Association between Hospital Volume and Within-Hospital Intensive Care Unit Transfer for Sickle Cell Disease in Children's Hospitals.
To assess the relationship between hospital volume and intensive care unit (ICU) transfer among hospitalized children with sickle cell disease (SCD). We conducted a retrospective cohort study of 83,477 SCD-related hospitalizations at children's hospitals (2009-2012) using the Pediatric Health Information System database. Hospital-level all-cause and SCD-specific volumes were dichotomized (low vs high). Outcomes were within-hospital ICU transfer (primary) and length of stay (LOS) total (secondary). Multivariable logistic/linear regressions assessed the association of hospital volumes with ICU transfer and LOS. Of 83,477 eligible hospitalizations, 1741 (2.1%) involving 1432 unique children were complicated by ICU transfer. High SCD-specific volume (OR 0.77, 95% CI 0.64-0.91) was associated with lower odds of ICU transfer while high all-cause hospital volume was not (OR 0.87, 95% CI 0.73-1.04). A statistically significant interaction was found between all-cause and SCD-specific volumes. When results were stratified according to all-cause volume, high SCD-specific volume was associated with lower odds of ICU transfer at low all-cause volume (OR 0.46, 95% CI 0.38-0.55). High hospital volumes, both all-cause (OR 0.94, 95% CI 0.92-0.97) and SCD-specific (OR 0.86, 95% CI 0.84-0.88), were associated with shorter LOS. Children's hospitals vary substantially in their transfer of children with SCD to the ICU according to hospital volumes. Understanding the practices used by different institutions may help explain the variability in ICU transfer among hospitals caring for children with SCD.


Physician Perspectives In Year 1 Of MACRA And Its Merit-Based Payment System: A National Survey.
We surveyed a national sample of internal medicine physicians in March-May 2017 to explore their beliefs about the newly implemented Merit-based Incentive Payment System (MIPS). Respondents believed that their efforts in the four focus areas identified in the survey would ultimately improve the value of care. When informed that those areas represented the four MIPS domains, the majority remained positive about the likely impact on value. However, expectations varied by physicians' characteristics and sense of control over the desired outcomes, and many respondents believed that unintended consequences could occur. Moreover, respondents generally reported low familiarity with the policy and disagreed with program guidelines for weighting domains in the composite score. These findings indicate the need to educate physicians about MIPS and suggest potentially fruitful approaches. Moving forward, policy makers should monitor for unintended consequences and explore ways to better align program guidelines with physicians' perspectives.


Improved bi-allelic modification of a transcriptionally silent locus in patient-derived iPSC by Cas9 nickase.
Homology directed repair (HDR)-based genome editing via selectable long flanking arm donors can be hampered by local transgene silencing at transcriptionally silent loci. Here, we report efficient bi-allelic modification of a silent locus in patient-derived hiPSC by using Cas9 nickase and a silencing-resistant donor construct that contains an excisable selection/counter-selection cassette. To identify the most active single guide RNA (sgRNA)/nickase combinations, we employed a lentiviral vector-based reporter assay to determine the HDR efficiencies in cella. Next, we used the most efficient pair of sgRNAs for targeted integration of an improved, silencing-resistant plasmid donor harboring a piggyBac-flanked puroΔtk cassette. Moreover, we took advantage of a dual-fluorescence selection strategy for bi-allelic targeting and achieved 100% counter-selection efficiency after bi-allelic excision of the selection/counter-selection cassette. Together, we present an improved system for efficient bi-allelic modification of transcriptionally silent loci in human pluripotent stem cells.


Automatic irrigation system with a fiber-optic pressure sensor regulating intrapelvic pressure for flexible ureteroscopy.
Increased intrapelvic pressure (IPP) due to irrigation during flexible ureteroscopy (f-URS) can pose a risk of postoperative severe urinary tract infection associated with pyelovenous backflow. An automatic regulation system for maintaining safe IPP levels could enable surgeons to perform f-URS safely without postoperative complications. This study aimed to assess the measurement accuracy of an ultra-miniature fiber-optic pressure sensor incorporated into a small-caliper ureteroscope for assessing IPP and to develop an automatic irrigation system linked to this sensor. A porcine kidney was used for the ex vivo experiment. The nephrostomy catheter, connected to the conventional pressure transducer, was placed on the renal pelvis to evaluate the actual IPP (a-IPP). For measuring IPP using the fiber-optic pressure sensor (fo-IPP) built into the f-URS, a diaphragm pressure sensor of Φ250 μm was used. To establish an irrigation system, the optimal proportional-integral-derivative (PID) controller was explored to accurately adjust the irrigation pump flow rate. A high correlation between a-IPP and fo-IPP was confirmed across irrigation pressure values of 60-180 mbar (all, r ≥ 0.7, p < 0.001). When performing bolus irrigation, although fo-IPP showed relatively a higher peak value than a-IPP, the response time of fo-IPP was equivalent to that of a-IPP. After PID parameter optimization, our automatic irrigation system based on fo-IPP smoothly and accurately regulated the intended IPP set in the 5-20 mmHg range without overshooting. We successfully developed and demonstrated an automatic irrigation system regulating IPP based on the PID controller for f-URS, utilizing a fiber-optic pressure sensor. Further research, including in vivo studies, will be needed to assess clinical feasibility.


[Effects of long term mental arithmetic on physiological parameters, subjective indices and task performances].
This study examined the effects of long term mental arithmetic on physiological parameters, subjective indices and task performances to investigate the psychophysiological changes induced by mental tasks. Fifteen male university students performed six successive trials of a ten-minute mental arithmetic task. They took a five-minute resting period before and after the tasks. CFF (Critical Flicker Fusion frequency) and subjective fatigue scores using a visual analog scale, POMS (Profiles of Mood States) and SFF (Subjective Feelings of Fatigue) were obtained after each task and resting period. The voices of participants who were instructed to speak five Japanese vowels ('a', 'i', 'u', 'e', 'o') were recorded after each block to investigate a chaotic property of vocal signals that is reported to be changed by fatigue. Subjective workload ratings were also obtained by the NASA-TLX (National Aeronautics and Space Administration-Task Load Index) after the task. Physiological signals of ECG (Electrocardiogram), PTG (Photoelectric Plethysmogram), SCL (Skin Conductance Level), TBV (Tissue Blood Volume) and Respiration were recorded for all experimental blocks. The number of answers, correct rates and average levels of task difficulty for each ten-minute task were used as task performance indices. In this experiment, the task performance did not decrease, whereas subjective fatigue increased. Activation of the sympathetic nervous system was suggested by physiological parameters.


Prevalence and determinants of troponin T elevation in the general population.
The prevalence and determinants of cardiac troponin T (cTnT) elevation in the general population are unknown, and the significance of minimally increased cTnT remains controversial. Our objective was to determine the prevalence and determinants of cTnT elevation in a large, representative sample of the general population. cTnT was measured from stored plasma samples in 3557 subjects of the Dallas Heart Study, a population-based sample. cTnT elevation (> or =0.01 microg/L) was correlated with clinical variables and cardiac MRI findings. The sample weight-adjusted prevalence of cTnT elevation in the general population was 0.7%. In univariable analyses, cTnT elevation was associated with older age, black race, male sex, coronary artery calcium by electron beam CT, a composite marker of congestive heart failure (CHF), left ventricular hypertrophy (LVH), diabetes mellitus (DM), and chronic kidney disease (CKD) (P<0.001 for each). Subjects with minimally increased (0.01 to 0.029 microg/L) and increased (> or =0.03 microg/L) cTnT had a similar prevalence of these characteristics. In multivariable logistic regression analysis, LVH, CHF, DM, and CKD were independently associated with cTnT elevation. In the general population, cTnT elevation is rare in subjects without CHF, LVH, CKD, or DM, suggesting that the upper limit of normal for the immunoassay should be <0.01 microg/L. Even minimally increased cTnT may represent subclinical cardiac injury and have important clinical implications, a hypothesis that should be tested in longitudinal outcome studies.


