutting Edge: IFN-γ Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii.
In vitro studies demonstrated that microglia and astrocytes produce IFN-γ in response to various stimulations, including LPS. However, the physiological role of IFN-γ production by brain-resident cells, including glial cells, in resistance against cerebral infections remains unknown. We analyzed the role of IFN-γ production by brain-resident cells in resistance to reactivation of cerebral infection with Toxoplasma gondii using a murine model. Our study using bone marrow chimeric mice revealed that IFN-γ production by brain-resident cells is essential for upregulating IFN-γ-mediated protective innate immune responses to restrict cerebral T. gondii growth. Studies using a transgenic strain that expresses IFN-γ only in CD11b(+) cells suggested that IFN-γ production by microglia, which is the only CD11b(+) cell population among brain-resident cells, is able to suppress the parasite growth. Furthermore, IFN-γ produced by brain-resident cells is pivotal for recruiting T cells into the brain to control the infection. These results indicate that IFN-γ produced by brain-resident cells is crucial for facilitating both the protective innate and T cell-mediated immune responses to control cerebral infection with T. gondii.


Tetrathiafulvalene-Based Helicene Ligand in the Design of a Dysprosium Field-Induced Single-Molecule Magnet.
The design of a coordination complex that involves a ligand combining both a tetrathiafulvalene core and a helicene fragment was achieved thanks to the reaction between the new 2-{1-[2-methyl[6]helicene]-4,5-[4,5-bis(propylthio)tetrathiafulvalenyl]-1 H-benzimidazol-2-yl}pyridine ligand (L) and the Dy(hfac)3·2H2O metalloprecursor. Magnetic investigations showed field-induced single-molecule-magnet (SMM) behavior under an applied magnetic field of 1000 Oe for [Dy(hfac)3(L)]·0.5CH2Cl2, while experimentally oriented single-crystal magnetic measurements allowed for determination of the magnetic anisotropy orientation. The magnetic behavior was rationalized through ab initio CASSCF/SI-SO calculations. This redox-active chiral-field-induced SMM paves the way for the design of switchable-multiproperty SMMs.


Association between hypotension, low ejection fraction and cognitive performance in cardiac patients.
Impaired cardiac function can adversely affect the brain via decreased perfusion. The purpose of this study was to determine if cardiac ejection fraction (EF) is associated with cognitive performance, and whether this is modified by low blood pressure. Neuropsychological testing evaluating multiple cognitive domains, measurement of mean arterial pressure (MAP), and measurement of EF were performed in 234 individuals with coronary artery disease. The association between level of EF and performance within each cognitive domain was explored, as was the interaction between low MAP and EF. Adjusted global cognitive performance, as well as performance in visuoconstruction and motor speed, was significantly directly associated with cardiac EF. This relationship was not entirely linear, with a steeper association between EF and cognition at lower levels of EF than at higher levels. Patients with low EF and low MAP at the time of testing had worse cognitive performance than either of these alone, particularly for the global and motor speed cognitive scores. Low EF may be associated with worse cognitive performance, particularly among individuals with low MAP and for cognitive domains typically associated with vascular cognitive impairment. Further care should be paid to hypotension in the setting of heart failure, as this may exacerbate cerebral hypoperfusion.


Management of patients with infective endocarditis by a multidisciplinary team approach: an operative protocol.
Even in the modern era of advanced diagnostic imaging, improved antibiotic therapy and potentially curative surgery, infective endocarditis remains a serious disease with high rates of morbidity and mortality. Reasons for such a persistently poor outcome may be represented by the changing epidemiology and microbiology, with new groups of patients at risk and new and more aggressive microorganisms. However, the inadequate use of both diagnostic (blood cultures and echocardiography) and therapeutic (antibiotics and surgery) means can influence the generally delayed diagnosis and poor prognosis seen in patients with infective endocarditis. We tried to identify the critical points in the management of patients with infective endocarditis and to elaborate a formal multidisciplinary approach based on the strict collaboration of specialists in infectious diseases, microbiology, cardiology and cardiac surgery. We hypothesized that this approach could increase the adherence to the published guidelines, and could represent a means to improve the outcome of patients with infective endocarditis.


Influence of crown/implant ratio on marginal bone loss: a systematic review.
With the increased use of short dental implants (<10 mm), a high crown/implant (C/I) ratio has become a common finding. However, the effect of the C/I ratio on the marginal bone loss (MBL) has not yet been examined extensively. Hence, the aim of the present systematic review is to explore the influence of the C/I ratio on the success rate and MBL of dental implants. Three electronic databases (PubMed, Ovid MEDLINE, and Cochrane Central) and a manual search for human trials with a minimal follow-up of 6 months are used for the present study. A statistical analysis of the influence of the C/I ratio was performed on the peri-implant MBL while considering follow-up period, type of implants, implant connection, and technical and biologic complications. One hundred ninety-six potential articles were identified on the selected databases. Only 57 articles were selected for full-text evaluation. According to the inclusion criteria, a total of 13 articles were included in this systematic review. A significant negative association between the C/I ratio and the MBL was found (P = 0.012). However, no statistically significant difference was found (P >0.15) for potential effects regarding the observation period, the type of implant connection, or between both methods of evaluating the C/I ratio. Within the limitations of the present study, the C/I ratio of implant-supported restorations has an effect on peri-implant marginal bone level. Within the range of 0.6/1 to 2.36/1, the higher the C/I ratio, the less the peri-implant MBL.