S-100 protein in white preadipocytes: an immunoelectronmicroscopic study.
Differentiation of adipocytes from their precursor cells (preadipocytes) is an important problem in the study of the pathogenesis of obesity. Unfortunately, among the immature stages of adipocytes, only relatively differentiated forms can be identified by their fine structure; because early preadipocytes cannot be distinguished from fibroblasts solely on the basis of their morphology, it is impossible to assess the size of the preadipocyte population. S-100 protein has been identified in various mammalian tissues and recently mature adipocytes have been shown to be positive for this protein. Because fibroblasts are negative for S-100 protein, the present study tested the S-100 immunoreactivity of preadipocytes by the peroxidase-antiperoxidase (PAP) preembedding method at the ultrastructural level both in vivo and in culture. Mature adipocytes and early preadipocytes, including fibroblast-like cells devoid of lipid droplets, were positive both in vivo and in culture. Endothelial cells and pericytes were negative; but flattened, lipid-free, fibroblast-like cells surrounding the pericytes were positive. True fibroblasts both in vivo and in culture were negative. Therefore, S-100 protein can be a useful biochemical marker in distinguishing fibroblasts from early preadipocytes.


Characterization of alternatively spliced transcript variants of CLEC2D gene.
Lectin-like transcript 1 (LLT1) encoded by CLEC2D gene is a C-type lectin-like molecule interacting with human CD161 (NKR-P1A) receptor expressed by natural killer cells and subsets of T cells. Using RT-PCR and sequencing, we identified several CLEC2D alternatively spliced transcript variants generated by exon skipping. In addition to the reported transcript variants 1 (LLT1) and 2, we identified a novel splice variant 4 and transcripts coding for putative soluble proteins. CLEC2D transcripts were detected primarily in hematopoietic cell lines and were found to be co-induced by the same activation signals. Although very low amounts of putative soluble CLEC2D protein isoforms could be produced by transfectants, CLEC2D isoforms 2 and 4 were efficiently expressed. By contrast to LLT1, which was detected on the cell surface, isoform 2 and 4 remained in the endoplasmic reticulum where they formed homodimers or heterodimers with LLT1. They failed to interact with CD161, leaving LLT1 as the sole ligand for this receptor. CLEC2D therefore uses gene splicing to generate protein isoforms that are structurally distinct and that have different biological activities.


Programmable Laser-Assisted Surface Microfabrication on a Poly(Vinyl Alcohol)-Coated Glass Chip with Self-Changing Cell Adhesivity for Heterotypic Cell Patterning.
Organs are composed of heterotypic cells with patterned architecture that enables intercellular interaction to perform specific functions. In tissue engineering, the ability to pattern heterotypic cells into desired arrangement will allow us to model complex tissues in vitro and to create tissue equivalents for regeneration. This study was aimed at developing a method for fast heterotypic cell patterning with controllable topological manipulation on a glass chip. We found that poly(vinyl alcohol)-coated glass showed a biphasic change in adhesivity to cells in vitro: low adhesivity in the first 24 h and higher adhesivity at later hours due to increased serum protein adsorption. Combining programmable CO2 laser ablation to remove poly(vinyl alcohol) and glass, we were able to create arrays of adhesive microwells of adjustable patterns. We tested whether controllable patterns of epithelial-mesenchymal interaction could be created. When skin dermal papilla cells and fibroblasts were seeded respectively 24 h apart, we were able to pattern these two cells into aggregates of dermal papilla cells in arrays of microwells in a background of fibroblasts sheet. Seeded later, keratinocytes attached to these mesenchymal cells. Keratinocytes contacting dermal papilla cells started to differentiate toward a hair follicle fate, demonstrating patternable epithelial-mesenchymal interaction. This method allows fast adjustable heterotypic cell patterning and surface topology control and can be applied to the investigation of heterotypic cellular interaction and creation of tissue equivalent in vitro.


Self-assembly of the first discrete 3d-4f-4f triple-stranded helicate.
The connection of an additional bidentate chelating unit at the extremity of a segmental bis-tridentate ligand in L5 provides an unprecedented sequence of binding sites for the self-assembly of heterometallic 3d-4f triple-stranded helicates. Thorough thermodynamic and structural investigations in acetonitrile show the formation of intricate mixtures of complexes when a single type of metal (3d or 4f) is reacted with L5. However, the situation is greatly simplified when Zn(II) (3d-block) and Lu(III) (4f-block) are simultaneously coordinated to L5, thus leading to only two identified species: the target C(3)-symmetrical trinuclear triple-stranded d-f-f helicate HHH-[ZnLu(2)(L5)(3)](8+) and a tetranuclear double-stranded complex [Zn(2)Lu(2)(L5)(2)](10+). Interestingly, the removal of Zn(II) from the former triple-helical complex has only a minor effect on the coordination of Lu(III), and translational autodiffusion coefficients show a simple reduction of the length of the molecular rigid cylinder from L = 2.7 nm in HHH-[ZnLu(2)(L5)(3)](8+) to L = 2.3 nm in HHH-[Lu(2)(L5)(3)](6+). Finally, the complete thermodynamic picture provides five novel stability macroconstants containing information about short-range (ca. 9 A) and long-range (ca. 18 A) intramolecular intermetallic d-f and f-f interactions.


Pharmacodynamic studies with a specific alpha 2-adrenoceptor agonist (BHT-933) in man.
We conducted pharmacodynamic studies in man with a specific alpha 2-adrenoceptor agonist BHT-933. The study involved nine male normotensive volunteers each of whom received BHT-933 5 mg or placebo in random order. BHT-933 significantly lowered systolic and diastolic blood pressure (BP) in supine and standing positions, the greatest effect occurring 3-4 h following drug administration. Supine values: placebo 116/73; BHT-933 99/64. Standing values: placebo 114/79; BHT-933 92/67. Heart rate was uninfluenced by BHT-933 even at the time of maximum fall in BP. Plasma noradrenaline concentration in the supine position was significantly reduced: placebo 2.5 +/- 0.8 nmol/L; BHT-933 1.7 +/- 0.6. The haemodynamic changes accompanying Valsalva's manoeuvre and cold pressor test were uninfluenced by BHT-933. All subjects experienced sedation and dry mouth following BHT-933 with a time course similar to that of the fall in BP. These results are consistent with an effect of BHT-933 on BP control through an action on alpha 2-receptors at the level of the brainstem.


Tooth brushing pattern classification using three-axis accelerometer and magnetic sensor for smart toothbrush.
The concept of intelligent toothbrush, capable of monitoring brushing motion, orientation through the grip axis, during toothbrushing was suggested in our previous study. In this study, we describe a tooth brushing pattern classification algorithm using three-axis accelerometer and three-axis magnetic sensor. We have found that inappropriate tooth brushing pattern showed specific moving patterns. In order to trace the position and orientation of toothbrush in a mouth, we need to know absolute coordinate information of toothbrush. By applying tilt-compensated azimuth (heading) calculation algorithm, which is generally used in small telematics devices, we could find the inclination and orientation information of toothbrush. To assess the feasibility of the proposed algorithm, 8 brushing patterns were preformed by 6 individual healthy subjects. The proposed algorithm showed the detection ratio of 98%. This study showed that the proposed monitoring system was conceived to aid dental care personnel in patient education and instruction in oral hygiene regarding brushing style.


Influence of Smoking Puff Parameters and Tobacco Varieties on Free Radicals Yields in Cigarette Mainstream Smoke.
Cigarette smoke is a major exogenous source of free radicals, and the resulting oxidative stress is one of the major causes of smoking-caused diseases. Yet, many of the factors that impact free radical delivery from cigarettes remain unclear. In this study, we machine-smoked cigarettes and measured the levels of gas- and particulate-phase radicals by electron paramagnetic resonance (EPR) spectroscopy using standardized smoking regimens (International Organization of Standardization (ISO) and Canadian Intense (CI)), puffing parameters, and tobacco blends. Radical delivery per cigarette was significantly greater in both gas (4-fold) and particulate (6-fold) phases when cigarettes were smoked under the CI protocol compared to the ISO protocol. Total puff volume per cigarette was the major factor with radical production being proportional to total volume, regardless of whether volume differences were achieved by changes in individual puff volume or puff frequency. Changing puff shape (bell vs sharp vs square) or puff duration (1-5 s), without changing volume, had no effect on radical yields. Tobacco variety did have a significant impact on free radical production, with gas-phase radicals highest in reconstituted > burley > oriental > bright tobacco and particulate-phase radicals highest in burley > bright > oriental > reconstituted tobacco. Our findings show that modifiable cigarette design features and measurable user smoking behaviors are key factors determining free radical exposure in smokers.


Iron supplementation improves appetite and growth in anemic Kenyan primary school children.
A randomized, double-blind, placebo-controlled iron supplementation trial was conducted in Kenya to examine the effect of iron supplements on appetite and growth in 87 primary school children. Sustained-release ferrous sulfate (150 mg) or placebo tablets were provided daily at school for 14 wk. Prior to tablet administration, baseline anthropometry, iron nutritional status (hemoglobin and serum ferritin), parasitic infections and clinical indicators of morbidity were measured. A baseline appetite test was conducted twice on each child by quantitatively measuring the ad libitum consumption of a midmorning snack. In addition, each child was asked for a subjective assessment of his or her appetite. Follow-up exams and appetite tests were identical to those at baseline. Findings indicated that provision of iron supplements resulted in improved growth and improved appetite (in terms of both energy intake of the snack and child report of appetite) as compared with children receiving the placebo. The increased energy intake from the snack was 10% of the daily estimated energy intake for children of this same age group living elsewhere in Kenya. Further research into the underlying physiological mechanisms may shed light on the relationship between iron nutritional status and appetite.


[The role of psychiatry in the Brazilian psychiatric reform].
Psychiatry emerged just over two hundred years ago as a special branch of medicine offering institutional care for the insane, since it encompassed the fields of medicine, natural history (biology) and philosophy (humanities). It appeared at a time marked by the transition with the exclusion apparatus of the marginalized people of the Old Regime and by epistemic pluralism. In this article, the contribution that psychiatry can make today - just over two centuries and some important conceptual and institutional rearrangements later - is discussed. It is well established in the academic world and socially legitimized, albeit at another moment of transition, in which new paradigms of care are established placing importance on the contextual and intersubjective situation of psychic distress. Redefining Pinelian intuition using contemporary vocabulary regarding the epistemological and ethical challenge of an area of knowledge and practice of care the scope of which is psychic distress, the thesis will be proposed that it is also necessary to articulate the planes of body, experience and narrative in an ongoing dialogue.


Should diabetes be considered a coronary heart disease risk equivalent?: results from 25 years of follow-up in the Renfrew and Paisley survey.
The purpose of our study was to confirm or refute the view that diabetes be regarded as a coronary heart disease (CHD) risk equivalent and to test for sex differences in mortality. This was a prospective cohort study of 7,052 men and 8,354 women aged 45-64 years from Renfrew and Paisley, Scotland, who were first screened in 1972-1976 and followed for 25 years. All-cause mortality was calculated as death per 1,000 person-years. A Cox proportional hazards model was used to adjust survival for age, smoking habit, blood pressure, serum cholesterol, BMI, and social class. There were 192 deaths in 228 subjects with diabetes and 2,016 deaths in 3,076 subjects with CHD. The highest mortality was in the group with both diabetes and CHD (100.2 deaths/1,000 person-years in men, 93.6 in women) and the lowest in the group with neither (29.2 deaths/1,000 person-years in men, 19.4 in women). Men and women with diabetes only and CHD only formed an intermediate risk group. The adjusted hazard ratio (HR) for CHD mortality in men with diabetes only compared with men with CHD only was 1.17 (95% CI 0.78-1.74; P = 0.56). Corresponding HR for women was 1.97 (1.27-3.08; P = 0.003). Diabetes without previous CHD carries a lifetime risk of vascular death as high as that for CHD alone. Women may be at particular risk. Our data support the view that cardiovascular risk factors in diabetes should be treated as aggressively as in people with CHD.


Beyond Saccharomyces pastorianus for modern lager brews: Exploring non-cerevisiae Saccharomyces hybrids with heterotic maltotriose consumption and novel aroma profile.
Non-domesticated, wild Saccharomyces yeasts have promising characteristics for beer diversification, particularly when used in the generation of de novo interspecific hybrids. A major motivation for the current work was the question whether attractive novel Saccharomyces interspecific hybrids can be created for the production of exotic lager beers without using the genomic resources of the ale yeast Saccharomyces cerevisiae. Importantly, maltotriose utilization is an essential characteristic typically associated with domesticated ale/lager brewing strains. A high-throughput screening on nearly 200 strains representing all eight species of the Saccharomyces genus was conducted. Three Saccharomyces mikatae strains were able to aerobically grow on maltotriose as the sole carbon source, a trait until recently unidentified for this species. Our screening also confirmed the recently reported maltotriose utilization of the S. jurei strain D5095T. Remarkably, de novo hybrids between a maltotriose-utilizing S. mikatae or S. jurei strain and the maltotriose-negative Saccharomyces eubayanus strain CBS 12357T displayed heterosis and outperformed both parents with regard to aerobically utilizing maltotriose as the sole source of carbon. Indeed, the maximum specific growth rates on this sugar were comparable to the well-known industrial strain, Saccharomyces pastorianus CBS 1513. In lager brewing settings (oxygen-limited), the new hybrids were able to ferment maltose, while maltotriose was not metabolized. Favorable fruity esters were produced, demonstrating that the novel hybrids have the potential to add to the diversity of lager brewing.


Crystal structure of arginase from Plasmodium falciparum and implications for L-arginine depletion in malarial infection .
The 2.15 A resolution crystal structure of arginase from Plasmodium falciparum, the parasite that causes cerebral malaria, is reported in complex with the boronic acid inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) (K(d) = 11 microM). This is the first crystal structure of a parasitic arginase. Various protein constructs were explored to identify an optimally active enzyme form for inhibition and structural studies and to probe the structure and function of two polypeptide insertions unique to malarial arginase: a 74-residue low-complexity region contained in loop L2 and an 11-residue segment contained in loop L8. Structural studies indicate that the low-complexity region is largely disordered and is oriented away from the trimer interface; its deletion does not significantly compromise enzyme activity. The loop L8 insertion is located at the trimer interface and makes several intra- and intermolecular interactions important for enzyme function. In addition, we also demonstrate that arg- Plasmodium berghei sporozoites show significantly decreased liver infectivity in vivo. Therefore, inhibition of malarial arginase may serve as a possible candidate for antimalarial therapy against liver-stage infection, and ABH may serve as a lead for the development of inhibitors.


Lipoprotein(a). A potential bridge between the fields of atherosclerosis and thrombosis.
Lipoprotein(a) (Lp[a]) represents a class of plasma lipoprotein particles that have overall characteristics similar to low-density lipoproteins but distinct from them by having apolipoprotein B100 linked to apolipoprotein(a) by disulfide bridge(s). This protein has recently been shown to have a striking amino acid sequence homology with plasminogen, a serine protease zymogen that on activation to plasmin promotes the conversion of fibrinogen to fibrin. The high incidence of Lp(a) in the plasma of patients with cardiovascular disease has been noted by many investigators. The new knowledge being rapidly acquired on the structure of Lp(a) should facilitate the understanding of the mechanism of its atherogenicity and perhaps shed light on its possible physiologic role.