The relationship between weight stigma and eating behavior is explained by weight bias internalization and psychological distress.
Weight stigma is associated with a range of negative outcomes, including disordered eating, but the psychological mechanisms underlying these associations are not well understood. The present study tested whether the association between weight stigma experiences and disordered eating behaviors (emotional eating, uncontrolled eating, and loss-of-control eating) are mediated by weight bias internalization and psychological distress. Six-hundred and thirty-four undergraduate university students completed an online survey assessing weight stigma, weight bias internalization, psychological distress, disordered eating, along with demographic characteristics (i.e., age, gender, weight status). Statistical analyses found that weight stigma was significantly associated with all measures of disordered eating, and with weight bias internalization and psychological distress. In regression and mediation analyses accounting for age, gender and weight status, weight bias internalization and psychological distress mediated the relationship between weight stigma and disordered eating behavior. Thus, weight bias internalization and psychological distress appear to be important factors underpinning the relationship between weight stigma and disordered eating behaviors, and could be targets for interventions, such as, psychological acceptance and mindfulness therapy, which have been shown to reduce the impact of weight stigma. The evidence for the health consequences resulting from weight stigma is becoming clear. It is important that health and social policy makers are informed of this literature and encouraged develop anti-weight stigma policies for school, work, and medical settings.


The genetics of loneliness: linking evolutionary theory to genome-wide genetics, epigenetics, and social science.
As a complex trait, loneliness is likely to be influenced by the interplay of numerous genetic and environmental factors. Studies in behavioral genetics indicate that loneliness has a sizable degree of heritability. Candidate-gene and gene-expression studies have pointed to several genes related to neurotransmitters and the immune system. The notion that these genes are related to loneliness is compatible with the basic tenets of the evolutionary theory of loneliness. Research on gene-environment interactions indicates that social-environmental factors (e.g., low social support) may have a more pronounced effect and lead to higher levels of loneliness if individuals carry the sensitive variant of these candidate genes. Currently, there is no extant research on loneliness based on genome-wide association studies, gene-environment-interaction studies, or studies in epigenetics. Such studies would allow researchers to identify networks of genes that contribute to loneliness. The contribution of genetics to loneliness research will become stronger when genome-wide genetics and epigenetics are integrated and used along with well-established methods in psychology to analyze the complex process of gene-environment interplay.


African Swine Fever Laboratory Diagnosis-Lessons Learned from Recent Animal Trials.
African swine fever virus (ASFV) causes a hemorrhagic disease in pigs with high socio-economic consequences. To lower the impact of disease incursions, early detection is crucial. In the context of experimental animal trials, we evaluated diagnostic workflows for a high sample throughput in active surveillance, alternative sample matrices for passive surveillance, and lateral flow devices (LFD) for rapid testing. We could demonstrate that EDTA blood is significantly better suited for early ASFV detection than serum. Tissues recommended by the respective diagnostic manuals were in general comparable in their performance, with spleen samples giving best results. Superficial lymph nodes, ear punches, and different blood swabs were also evaluated as potential alternatives. In summary, all matrices yielded positive results at the peak of clinical signs and could be fit for purpose in passive surveillance. However, weaknesses were discovered for some matrices when it comes to the early phase of infection or recovery. The antigen LFD showed variable results with best performance in the clinical phase. The antibody LFD was quite comparable with ELISA systems. Concluding, alternative approaches are feasible but have to be embedded in control strategies selecting test methods and sample materials following a "fit-for-purpose" approach.


Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors.
Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GIST. Most GISTs eventually acquire imatinib resistance due to secondary mutations in the KIT kinase domain, but it is unclear whether these genomic resistance mechanisms require other cellular adaptations to create a clinically meaningful imatinib-resistant state. Using phospho-RTK and immunoblot assays, we demonstrate activation of KIT and insulin receptor (IR) in imatinib-resistant GIST cell lines (GIST430 and GIST48) and biopsies with acquisition of KIT secondary mutations, but not in imatinib-sensitive GIST cells (GIST882 and GIST-T1). Treatment with linsitinib, a specific IR inhibitor, inhibited IR and downstream intermediates AKT, MAPK, and S6 in GIST430 and GIST48, but not in GIST882, exerting minimal effect on KIT phosphorylation in these cell lines. Additive effects showing increased apoptosis, antiproliferative effects, cell-cycle arrest, and decreased pAKT and pS6 expression, tumor growth, migration, and invasiveness were observed in imatinib-resistant GIST cells with IR activation after coordinated inhibition of IR and KIT by linsitinib (or IR shRNA) and imatinib, respectively, compared with either intervention alone. IGF2 overexpression was responsible for IR activation in imatinib-resistant GIST cells, whereas IR activation did not result from IR amplification, IR mutation, or KIT phosphorylation. Our findings suggest that combinatorial inhibition of IR and KIT warrants clinical evaluation as a novel therapeutic strategy in imatinib-resistant GISTs. Cancer Res; 77(18); 5107-17. ©2017 AACR.