Peptides mimicking the unique ARTS-XIAP binding site promote apoptotic cell death in cultured cancer cells.
XIAP [X-linked inhibitor of apoptosis (IAP) protein] is the best characterized mammalian caspase inhibitor. XIAP is frequently overexpressed in a variety of human tumors, and genetic inactivation of XIAP in mice protects against lymphoma. Therefore, XIAP is an attractive target for anticancer therapy. IAP antagonists based on a conserved IAP-binding motif (IBM), often referred to as "Smac-mimetics," are currently being evaluated for cancer therapy in the clinic. ARTS (Sept4_i2) is a mitochondrial proapoptotic protein which promotes apoptosis by directly binding and inhibiting XIAP via a mechanism that is distinct from all other known IAP antagonists. Here, we investigated the ability of peptides derived from ARTS to antagonize XIAP and promote apoptosis in cancer cell lines. The ability of synthetic peptides, derived from the C-terminus of ARTS, to bind to XIAP, stimulate XIAP degradation, and induce apoptosis was examined. We compared the response of several cancer cell lines to different ARTS-derived peptides. Pull-down assays were used to examine binding to XIAP, and apoptosis was evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, caspase activation, and Western blot analyses of caspase substrates. The C-terminus of ARTS contains a unique sequence, termed ARTS-IBM (AIBM), which is important for binding to XIAP and cell killing. AIBM peptides can bind to XIAP-BIR3, penetrate cancer cells, reduce XIAP levels, and promote apoptosis. Short synthetic peptides derived from the C-terminus of ARTS are sufficient for binding to XIAP and can induce apoptosis in cancer cells. These results provide proof-of-concept for the feasibility of developing ARTS-based anticancer therapeutics.


Experimental radar data for monitoring brain atrophy progression.
This data set contains complex frequency domain signals obtained from unidirectional antennas mainly fabricated for radar-based head imaging. Data were obtained as part of a project investigating radar-based microwave imaging for monitoring neurodegenerative diseases, especially Alzheimer's disease. The wearable device, measurement setup, and phantoms used are described. Multiple experiments were performed to get the data from three lamb brain phantoms that realistically mimic the whole-brain atrophy due to Alzheimer's disease. Microwave imaging has shown great potential for breast and brain screening due to its low cost, non-ionizing, portable, and wearable nature. Most of the studies are based on simulations with good results, but further evaluation on experimental data is required before its clinical viability. This work provides an open-source experimental dataset that can be used to evaluate novel signal processing and imaging techniques and validate simulation results. The data provide both the magnitude and phase value at each discrete frequency, making this data set useful for both time-delay and phase-shift based imaging algorithms.


Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer.
This study compared the efficacy and safety of patupilone with those of pegylated liposomal doxorubicin (PLD) in patients with platinum-refractory or -resistant epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. Patients with three or fewer prior regimens were eligible if they had received first-line taxane/platinum-based combination chemotherapy and were platinum refractory or resistant. Patients were randomly assigned to receive patupilone (10 mg/m(2) intravenously every 3 weeks) or PLD (50 mg/m(2) intravenously every 4 weeks). A total of 829 patients were randomly assigned (patupilone, n = 412; PLD, n = 417). There was no statistically significant difference in overall survival (OS), the primary end point, between the patupilone and PLD arms (P = .195; hazard ratio, 0.93; 95% CI, 0.79 to 1.09), with median OS rates of 13.2 and 12.7 months, respectively. Median progression-free survival was 3.7 months for both arms. The overall response rate (all partial responses) was higher in the patupilone arm than in the PLD arm (15.5% v 7.9%; odds ratio, 2.11; 95% CI, 1.36 to 3.29), although disease control rates were similar (59.5% v 56.3%, respectively). Frequently observed adverse events (AEs) of any grade included diarrhea (85.3%) and peripheral neuropathy (39.3%) in the patupilone arm and mucositis/stomatitis (43%) and hand-foot syndrome (41.8%) in the PLD arm. Patupilone did not demonstrate significant improvement in OS compared with the active control, PLD. No new or unexpected serious AEs were identified.


Chicken sterol carrier protein 2/sterol carrier protein x: cDNA cloning reveals evolutionary conservation of structure and regulated expression.
The chicken is a useful model for studies of lipid biochemistry because of the profound changes in lipid metabolism during development and the marked effects of estrogen on its lipids. Here we report the cloning of a cDNA encoding chicken sterol carrier protein 2 (SCP2)/sterol carrier protein x (SCPx), proteins that are believed to play key roles in intracellular lipid movement and metabolism. The 2.4-kb clone, isolated from a liver cDNA library by homology screening with a rat SCP2 cDNA, encodes a 58-kDa polypeptide, SCPx, which encompasses the sequence for SCP2 at its C-terminus. Comparison of the deduced amino acid sequence of the chicken protein with those of mammals revealed conservation of structure from an evolutionary standpoint. Like the other vertebrate SCPx proteins, the chicken protein contains a conserved Arg-Gly-Asp sequence and a cysteine residue in the N-terminus that aligns with the active site cysteine of Escherichia coli 3-ketoacyl-CoA thiolase, a protein that was previously shown to be homologous to vertebrate SCPx. Northern blot analysis of poly(A)+ RNA from different chicken tissues revealed two mRNA species, one of 2.5 kb, encoding SCPx, and one of 1.4 kb, presumably encoding SCP2. High levels of the 2.5 and 1.4-kb mRNAs were found in liver, intestine, and ovarian granulosa cells, consistent with a role for these proteins in lipid metabolism. There was no change in the 2.5-kb mRNA in chicken liver with development (Day 20 embryo to 4 weeks posthatch), but there was a 10-fold increase in the 1.4-kb mRNA by 1 week posthatch. Treatment of roosters with a single injection of estradiol (25 mg/kg) caused a twofold increase in the 2.5-kb mRNA in liver at 6 h after estradiol administration, reaching a maximum fourfold increase at 48 h, while the 1.4-kb mRNA increased twofold at 48 h. The two SCP2/SCPx mRNAs were most abundant in granulosa cells from small follicles. A reduction in SCP2/SCPx gene expression was observed with follicular maturation, correlating with falling estrogen production. In summary, we have documented (i) marked conservation of SCP2/SCPx structure across species and (ii) developmental and hormonal regulation of the mRNAs which encode proteins thought to be involved in lipid metabolism.


Cues to action in the process of changing lifestyle.
This research has been carried out in order to evaluate cues to action in health behavior. Which cues produce changes and how does the process of change proceed? In-depth qualitative interviews based on the Grounded Theory Method were made with 21 40-year-old men. Ten men were interviewed three times during a 1-year period to trace the process of change. In total 40 interviews were carried out during 1989-1990. All the interviewees were randomly selected from the population registers in the municipalities of Aarhus and Vejle. The main themes of the interviews are changes in previous health behavior, motivation for intentions to change in health behavior, and the role of health education in the process of change. Health behavior determinants seem to be knowledge, attitude, confidence, social influence, experiences and possibilities for change. Individuals typically exhibit a wide range of these determinants which makes it difficult to affect behavioral change through health education. Cues to action seem to arise from social influence, experiences, or underlying shifts in the possibilities of change. Experiences and social influence due to the health behavior in question seem to initiate changes in confidence, attitude and thereby motivation to change. Cues to action arising from these determinants are categorized as own illness or illness among friends and relatives, changes in self-perception, exceeded limits determined by the behavior in question, and social pressure. Shifts in the possibilities for change, such as change of partner or other life events, produce changes also affecting health behavior. A strategy to initiate changes in health behavior could be to create cues to action through personal experiences in the context of a specific health behavior or to establish contact to people when they are experiencing new life circumstances.


Normal ranges for immunochemiluminometric gonadotropin assays.
We sought to establish normative data for spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays (ICMA) in children and adolescents. Random serum samples were obtained from 375 normal subjects (0.1 to 17.7 years, 230 female subjects). Intravenous GnRH stimulation tests were performed in 41 normal subjects (4.8 to 18 years, 20 female subjects). Normal ranges were calculated by age and Tanner stage. Immunochemiluminometric assays of LH and FSH concentrations were compared with levels obtained by a sensitive immunofluorometric assay and a less sensitive radioimmunoassay. Random gonadotropin concentrations in normal children followed the pattern of transient elevation in infancy, low but measurable prepubertal levels, and markedly increased values at puberty. Spontaneous LH levels were higher in male infants but were not statistically different in boys and girls after infancy. Mean prepubertal LH was 0.04 +/- 0.04 IU/L (n = 66), rising 100-fold during puberty. Spontaneous FSH levels were much higher than LH values, were higher in female infants, and rose threefold at puberty. Peak GnRH-stimulated LH was identical in prepubertal boys and girls (1.8 +/- 1.3 IU/L, n = 17) and increased 20-fold at puberty. Mean peak GnRH-stimulated FSH was highest in prepubertal female subjects. Luteinizing hormone values measured by ICMA and immunofluorometric assay were highly correlated, but radioimmunoassay levels diverged markedly from ICMA levels at lower concentrations. Because absolute levels were higher, FSH values correlated adequately in the three assays throughout the normal physiologic range. Measurement of LH by ICMA is much more sensitive than older assay methods. Spontaneous LH can be accurately measured by ICMA to the very low levels present in normal prepubertal children, providing a potentially important biochemical discriminator of pubertal status. An ICMA GnRH-stimulated LH level greater than 5 IU/L is suggestive of maturing gonadotropin secretion. The ICMA LH assays provide significant enhancement in sensitivity; these assays should be used when levels may be low, and by their accuracy may reduce the time and expense of testing procedures.


Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy.
Ketogenic diet (KD), which is high in fat and low in carbohydrates, mimics the metabolic state of starvation and is used therapeutically for pharmacoresistant epilepsy. It is known that generation of triiodothyronine (T3) from thyroxine (T4) decreases during fasting periods. The aim of this study was to evaluate the thyroid function of children receiving KD for at least 1 year due to drug-resistant epilepsy. A total of 120 patients [63 males, 52.5%; mean age 7.3±4.3 years, median interquartile range (IQR): 7.0 (4-10 years)] treated with KD for at least 1 year were enrolled. Seizure control, side effects, and compliance with the diet were recorded, and free T3, free T4, and thyroid-stimulating hormone (TSH) levels were measured at baseline and at post-treatment months 1, 3, 6, and 12. The Mann-Whitney U-test, repeated measures analysis of variance (ANOVA) with post-hoc Bonferroni correction, and logistic regression analysis were used for data analysis. Hypothyroidism was diagnosed and L-thyroxine medication was initiated for eight, seven and five patients (20 patients in total, 16.7%) at 1, 3, and 6 months of KD therapy, respectively. Logistic regression analysis showed that baseline TSH elevation [odds ratio (OR): 26.91, 95% confidence interval (CI) 6.48-111.76, p<0.001] and female gender (OR: 3.69, 95% CI 1.05-12.97, p=0.042) were independent risk factors for development of hypothyroidism during KD treatment in epileptic children. KD causes thyroid malfunction and L-thyroxine treatment may be required. This is the first report documenting the effect of KD treatment on thyroid function. Thyroid function should be monitored regularly in epileptic patients treated with KD.


Preoperative Pain Sensitization Is Associated With Postoperative Pillar Pain After Open Carpal Tunnel Release.
Postoperative pillar pain (deep-seated wrist pain worsened by leaning on the heel of the hand) sometimes occurs after carpal tunnel release (CTR), leading to weakness in the hand and delayed return to work. Increased pain sensitivity has been found to be associated with worse symptoms and poorer treatment response in a number of chronic musculoskeletal conditions, but few studies have investigated the association of pain sensitization with pillar pain after CTR. (1) Is preoperative pain sensitization in patients with carpal tunnel syndrome (CTS) associated with increased severity of pillar pain after open CTR? (2) What other demographic, electrophysiological, or preoperative clinical characteristics are associated with pillar pain after CTR? Over a 35-month period, one surgeon performed 162 open carpal tunnel releases. Patients were eligible if they had sufficient cognitive and language function to provide informed consent and completed a self-reported questionnaire; they were not eligible if they had nerve entrapment other than CTR or if the surgery was covered by workers compensation insurance. Based on these criteria, 148 (91%) were approached for this study. Of those, 17 (9%) were lost to followup before 12 months, leaving 131 for analysis. Their mean age was 54 years (range, 32-78 years), and 81% (106 of 131) were women; 34% (45 of 131) had less than a high school education. We preoperatively measured pain sensitization by assessing the patients' pressure pain thresholds by stimulating pressure-induced pain in the pain-free volar forearm and administering a self-reported Pain Sensitivity Questionnaire minor subscale, an instrument that assesses pain intensity in daily life situations. We evaluated postoperative pillar pain using the "table test" (having the patient lean on a table with their weight on their hands placed on the table's edge with elbows straight) with an 11-point ordinal scale at 3, 6, and 12 months after their surgical procedures. We conducted bivariate and multivariable analyses to determine whether the patients' clinical, demographic, and pain sensitization factors were associated with their postoperative pillar pain severity after CTR. After controlling for relevant confounding variables such as age, education level, and functional states, we found that increased pillar pain severity was associated with the pressure pain threshold (β = -1.02 [-1.43 to -0.61], partial R = 11%, p = 0.021) and Pain Sensitivity Questionnaire minor (β = 1.22 [0.73-1.71], partial R = 17%, p = 0.013) at 3 months, but by 6 months, only Pain Sensitivity Questionnaire minor (β = 0.92 [0.63-1.21], partial R = 13%, p = 0.018) remained an associated variable for pillar pain. Additionally, gender (women) was associated with increased pain severity at 3 (β = 0.78 [0.52-1.04], partial R = 9%, p = 0.023) and 6 months (β = 0.72 [0.41-1.01], partial R = 8%, p = 0.027). At 3 months, pressure pain threshold, Pain Sensitivity Questionnaire minor, and gender (women) collectively accounted for 37% of the variance in pillar pain severity; at 6 months, Pain Sensitivity Questionnaire minor and gender (women) accounted for 21% of the variance, but no relationship between those factors and pillar pain was observed at 12 months. Gender (women) and preoperative pain sensitization measured by pressure pain threshold and self-reported Pain Sensitivity Questionnaire were associated with pillar pain severity up to 3 and 6 months after CTR, respectively. However, the influence of pain sensitization on pillar pain was diminished at 6 months and it did not show persistent effects beyond 12 months. Pain sensitization seems to be more important in the context of recovery from surgical intervention (in the presence of a pain condition) than in healthy states, and clinicians should understand the role of pain sensitization in the postoperative management of CTS. Future research may be needed to determine if therapeutic interventions to reduce sensitization will decrease the risk of pillar pain. Level III, prognostic study.


Water dissociation at the water-rutile TiO2(110) interface from ab initio-based deep neural network simulations.
The interaction of water with TiO2 surfaces is of crucial importance in various scientific fields and applications, from photocatalysis for hydrogen production and the photooxidation of organic pollutants to self-cleaning surfaces and bio-medical devices. In particular, the equilibrium fraction of water dissociation at the TiO2-water interface has a critical role in the surface chemistry of TiO2, but is difficult to determine both experimentally and computationally. Among TiO2 surfaces, rutile TiO2(110) is of special interest as the most abundant surface of TiO2's stable rutile phase. While surface-science studies have provided detailed information on the interaction of rutile TiO2(110) with gas-phase water, much less is known about the TiO2(110)-water interface, which is more relevant to many applications. In this work, we characterize the structure of the aqueous TiO2(110) interface using nanosecond timescale molecular dynamics simulations with ab initio-based deep neural network potentials that accurately describe water/TiO2(110) interactions over a wide range of water coverages. Simulations on TiO2(110) slab models of increasing thickness provide insight into the dynamic equilibrium between molecular and dissociated adsorbed water at the interface and allow us to obtain a reliable estimate of the equilibrium fraction of water dissociation. We find a dissociation fraction of 22 ± 6% with an associated average hydroxyl lifetime of 7.6 ± 1.8 ns. These quantities are both much larger than corresponding estimates for the aqueous anatase TiO2(101) interface, consistent with the higher water photooxidation activity that is observed for rutile relative to anatase.