MATERIALS SCIENCE: Deformations in Extreme Matter.
Most materials become narrower in cross section when stretched, but some materials, such as foams, have the counterintuitive property of becoming fatter when stretched (they have a negative Poisson's ratio). In this Perspective, Lakes discusses how his unusual property may arise in isotropic and anisotropic materials. He highlights the study by Baughman et al., who show that anisotropic materials with a negative Poisson's ratio in one direction can be incompressible, i.e., without an overall change in volume upon stretching. This behavior is predicted for materials with very high density, such as neutron star crusts, or very low density, such as ion plasmas, and the validity of the prediction is demonstrated with experimental data for ion plasmas.


Factors and outcomes associated with inpatient cardiac arrest following emergent endotracheal intubation.
Inpatient peri-intubation cardiac arrest (PICA) following emergent endotracheal intubation (ETI) is an uncommon but potentially preventable type of cardiac arrest (CA). Limited published data exist describing factors associated with inpatient PICA and patient outcomes. This study identifies risk factors associated with PICA among hospitalized patients emergently intubated out of the operating room and compares PICA to other types of inpatient CA. Retrospective case-control study of patients at our institution over a five-year period. Cases were defined as inpatients emergently intubated outside of the operating room that experienced cardiac arrest within 20min after ETI. The control group consisted of inpatients emergently intubated out of the operating room without CA. Predictors of PICA were identified through univariate and multivariate analysis. Clinical outcomes were compared between PICA and other inpatient CAs, identified through a prospectively enrolled CA registry at our institution. 29 episodes of PICA occurred over 5 years, accounting for 5% of all inpatient arrests. Shock index ≥1.0, intubation within one hour of nursing shift change, and use of succinylcholine were independently associated with PICA. Sustained ROSC, survival to discharge, and neurocognitive outcome did not differ significantly between groups. Patients outcomes following PICA were comparable to other causes of inpatient CA. Potentially modifiable factors were associated with PICA. Hemodynamic resuscitation, optimized staffing strategies, and possible avoidance of succinylcholine were associated with decreased risk of PICA. Clinical trials testing targeted strategies to optimize peri-intubation care are needed to identify effective interventions to prevent this potentially avoidable type of CA.


Diabetes mellitus in peninsular Malaysia: ethnic differences in prevalence and complications.
Estimated prevalence of diabetes mellitus in Malaysia was about 2%. Diabetes was most common in Indians especially males and least common in Chinese. There was a slight male preponderance seen in Malays and Indians. Positive family history was obtained in 14% of cases most commonly in Malays, almost 1/3 of whom had more than one family member with diabetes. Familial association was uncommon in Chinese. Over 50% of patients were overweight. Obesity was noted in nearly 70% of female Malays and Indians while the majority of Chinese were not overweight. More than 80% of patients were non insulin requiring. Youth onset diabetes was considered rare; those 10 years and below were estimated to be only 0.4% and below 20 years of age between 2%-4% of the diabetic population. Females were twice as common than males in this type of diabetes and familial association was greater. Malnutrition-related diabetes and pancreatic calcification were not well-documented but youth-onset non insulin requiring diabetics with mild symptoms but strong family history of diabetes were observed. More than half of hospital-based patients had evidence of complications, mainly amongst Malays and Indians. Hypertension was the most frequent associated disease followed by foot ulcers and ischaemic heart disease. Hypertension usually associated with chronic renal failure was most common amongst Malays while gangrenic ulcers and heart diseases were seen mainly in Indians. The major causes of death were chronic renal failure, myocardial infarction, ketoacidosis, stroke and septicaemia related to gangrene.(ABSTRACT TRUNCATED AT 250 WORDS)


Chromosome 2 (2p16) abnormalities in Carney complex tumours.
Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia and lentiginosis syndrome characterised by spotty skin pigmentation, cardiac, skin, and breast myxomas, and a variety of endocrine and other tumours. The disease is genetically heterogeneous; two loci have been mapped to chromosomes 17q22-24 (the CNC1 locus) and 2p16 (CNC2). Mutations in the PRKAR1A tumour suppressor gene were recently found in CNC1 mapping kindreds, while the CNC2 and perhaps other genes remain unidentified. Analysis of tumour chromosome rearrangements is a useful tool for uncovering genes with a role in tumorigenesis and/or tumour progression. CGH analysis showed a low level 2p amplification recurrently in four of eight CNC tumours; one tumour showed specific amplification of the 2p16-p23 region only. To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs). Consistent cytogenetic changes of the region were detected in 40 (87%) of the samples analysed. Twenty-four samples (60%) showed amplification of the region represented as homogeneously stained regions (HSRs). The size of the amplicon varied from case to case, and frequently from cell to cell in the same tumour. Three tumours (8%) showed both amplification and deletion of the region in their cells. Thirteen tumours (32%) showed deletions only. These molecular cytogenetic changes included the region that is covered by BACs 400-P-14 and 514-O-11 and, in the genetic map, corresponds to an area flanked by polymorphic markers D2S2251 and D2S2292; other BACs on the centromeric and telomeric end of this region were included in varying degrees. We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC patients, including those with germline, inactivating PRKAR1A mutations. These changes are mostly amplifications of the 2p16 region, that overlap with a previously identified amplicon in sporadic thyroid cancer, and an area often deleted in sporadic adrenal tumours. Both thyroid and adrenal tumours constitute part of CNC indicating that the responsible gene(s) in this area may indeed be involved in both inherited and sporadic endocrine tumour pathogenesis and/or progression.