Psychosocial and neo-material dimensions of SES and health revisited: predictors of self-rated health in a Canadian national survey.
This study addresses questions concerning psychosocial processes of relative comparison in the production of socio-economic inequalities in health. Specifically, the importance for health of perceptions of status, different 'reference groups' and 'reference points' in such comparisons is problematized and investigated empirically. Using data from a cross-sectional telephone survey of the Canadian population in 2000 (n=1331), the paper investigates relationships between self-rated health status (SRHS) and: (1) 'actual' absolute socio-economic standing, (2) perceived relative socio-economic standing (relative to other Canadians and to Canadians of the previous generation), and (3) 'actual' relative socio-economic standing (relative to others in respondents' province of residence and neighbourhood of residence). Measures of actual absolute socio-economic status (SES) (household income, personal income and education) were strongly related to SRHS. Results for perceived relative SES were mixed. Perceived SES relative to all Canadians was a strong predictor of SRHS before and after controlling for age and gender while perceived SES relative to the previous generation was unrelated to SRHS. Actual relative income was strongly related to SRHS for all reference points (10th, 50th and 90th percentiles) in both reference groups analysed (neighbourhoods and provinces). Within neighbourhoods, however, comparisons with those at the top of the income ladder appeared to be somewhat more salient for SRHS than were comparisons to other levels. We conclude that there is some evidence of the importance of both psychosocial and neo-material aspects of SES for Canadians' self-rated health, but that further empirical research is needed that accounts for the numerous ways in which psychosocial processes of relative social comparison may take place.


Thymosin beta-4 and venous ulcers: clinical remarks on a European prospective, randomized study on safety, tolerability, and enhancement on healing.
The objective of this double-blind, placebo-controlled, dose-escalation study is to evaluate safety, tolerability, and enhancement on healing of thymosin beta-4 (Tbeta-4) administered topically in patients with venous ulcers. Three groups of patients, coming from 10 sites, 5 from Italy and 5 from Poland, will be enrolled sequentially. Twenty-four patients within each group will be randomized to Tbeta-4 or placebo in a 3:1 ratio and will be treated with increasing doses of Tbeta-4. When review safety data show no-dose-limiting adverse events, a new group will be enrolled. So, the study design comprehends 72 patients treated for 84 days and followed for 14 days at the end of treatment. Blood samples will be taken on day 0 and at the end of treatment visit to measure plasma levels of Tbeta-4. Every week each patient is visited and blood samples are taken for clinical chemistry, hematology, coagulation, and urinalysis. Each ulcer is treated with debridement, if necessary, and compression therapy with standard compression stockings class 2. Efficacy parameters are incidence of healing defined as the percentage of patients who have complete closure of the index ulcer at day 84 and, mean time to complete healing. Ulcer area will be calculated by digital planimetry and photographic analysis. The study is ongoing and a total of 21 patients have been enrolled so far in the first treatment group at the lower dose. Patients' compliance and motivated and well-trained teams seem to be the most suitable parameters of a successfully conducted study.


Prognostic capacity of a clinically indicated exercise test for cardiovascular mortality is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans.
Exercise capacity, heart rate recovery and T-wave alternans are independent predictors of cardiovascular mortality. We tested whether these parameters contain supplementary prognostic information. A total of 3609 consecutive patients (2157 men) referred for a routine, clinically indicated bicycle exercise test were enrolled in the Finnish Cardiovascular Study (FINCAVAS). Exercise capacity was measured in metabolic equivalents, heart rate recovery as the decrease in heart rate from maximum to one minute post-exercise, and T-wave alternans by time-domain Modified Moving Average method. During 57-month median follow-up (interquartile range 35-78 months), 96 patients died of cardiovascular causes (primary endpoint) and 233 from any cause. All three parameters were independent predictors of cardiovascular mortality when analysed as continuous variables. Adding metabolic equivalents (p < 0.001), heart rate recovery (p = 0.002) or T-wave alternans (p = 0.01) to the linear model improved its predictive power for cardiovascular mortality. The combination of low exercise capacity (<6 metabolic equivalents), reduced heart rate recovery (≤12 beats/min) and elevated T-wave alternans (≥60 μV) yielded the highest hazard ratio for cardiovascular mortality of 16.5 (95% confidence interval 4.0-67.7, p < 0.001). Harrell's C index was 0.719 (confidence interval 0.665-0.772) for cardiovascular mortality with previously defined cutpoints (<8 units for metabolic equivalents, ≤18 beats/min for heart rate recovery and ≥60 μV for T-wave alternans). The prognostic capacity of the clinical exercise test is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans.


[Mechanical recanalization and local thrombolysis in a patient with fulminant pulmonary embolism and craniocerebral trauma].
A 77-year-old female patient presenting with recurrent pulmonary embolism and shock had a severe craniocerebral trauma after collapsing at home 2 days before admission. Since systemic thrombolytic therapy appeared hazardous in this patient, percutaneous fragmentation and distal dispersion of the proximal pulmonary emboli was performed using a pigtail catheter. This procedure improved cardiac output immediately by 15%, whereas the mean pulmonary artery pressure dropped only slightly from 48 to 46 mmHg. Thereafter, a streptokinase infusion of 100,000 IU during 1 h was instituted through the pigtail catheter into the pulmonary artery. 12 hours after the treatment was started, cardiac output was raised by 70% and mean pulmonary artery pressure was decreased from 48 to 25 mmHg. 14 days after admission, control ventilation-perfusion scan showed a markedly improved pulmonary perfusion, and right heart catheterization revealed normal right heart pressures. The patient recovered rapidly and there was no evidence of recurrent pulmonary embolism 18 months later. This report demonstrates that a percutaneous catheter fragmentation of proximal pulmonary emboli combined with local intermediate-dose infusion of streptokinase may be a helpful therapeutic option in patients with massive pulmonary embolism in whom systemic thrombolytic therapy is contraindicated.


Combining opioid and adrenergic mechanisms for chronic pain.
Chronic pain is a highly prevalent medical problem in the United States. Although opioids and serotonin-norepinephrine reuptake inhibitors (SNRIs) have demonstrated efficacy for relief of chronic pain, each has risks of adverse events in patients. Because of the risk of opioid abuse and addiction, combinations reducing opioid requirements are particularly valuable. Opioid and SNRI agents relieve pain by different pathways; concurrent use of each agent separately offers many potential benefits: complementary and possibly synergistic analgesic efficacy, separate titrations of opioid and SNRI effects, and the reduction of opioid requirements. However, few clinical studies have investigated the ideal ratios for combinations of opioids and SNRIs. A number of factors affect whether specific combinations have additive, synergistic, less than additive efficacy, or increase adverse events in patients, including general pharmacokinetic considerations, the potential for pharmacodynamic drug interactions, dose, and timing. Because there is little clinical evidence guiding combination therapy with separate opioid and SNRI agents, using single-molecule agents provides safe and effective therapy and should be the first option presented to patients. The use of empiric combinations of separate opioid and SNRI combinations needs to be considered in light of clinical cautions, including the lack of published evidence to guide dose conversion from any opioid to tramadol or to tapentadol, and vice versa; the need to avoid combinations with known drug interactions; and the need to titrate the dose when adding an SNRI to an opioid, and vice versa.