Incorporation of three or two distal double bonds at the methylene bridges of the calix[4]arene scaffold.
Partial oxidation of the 1,3-alternate atropisomer of p-tert-butylcalix[4]arene tetraacetate with CrO3 afforded mainly a mixture of trioxo- and tetraoxo-calix[4]arene tetraacetate derivatives. The trioxotetrahydroxy derivative 6 was isolated from the mixture after hydrolysis of the crude product, followed by trituration with ethanol. Trioxocalix[4]arene adopts in the crystal a 1,2-alternate conformation. Acetylation or alkylation of the tetrahydroxytrioxocalix[4]arene 6 with acetic anhydride and 1-bromobutane, respectively, afforded exclusively a single atropisomer of the product, which in both cases were characterized as the 1,3-alternate form. Addition of MeLi to the tetramethyl and tetrabutyl ether of the trioxocalix[4]arenes followed by 3-fold elimination of water yielded calixarene derivatives possessing three exocyclic double bonds at the bridges. Reaction of the dioxotetramethoxy calix[4]arene 9b with MeLi followed by 2-fold elimination of water afforded calixarene 11 with a pair of distal exocyclic double bonds at the bridges. Both the tetramethyl ether derivatives 9b and 11 exist in solution as a mixture of the 1,2-alternate and 1,3-alternate conformers, but in the crystal both adopt a 1,2-alternate conformation.


Surgical therapy for small-bowel carcinoid tumors.
Eighty-two symptomatic patients with carcinoid tumors of the small intestine were examined and treated over a 20-year period. Common clinical features included weight loss, diarrhea, and symptoms of intermittent bowel obstruction; 25 patients (30%) exhibited the carcinoid syndrome. Multiple carcinoid tumors occurred in 23 patients (28%), and hepatic metastases were present in 30 (37%). All patients underwent operation. The overall mortality was 7%, and the cumulative five-year survival rate was 59%. Two factors influenced prognosis after operation: hepatic metastases and incomplete resection. Other variables, including the sex and age of the patient and the size of the primary tumor, were of no additional prognostic value. Wide resection of the tumor, including regional lymph nodes, is indicated, regardless of the size of the primary tumor.


A monomeric histidine kinase derived from EnvZ, an Escherichia coli osmosensor.
Histidine kinases function as dimers. The kinase domain of the osmosensing histidine kinase EnvZ of Escherichia coli consists of two domains: domain A (67 residues) responsible for histidine phosphotransfer and dimerization, and domain B (161 residues) responsible for the catalytic and ATP-binding function. The individual structures of these two domains have been recently solved by NMR spectroscopy. Here, we demonstrate that an enzymatically functional monomeric histidine kinase can be constructed by fusing in tandem two domains A and one domain B to produce a single polypeptide (A-A-B). We show that this protein, EnvZc[AAB], is soluble and exists as a stable monomer. The autophosphorylation and OmpR kinase activities of the monomeric EnvZc[AAB] are similar to that of the wild-type EnvZ, while OmpR-binding and phosphatase functions are reduced. V8 protease digestion and mutational analyses indicate that His-243 of only the amino proximal domain A is phosphorylated. Based on these results, molecular models are proposed for the structures of EnvZc[AAB] and the kinase domain of EnvZ. The present results demonstrate for the first time the construction of a functional, monomeric histidine kinase, further structural studies of which may provide important insights into the structure-function relationships of histidine kinases.


Novel peptides for small-caliber graft functionalization selected by a phage display of endothelial-positive/platelet-negative combined selection.
Coronary artery disease is the leading cause of death in the world. While transplantation of autologous vessels remains a viable option, often patients may have a limited availability of suitable veins/arteries. Nowadays, despite the efforts of research made towards developing synthetic vessels, the small-diameter conduits have not fully met clinical needs. Surface modifications to mimic the vascular wall or seeding of endothelial cells within the lumen of the graft prior implantation are common approaches. However, due to the difficulties of the seeding methods, the immobilization of short recognition sequences presenting cell binding motifs remains one of the most promising strategies. In this paper, about 600 endothelial cell specific peptides have been reviewed and compared with three sequences selected by an improved phage display biopanning protocol. Indeed, the standard protocol has been ameliorated by (i) a positive selection of Endothelial Progenitor Cell (EPC)-binding phage clones, (ii) a negative selection against platelet binding phage clones, and (iii) the introduction of the phage binding index (PBI), which is a target affinity scoring function. The selected peptides were used to modify the ePTFE surface, and our results indicated that the peptide modified surfaces may be useful in solving the problems of small calibre grafts.


Effect of conjugated (EK)10 peptide on structural and dynamic properties of ubiquitin protein: a molecular dynamics simulation study.
Peptide conjugation modulates the stability and function of enzymes and therapeutic proteins. It remains unclear how the attached peptides influence the properties of the original protein. To shed light on this question, this work investigates the structural and dynamic properties of two model protein-peptide conjugates: (glutamic acid-lysine)10-N-ubiquitin and ubiquitin-C-(glutamic acid-lysine)10 using molecular dynamics simulations. The effect of the conjugated peptide on the properties of ubiquitin protein is investigated by analysing the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of Cα atoms on amino acid residues, the secondary structure of amino acid residues, solvent accessible surface area of protein regions and residue-residue distance. The simulation results show that the N-terminal and C-terminal conjugated peptides maintain the stability of the ubiquitin protein at room temperature and enhance its ability to resist the denaturing effect of high temperature. The simulations also show that the conjugated peptide can adjust the secondary structures of distant amino acid residues via the allosteric effect. This work further discusses the effect of such a change in the secondary structure of amino acid residues on the function of the ubiquitin protein. The simulations show the importance of the anchoring position and allosteric effect of the conjugated peptide on its ability to influence the stability and function of the protein.


Direct and indirect antibody-induced TX-100 resistance of cell surface antigens.
Translocation into detergent-insoluble microdomains (rafts) represents one of the earliest events in the process of cell activation, which follows the binding of surface receptor with natural ligand or mimicking antibody. In this study, the antibody-induced TX-100 resistance of surface antigens has been studied utilizing flow cytometry on TX-100 extracted cells. TX-100 resistance was evaluated by the ratio of antigen retained on the cells after detergent extraction compared with mAb-pretreated and untreated cells. All the antigens under study except CD98 demonstrated antibody-induced TX-100 resistance if the cells were treated with monoclonal antibodies and further cross-linked with secondary antibodies prior to lysis. CD20, CD5, and sIgM molecules were capable of transferring into TX-100-insoluble state in the absence of additional cross-linking. The experiments on modification of raft and cytoskeletal components of the cell, as well as the data on co-localization of TX-100-resistant antigens with raft and cytoskeletal markers strongly indicate that antibody-induced TX-100 resistance of antigens is mainly related to the translocation of antigens into lipid microdomains.


Effects of dapagliflozin on serum uric acid levels in hospitalized type 2 diabetic patients with inadequate glycemic control: a randomized controlled trial.
Raised serum uric acid (SUA) level is commonly observed in patients with type 2 diabetes mellitus (T2DM) and is associated with increased morbidity and mortality. Sodium-glucose cotransporter 2 inhibitor, a novel oral diabetic drug, might exert a potential hypouricemic effect. We evaluated the effects of dapagliflozin on SUA levels in hospitalized T2DM patients with inadequate glycemic control. In this randomized controlled trial, 59 T2DM hospitalized patients with inadequate glycemic control were assigned to the dapagliflozin 10 mg group (n=29) or the control group (n=30). The primary outcome was changes in SUA levels from the baseline to good glycemic control. Additional outcomes included correlations between baseline SUA levels, urinary parameters, and the changes in SUA levels. This trial is registered in the Chinese Clinical Trial Registry (number ChiCTR1800015830). Compared to baseline level, SUA levels had significantly decreased in both groups (P<0.001 for the dapagliflozin group and P=0.013 for the control group). Mean changes from baseline in SUA levels for dapagliflozin vs the control group were 68.03 vs 25.90 μmol/L (P=0.0406). Adjusted mean SUA levels were lower in the dapagliflozin group (273.28 vs 307.57 μmol/L; P=0.0089). In T2DM patients treated with dapagliflozin, the decrease in SUA levels was positively correlated with baseline SUA levels (P<0.0001) but not correlated with changes in 24-hour urine volume, 24-hour urine glucose, or 24-hour urinary uric acid. Dapagliflozin could improve glycemic control and lower SUA levels in hospitalized patients with uncontrolled T2DM. Longer-time trials are required to further demonstrate the hypouricemic effect of dapagliflozin and explore the potential underlying mechanisms.


Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. Liposorber Study Group.
The short-term effectiveness of low-density lipoprotein (LDL) apheresis using a dextran sulfate cellulose adsorption column technique was previously examined in a 9-center, 22-week controlled trial in 64 patients with familial hypercholesterolemia (FH) who did not adequately respond to diet and drug therapy. Forty-nine patients (40 treatment, 9 controls) subsequently received LDL apheresis procedures as part of an optional follow-up phase. This study reports on the long-term safety, lipid lowering, and clinical efficacy of LDL apheresis for the 5-year period that includes both the initial controlled study and follow-up phase. During this time, patients received a total of 3,902 treatments of which 3,314 treatments were given during the follow-up phase. Adverse events were infrequent, occurring in 142 procedures (3.6%). Immediate reduction in LDL cholesterol was 76% both in homozygotes and in heterozygotes. Patients with homozygous FH had a progressive decrease in pretreatment LDL cholesterol level along with an increase in high-density lipoprotein (HDL) cholesterol level. There was no appreciable change in pretreatment lipoprotein level over time in heterozygotes. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy. These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with heterozygous and homozygous FH who are inadequately controlled with drug therapy.


[Working conditions and morbidity of workers at the present-day shoe manufacturing factory].
Poor working factors of present-day industry (SALAMANDER technology) include high intensity of labour, monotonicity, forced posture, constant wide-range noise, fumes of organic solvents, dust of organic origin, etc. The working conditions in producing departments are considered to be of degrees of 1-3 of hazard class 3. The highest incidence rates were noted in age groups under 30 years and above 50 years and in workers with over 10-year length of service. There were prevalent acute respiratory diseases, influenza, osteomuscular and connective tissue, hypertensive and ENT diseases in the pattern of mortality with temporary disability. Comprehensive medical examinations revealed high incidence of ENT diseases due to exposure to chemical agents and organic dust.


Cardiovascular response to stress: baroreflex resetting and hemodynamics.
Borderline hypertensive rats (BHR) were used to test the hypothesis that baroreflex resetting prevents a fall in blood pressure (BP) when cardiac output (CO) is reduced during air-jet stress. Eight-week-old BHR were instrumented with flow probes around the ascending aorta for measuring CO, femoral and jugular catheters were inserted for measurement of arterial pressure and infusion of drugs, and sinoaortic baroreceptors were either denervated (SAD) or left intact. Alternating bolus injections of phenylephrine and sodium nitroprusside were given at baseline and during air-jet stress to assess the baroreflex. Air-jet stress immediately shifted the midpoint of the baroreflex curve for heart rate (HR) to a higher BP levels. When metoprolol was administered during air-jet stress, HR was reduced and CO reverted to prestress levels, but the stress-induced pressor response was not changed. In SAD BHR, air-jet stress caused an elevation of BP that was not different from intact rats. Administration of metoprolol to SAD rats during air-jet stress resulted in a further elevation rather than a reduction in BP. We conclude that the sinoaortic cardiac baroreflex is reset during air-jet stress and that it integrates reflex changes in BP during stress. The arterial baroreflex is not, however, necessary for the initiation or maintenance of the pressor response during stress, nor does it prevent a fall in BP when CO is compromised during stress.


ANAEROBIC GROWTH OF FUSARIUM OXYSPORUM.
Gunner, H. B. (Cornell University, Ithaca, N.Y.), and M. Alexander. Anaerobic growth of Fusarium oxysporum. J. Bacteriol. 87:1309-1316. 1964.-Fusarium oxysporum, an alleged obligate aerobe, was found to be capable of growth in the absence of molecular oxygen, provided the medium contained yeast extract, MnO(2), nitrate, selenite, or ferric ions. The active substance in yeast extract was not identified. The fungus possessed hydrogenase, and was capable of utilizing H(2). Under anaerobic conditions, the fungus effected the reduction of nitrate, ceric, ferric, selenite, and tellurite ions, as well as the reduction of several inorganic sulfur compounds and indicators having positive oxidation-reduction potentials. The products of anaerobic nitrate-dependent growth were ethanol, CO(2), acetic acid, and ammonia. Possible explanations for the apparent inability of obligate aerobes to grow in the absence of O(2) are discussed.


Positron emission tomography of sodium glucose cotransport activity in high grade astrocytomas.
A novel glucose transporter, the sodium glucose cotransporter 2 (SGLT2), has been demonstrated to contribute to the demand for glucose by pancreatic and prostate tumors, and its functional activity has been imaged using a SGLT specific PET imaging probe, α-methyl-4-[F-18]fluoro-4-deoxy-D-glucopyaranoside (Me-4FDG). In this study, Me-4FDG PET was extended to evaluate patients with high-grade astrocytic tumors. Me-4FDG PET scans were performed in four patients diagnosed with WHO Grade III or IV astrocytomas and control subjects, and compared with 2-deoxy-2-[F-18]fluoro-D-glucose (2-FDG) PET and magnetic resonance imaging (MRI) of the same subjects. Immunocytochemistry was carried out on Grade IV astrocytomas to determine the cellular location of SGLT proteins within the tumors. Me-4FDG retention was pronounced in astrocytomas in dramatic contrast to the lack of uptake into the normal brain, resulting in a high signal-to-noise ratio. Macroscopically, the distribution of Me-4FDG within the tumors overlapped with that of 2-FDG uptake and tumor definition using contrast-enhanced MRI images. Microscopically, the SGLT2 protein was found to be expressed in neoplastic glioblastoma cells and endothelial cells of the proliferating microvasculature. This preliminary study shows that Me-4FDG is a highly sensitive probe for visualization of high-grade astrocytomas by PET. The distribution of Me-4FDG within tumors overlapped that for 2-FDG, but the absence of background brain Me-4FDG resulted in superior imaging sensitivity. Furthermore, the presence of SGLT2 protein in astrocytoma cells and the proliferating microvasculature may offer a novel therapy using the SGLT2 inhibitors already approved by the FDA to treat type 2 diabetes mellitus.


[Working with mercury: cause of infertility in women?].
According to animal experiments, case reports and epidemiological studies, exposition to a high concentration of metallic mercury vapour may cause an increase in reproductive problems. A report on this matter is summarized here as far as it regards women. It seems warranted to conclude that negative reproductive effects are unlikely unless, due to a failing hygiene, the concentration of mercury vapour exceeds the MAC (maximum approved concentration) for women. However, the relationship between concentrations smaller than females' MAC value and problems with cycle and conception need more research.


Isoflavonoid levels in spot urine are associated with frequency of dietary soy intake in a population-based sample of middle-aged and older Chinese in Singapore.
Soy products contain high amounts of isoflavonoids, which have been shown to exhibit possible cancer-protective properties. Chinese populations in Asia, in particular, have a high level of soy intake and a relatively low risk of hormone-dependent cancers. In this study, we assessed the distributions of dietary soy isoflavonoids (daidzein, genistein, and glycitein) and urinary soy isoflavonoids and their metabolites (daidzein, genistein, glycitein, equol, and O-desmethylangolensin) among 147 Singapore Chinese (76 men and 71 women) ages 45-74 years, who are participants of the Singapore Cohort Study on diet and cancer. Urinary values were measured from spot samples collected 10-20 months following recruitment, when usual dietary habits were assessed by a structured food frequency/portion size questionnaire administered in person. Dietary levels of daidzein and genistein were comparable within individuals and about seven times higher than the level of dietary glycitein. All three dietary isoflavonoids showed an approximately 3.5-fold difference between the 25th and 75th percentile values. Similarly, daidzein was the most abundant and glycitein the least abundant of the five isoflavonoid compounds in urine. There was a 4.9-fold difference between the 25th and 75th percentile values for the sum of the five urinary isoflavonoids. Among study subjects, there were statistically significant, dose-dependent associations between frequency of overall soy intake and levels of urinary daidzein (two-sided P = 0.03) and sum of urinary daidzein, genistein, and glycitein (two-sided P = 0.04). In contrast, there were no associations between frequency of overall soy intake and levels of the two daidzein metabolites (equol and O-desmethylangolensin) in urine (two-sided P = 0.85 and 0.34, respectively). We suggest that within the range of exposures experienced by Singapore Chinese, urinary level of daidzein or the sum of daidzein, genistein, and glycitein obtained from a spot sample can serve as a biomarker of current soy consumption in epidemiological studies of diet-disease associations.


Proposed cutoff values to define bladder outlet obstruction in women.
There is no accepted urodynamic definition of outlet obstruction in women. Currently, the diagnosis is made on the basis of history and radiographic and endoscopic findings. The goal of this study is to design a pressure-flow nomogram (PdetQmax/Qmax) and define cut-off values for obstruction. Two groups were studied prospectively in an open study: 124 control and 35 clinically obstructed patients. All had a complete history, physical examination, normal neurologic evaluation, cystoscopy, voiding cystography, and urodynamics-with-pressure-flow study. Pressure-flow plot and receiver operator characteristic curves (ROCs) were constructed to determine optimal cut-off values to predict obstruction for peak flow rate (Qmax) and detrusor pressure at maximal flow (PdetQmax). The etiology of obstruction was previous anti-incontinence surgery (n = 13), large cystocele (n = 11), urethral stricture (n = 6), and other (n = 5). On the basis of ROC curves, using cut-off values of Qmax of 15 mL/s or less and 12 mL/s or less, sensitivity was 85.7% and 71.4%, and specificity 78.2% and 90.3%, respectively. Using cut-off values of PdetQmax of more than 25 and more than 30 cm H2O, sensitivity was 74.3% and 71.4%, and specificity 79.8% and 88.7%, respectively. Using a combined cut-off value of Qmax of 1 5 mL/s or less and PdetQmax of more than 20 cm H2O, sensitivity was 74.3% and specificity was 91.1%. Based on this prospective, controlled study, preliminary cut-off values were obtained for refining the definition of outlet obstruction in women.


A road map to assess critical materials content in boron industrial wastes using sustainable micro-X-ray fluorescence and total reflection X-ray fluorescence instrumentation.
Turkey is the leading country in the world in terms of boron production and sale. Increasing boron production goes along with an increasing generation of boron wastes. The pollution of the soil and the air around the waste piles, as well as the occupation of several square kilometers of ground, are major environmental problems. It is, therefore, very important to make use of the wastes to both protect the environment and create revenue. This work presenteda road map for fast screening of boron waste for critical elements followed by determination of the elements using small footprint low power instrumentation. The sample preparation was kept to a minimum. A procedure that allowed an assessment of critical materials in industrial production waste with minimal consumption of hazardous acids, energy, and time was presented. The samples were first screened for valuable and hazardous elements by micro-X-ray fluorescence (XRF). Samples with considerable contents of Cs, Rb, and Aswere then prepared as slurries for the total reflection XRF (TXRF) measurement. To evaluate the TXRF procedure, a standard reference material was analyzed. As a result, Rb and Cs in concentrations up to 420 ± 70 and 1500 ± 200 mg/kg were detected in some of the waste forms. The time savings were in order of a factor of 3 when comparing the prescreening combined micro-XRF and TXRF approach to an all TXRFanalysis approach.


Uric acid and evolution.
Uric acid (UA) is the end product of purine metabolism in humans due to the loss of uricase activity by various mutations of its gene during the Miocene epoch, which led to humans having higher UA levels than other mammals. Furthermore, 90% of UA filtered by the kidneys is reabsorbed, instead of being excreted. These facts suggest that evolution and physiology have not treated UA as a harmful waste product, but as something beneficial that has to be kept. This has led various researchers to think about the possible evolutionary advantages of the loss of uricase and the subsequent increase in UA levels. It has been argued that due to the powerful antioxidant activity of UA, the evolutionary benefit could be the increased life expectancy of hominids. For other authors, the loss of uricase and the increase in UA could be a mechanism to maintain blood pressure in times of very low salt ingestion. The oldest hypothesis associates the increase in UA with higher intelligence in humans. Finally, UA has protective effects against several neurodegenerative diseases, suggesting it could have interesting actions on neuronal development and function. These hypotheses are discussed from an evolutionary perspective and their clinical significance. UA has some obvious harmful effects, and some, not so well-known, beneficial effects as an antioxidant and neuroprotector.


Pneumoconiosis in Georgia kaolin workers.
Middle Georgia kaolin workers (n = 459) were surveyed for the presence of pneumoconiosis by chest radiograph and for respiratory symptoms by questionnaire. Pulmonary function was measured in all workers by spirometry. The overall prevalence of pneumoconiosis in this population was 9.2%. Multivariate analysis demonstrated that the only significant correlates with the radiographic presence of pneumoconiosis were ages greater than 55 yr and greater than 15 yr work exposure in the job category associated with greatest dust exposure. There was no correlation between the radiographic presence of pneumoconiosis and respiratory symptoms, cigarette smoking, or history of tuberculosis. Except in cases of complicated pneumoconiosis (large opacities), spirograms of workers with radiographic evidence of pneumoconiosis were not significantly different from spirograms of workers with normal radiographs. Clinical impairment of pulmonary function does not occur except in advanced cases, and appears to be mild even in these.


Yessotoxins, a group of marine polyether toxins: an overview.
Yessotoxin (YTX) is a marine polyether toxin that was first isolated in 1986 from the scallop Patinopecten yessoensis. Subsequently, it was reported that YTX is produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. YTXs have been associated with diarrhetic shellfish poisoning (DSP) because they are often simultaneously extracted with DSP toxins, and give positive results when tested in the conventional mouse bioassay for DSP toxins. However, recent evidence suggests that YTXs should be excluded from the DSP toxins group, because unlike okadaic acid (OA) and dinophyisistoxin-1 (DTX-1), YTXs do not cause either diarrhea or inhibition of protein phosphatases. In spite of the increasing number of molecular studies focused on the toxicity of YTX, the precise mechanism of action is currently unknown. Since the discovery of YTX, almost forty new analogues isolated from both mussels and dinoflagellates have been characterized by NMR or LC-MS/MS techniques. These studies indicate a wide variability in the profile and the relative abundance of YTXs in both, bivalves and dinoflagellates. This review covers current knowledge on the origin, producer organisms and vectors, chemical structures, metabolism, biosynthetic origin, toxicological properties, potential risks to human health and advances in detection methods of YTXs.


Incidence of clinically manifest ulcers and their complications in patients with rheumatoid arthritis.
Non-steroidal anti-inflammatory drugs (NSAIDs) are often prescribed in patients with rheumatoid arthritis (RA). Because of its frequency and severity, NSAID gastropathy is the most important side effect. The clinical spectrum of NSAID gastropathy includes gastrointestinal complaints, ulcers and their complications. To reduce NSAID gastropathy, rheumatologists in greater Amsterdam decided in January 1997 that prophylactic agents should be prescribed for patients with RA at high risk for NSAID gastropathy, defined as age 60 or older or a history of gastrointestinal (GI) ulcers, or both. To determine the incidence of clinically manifest ulcers and their complications in patients with RA at high risk for NSAID gastropathy during a period in which prophylaxis was recommended. Published reports show that the incidence of clinically manifest ulcers and their complications varies from 1.3% to 5%. Within one year, three questionnaires were sent to all outpatients with RA of our clinic (n=2680). The patients were asked if they had had a gastroscopy and/or complication of an ulcer in the preceding months. When a GI event (ulcer or complication) had occurred an analysis was carried out to determine whether the event was possibly related to a compliance failure or a policy failure-for example, no prophylaxis prescribed when it was recommended. The response rate for the three questionnaires was 88%, 76%, and 77%, respectively. All three questionnaires were returned by 1856 patients; NSAIDs were used in 1246 (67%) of them. Of the NSAID users 731 (59%) were in the high risk group. Clinically manifest ulcers occurred in seven high risk NSAID users (four gastric ulcers, two duodenal ulcers, and in one patient both types of ulcer). Complications of ulcers were diagnosed in eight (other) patients: seven (upper) GI bleedings and one perforation. Thus the incidence during one year of clinically manifest ulcers in the high risk group was 1.0% and of complications of ulcers 1.1%, together 2.1%. In the group of 15 patients with GI events, only one patient had not taken the adequately prescribed gastroprotective drugs (compliance failure). Misguidedly, gastroprotective drugs were not prescribed in seven patients (policy failure), but in the remaining seven patients gastroprotective drugs were adequately prescribed and used. The incidence of clinically manifest ulcers and of complications of ulcers in patients with RA at high risk for NSAID gastropathy is relatively low, and might be related to our strategy to prescribe prophylactic agents in these patients.


Modeling multiple risks during infancy to predict quality of the caregiving environment: contributions of a person-centered approach.
The primary goal of this study was to compare several variable-centered and person-centered methods for modeling multiple risk factors during infancy to predict the quality of caregiving environments at six months of age. Nine risk factors related to family demographics and maternal psychosocial risk, assessed when children were two months old, were explored in the understudied population of children born in low-income, non-urban communities in Pennsylvania and North Carolina (N = 1047). These risk factors were (1) single (unpartnered) parent status, (2) marital status, (3) mother's age at first child birth, (4) maternal education, (5) maternal reading ability, (6) poverty status, (7) residential crowding, (8) prenatal smoking exposure, and (9) maternal depression. We compared conclusions drawn using a bivariate approach, multiple regression analysis, the cumulative risk index, and latent class analysis (LCA). The risk classes derived using LCA provided a more intuitive summary of how multiple risks were organized within individuals as compared to the other methods. The five risk classes were: married low-risk; married low-income; cohabiting multiproblem; single low-income; and single low-income/education. The LCA findings illustrated how the association between particular family configurations and the infants' caregiving environment quality varied across race and site. Discussion focuses on the value of person-centered models of analysis to understand complexities of prediction of multiple risk factors.