Initial treatment choices to achieve sustained response in major depression: a systematic review and network meta-analysis.
Major depression is often a relapsing disorder. It is therefore important to start its treatment with therapies that maximize the chance of not only getting the patients well but also keeping them well. We examined the associations between initial treatments and sustained response by conducting a network meta-analysis of randomized controlled trials (RCTs) in which adult patients with major depression were randomized to acute treatment with a psychotherapy (PSY), a protocolized antidepressant pharmacotherapy (PHA), their combination (COM), standard treatment in primary or secondary care (STD), or pill placebo, and were then followed up through a maintenance phase. By design, acute phase treatment could be continued into the maintenance phase, switched to another treatment or followed by discretionary treatment. We included 81 RCTs, with 13,722 participants. Sustained response was defined as responding to the acute treatment and subsequently having no depressive relapse through the maintenance phase (mean duration: 42.2±16.2 weeks, range 24-104 weeks). We extracted the data reported at the time point closest to 12 months. COM resulted in more sustained response than PHA, both when these treatments were continued into the maintenance phase (OR=2.52, 95% CI: 1.66-3.85) and when they were followed by discretionary treatment (OR=1.80, 95% CI: 1.21-2.67). The same applied to COM in comparison with STD (OR=2.90, 95% CI: 1.68-5.01 when COM was continued into the maintenance phase; OR=1.97, 95% CI: 1.51-2.58 when COM was followed by discretionary treatment). PSY also kept the patients well more often than PHA, both when these treatments were continued into the maintenance phase (OR=1.53, 95% CI: 1.00-2.35) and when they were followed by discretionary treatment (OR=1.66, 95% CI: 1.13-2.44). The same applied to PSY compared with STD (OR=1.76, 95% CI: 0.97-3.21 when PSY was continued into the maintenance phase; OR=1.83, 95% CI: 1.20-2.78 when PSY was followed by discretionary treatment). Given the average sustained response rate of 29% on STD, the advantages of PSY or COM over PHA or STD translated into risk differences ranging from 12 to 16 percentage points. We conclude that PSY and COM have more enduring effects than PHA. Clinical guidelines on the initial treatment choice for depression may need to be updated accordingly.


Air quality model evaluation data for organics. 6. C3-C24 organic acids.
The atmospheric concentrations of 47 carboxylic acids in the semivolatile and particle phases are quantified in the Los Angeles area, as part of a larger study of the vapor-phase, semivolatile, and particle-phase organic compounds. Variations in the spatial and temporal distributions of acid concentrations are analyzed to determine whether atmospheric formation or primary emissions are responsible for the observed levels. Relatively low molecular weight aliphatic dicarboxylic acids (e.g., butanedioic acid, hexanedioic acid, and propanedioic acid) and some n-alkanoic acids (e.g., n-octanoic acid and n-nonanoic acid) are found at an offshore sampling location at levels comparable to urban area concentrations indicating that these compounds or their atmospheric precursors may be derived from long-range transport or natural background sources. Some aromatic carboxylic acids (e.g., benzoic acid and 1,2-benzenedicarboxylic acid) have spatial and temporal distributions suggesting that formation from anthropogenic emissions of gaseous precursors dominates their atmospheric concentrations. Additionally, the distributions of aliphatic carboxylic acid concentrations known to be emitted from primary sources (e.g., hexadecanoic acid and octadecanoic acid) are consistent with direct emissions as the dominant source of these compounds.


Metal substitution in transferrins: the crystal structure of human copper-lactoferrin at 2.1-A resolution.
The structural consequences of binding a metal other than iron to a transferrin have been examined by crystallographic analysis of human copper-lactoferrin, Cu2Lf. X-ray diffraction data were collected from crystals of Cu2Lf, using a diffractometer, to 2.6-A resolution, and oscillation photography on a synchrotron source, to 2.1-A resolution. The structure was refined crystallographically, by restrained least-squares methods, starting with a model based on the isomorphous diferric structure from which the ligands, metal ions, anions, and solvent molecules had been deleted. The final model, comprising 5321 protein atoms (691 residues), 2 Cu2+ ions, 2 (bi)carbonate ions, and 308 solvent molecules has good stereochemistry (rms deviation of bond lengths from standard values of 0.018 A) and gives a crystallographic R value of 0.196 for 43,525 reflections in the range 7.5-2.1-A resolution. The copper coordination is different in the two binding sites. In the N-terminal site, the geometry is square pyramidal, with equatorial bonds to Asp 60, Tyr 192, His 253, and a monodentate anion and a longer apical bond to Tyr 92. In the C-terminal site, the geometry is distorted octahedral, with bonds to Asp 395, Tyr 435, Tyr 528, and His 597 and an asymmetrically bidentate anion. The protein structure is the same as for the diferric protein, Fe2Lf, demonstrating that the closure of the protein domains over the metal is the same in each case irrespective of whether Fe3+ or Cu2+ is bound and that copper could be transported and delivered to cells equally well as iron. The differences in metal coordination are achieved by small movements of the metal ion and anion within each binding site, which do not affect the protein structure.


Inhibition of arylhydrocarbon hydroxylase induction in BALB/C mouse liver by delta9-tetrahydrocannabinol.
The effects of single administration of delta9-THC on the induction of arylhydrocarbon hydroxylase activity by phenobarbital and 3-methyl cholanthrene were determined. delta9-THC completely suppressed the induction by phenobarbital and reduced the 3-methylcholanthrene induction from 455% to 177% of control. delta9-THC had no effect on phenobarbital induction when both drugs were administered daily for 2 days and mice killed on the third day. Arylhydrocarbon hydroxylase was not the only enzyme effected as delta9-THC also inhibited the induction of aminopyrine demethylase by phenobarbital. These drugs do not have any interactive effect on microsomal protein synthesis but are potent antagonists in the synthesis of nuclear RNA.


Transient beneficial effects of exendin-4 treatment on the function of microencapsulated mouse pancreatic islets.
Transplantation of microencapsulated islets may reduce hyperglycemia in the absence of immunosuppression. However, the efficiency of microencapsulated islet transplantation is low, requiring more islets to achieve normoglycemia than in vascularized islet transplantation. Exendin-4 (a glucagon-like receptor agonist) has been previously shown to improve islet transplantation outcome in rodents. We investigated whether this treatment would enhance the function of microencapsulated islets in vitro and in vivo. Encapsulated or naked islets were cultured with or without exendin-4 for 72 h. To test in vitro function, insulin release and glucose oxidation rates were measured in the absence or presence of exendin-4. In addition, in vivo function of a minimal mass of 350 microencapsulated islets was assessed by syngeneic transplantation into the peritoneal cavity of alloxan-diabetic mice. Glucose oxidation rates of microencapsulated islets were improved by 72-h pretreatment with exendin-4. Insulin release was increased both acutely after glucose stimulation and over a 40-h culture period by the presence of exendin-4. Transplantation outcome of microencapsulated islets cultured with exendin-4 was initially improved, but by day 7 there were no differences compared with control cultured microencapsulated islets. Culture of microencapsulated islets with exendin-4 increases glucose oxidation and insulin release rates, but the increased function seen in vitro was not enough to improve the long term outcome in a transplantation model.


Heterotopic ossification following traumatic brain injury and spinal cord injury.
Heterotopic ossification associated with neurologic injury, or neurogenic heterotopic ossification, tends to form at major synovial joints surrounded by spastic muscles. It is commonly associated with traumatic brain or spinal cord injury and with other causes of upper motor neuron lesions. Heterotopic ossification can result in a variety of complications, including nerve impingement, joint ankylosis, complex regional pain syndrome, osteoporosis, and soft-tissue infection. The associated decline in range of motion may greatly limit activities of daily living, such as positioning and transferring and maintenance of hygiene, thereby adversely affecting quality of life. Management of heterotopic ossification is aimed at limiting its progression and maximizing function of the affected joint. Nonsurgical treatment is appropriate for early heterotopic ossification; however, surgical excision should be considered in cases of joint ankylosis or significantly decreased range of motion before complications arise. Patient selection, timing of excision, and postoperative prophylaxis are important components of proper management.


Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine.
The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC(50) = 31 ± 2 nM) and a moderately selective eqBuChE inhibitor (IC(50) = 4.7 ± 0.2 μM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC(50) = 25 ± 3 nM, K(i) = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Aβ aggregation induced by hAChE by 30.6%.


Modulation of keratinocyte growth factor and its receptor in reepithelializing human skin.
We investigated the expression and distribution of keratinocyte growth factor (KGF) (FGF-7) and its receptor (KGFR) during reepithelialization of human skin. KGF mRNA levels increased rapidly by 8-10-fold and remained elevated for several days. In contrast, KGFR transcript levels decreased early but were significantly elevated by 8-9 d. A KGF-immunoglobulin G fusion protein (KGF-HFc), which specifically and sensitively detects the KGFR, localized the receptor to differentiating keratinocytes of control epidermis, but revealed a striking decrease in receptor protein expression during the intermediate period of reepithelization. Suramin, which blocked KGF binding and stripped already bound KGF from its receptor, failed to unmask KGFRs in tissue sections from the intermediate phase of wound repair. The absence of KGFR protein despite increased KGFR transcript levels implies functional receptor downregulation in the presence of increased KGF. This temporal modulation of KGF and KGFRs provides strong evidence for the functional involvement of KGF in human skin reepithelialization.


Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors.
The molecular basis of Cushing's disease is not known. One of the most characteristic features of such tumors is their resistance to corticosteroid feedback at the pituitary level. We have hypothesized that abnormalities of the glucocorticoid receptor (GR) gene might play a role in the development of Cushing's disease via an increase in the relative production of the nonligand-binding splice variant of the GR, GR beta, known to exert dominant negative effects over the ligand-binding isoform, GR alpha. Alternatively, a change in overall GR expression, or mutations of some functional domains of the GR gene, might be involved in the pathogenesis of corticotroph tumors. We studied 22 tumors (17 pituitary ACTH-secreting tumors, 2 ectopic ACTH-producing tumors, 2 prolactinomas, and 1 nonfunctioning adenoma) and three normal pituitaries. RT-PCR was performed with primers specific to GR alpha and GR beta complementary DNA, followed by Southern blotting using an internal probe, and the ratio of the two bands quantitated by densitometry. We also assessed the overall expression of GR relative to the message of both the POMC gene and a housekeeping gene. Single-strand conformation polymorphism analysis of the DNA-binding domain and splice junction region of the gene was also performed. GR alpha messenger RNA was expressed at 37.3-fold +/- 5.7 (range, 32 to 46) excess, as compared with the GR beta subform. This pattern was observed both in the tumor samples and in the normal pituitaries used as controls. A majority of the ACTH-secreting tumors (16/19), including the ectopic secretors, showed variable but increased overall GR expression, whereas 3 tumors showed an expression approximately equivalent to the normal controls; however, no correlation was found between these two groups and the response to the high-dose dexamethasone test, nor was there any correlation with tumor histology. No mutations were found in any of the tumors by PCR-single-strand conformation polymorphism analysis. In conclusion, although both pituitary and ectopic ACTH-secreting tumors are at least partially glucocorticoid-resistant, no significant abnormalities in the relative expression of the two main GR subforms were observed in a series of such tumors. Additionally, mutations of regions critical to normal function of the receptor do not seem to be a frequent event in these tumors.


Stereoselective determination of hydroxychloro-quine and its major metabolites in human urine by solid-phase microextraction and HPLC.
The enantioselective analysis of hydroxychloroquine (HCQ) and its major metabolites was achieved by HPLC and solid-phase microextraction. The chromatographic separation was performed on a Chiralcel OD-H column using hexane/methanol/ethanol (96:2:2, v/v/v) plus 0.2% diethylamine as the mobile phase, at the flow rate of 1.3 mL/min. The main extraction parameters were optimized. The best condition was achieved by the addition of 10% NaCl and 1 mL phosphate buffer 1 mol/L pH 11 to 3 mL human urine. The extraction was conducted for 40 min at 25 degrees C and the desorption time was 3 min using methanol (100%). PDMS-DVB 60 microm fiber was used in this study. The mean recoveries were 9.3, 9.2, and 14.4% for HCQ, desethylhydroxychloroquine (DHCQ), and desethylchloroquine (DCQ), respectively. The method was linear over the range of 50-1000 ng/mL for HCQ enantiomers and over the range of 42-416 ng/mL for DCQ and DHCQ enantiomers. Within-day and between-day precision and accuracy assays for HCQ and its metabolites were lower than 15%. The preliminary 48 h urinary excretion study performed in human urine showed to be stereoselective. The amount of (+)-(S)-enantiomer excreted was higher than its antipode.


The Impacts of Fluctuating Light on Crop Performance.
Rapidly changing light conditions can reduce carbon gain and productivity in field crops because photosynthetic responses to light fluctuations are not instantaneous. Plant responses to fluctuating light occur across levels of organizational complexity from entire canopies to the biochemistry of a single reaction and across orders of magnitude of time. Although light availability and variation at the top of the canopy are largely dependent on the solar angle and degree of cloudiness, lower crop canopies rely more heavily on light in the form of sunflecks, the quantity of which depends mostly on canopy structure but also may be affected by wind. The ability of leaf photosynthesis to respond rapidly to these variations in light intensity is restricted by the relatively slow opening/closing of stomata, activation/deactivation of C3 cycle enzymes, and up-regulation/down-regulation of photoprotective processes. The metabolic complexity of C4 photosynthesis creates the apparently contradictory possibilities that C4 photosynthesis may be both more and less resilient than C3 to dynamic light regimes, depending on the frequency at which these light fluctuations occur. We review the current understanding of the underlying mechanisms of these limitations to photosynthesis in fluctuating light that have shown promise in improving the response times of photosynthesis-related processes to changes in light intensity.


Flavor Alterations Associated with Miracle Fruit and Gymnema sylvestre.
Taste and flavor (retronasal olfaction) interact in the brain. The rules of that interaction are not well understood. This study uses 2 taste modifiers that alter sweet to examine the effects on flavors. Subjects used the Global Sensory Intensity Scale to assess the aroma, sweetness, sourness, and flavor of 10 foods. As previous work had shown, miracle fruit added sweetness to acids, which secondarily reduced sourness (mixture suppression) and Gymnema sylvestre reduced sweetness in sweet foods as well as the sweetness induced by miracle fruit. In this study, multiple regression showed that both sweet and sour contribute to flavor. Gymnema sylvestre reduced the perceived sweet of predominantly sweet foods (chocolate and maple syrup) as expected; reducing the sweet, reduced the flavor. The effects of miracle fruit were complicated by its dual action: intensification of sweet and reduction of sour. Predominantly sour foods (vinegar, lemon, mustard, pickle) were sweetened by miracle fruit but any flavor enhancement associated with the added sweet appears to have been countered by the flavor reduction associated with reduced sourness. Moderately sour foods that are also sweet (tomatoes, strawberries) were sweetened by miracle fruit and thus flavor was enhanced; flavor loss through sour reduction was apparently not sufficient to counter the flavor enhancement due to increased sweet so the net result was that tomato and strawberry flavors were enhanced. The flavors of control foods (not predominantly sweet or sour [sausage, peanuts]) showed only small changes.


Effectiveness of a Web-Based Intervention for Preventing Substance Use in Young Adults in Taiwan: Quasi-Experimental Study.
Substance use has been one of the most alarming public health problems worldwide, particularly among younger generations. This study evaluated the effectiveness of a web-based substance use prevention intervention targeted at adults aged 20-29 years. The intervention materials comprised 5 sets of infographics and 1 animation, all of which focused on mixed themes: (1) the concept of substance use and its harmful effects on health; (2) misinformation regarding new psychoactive substances; (3) regulation of illicit drugs, particularly marijuana; (4) the brain disease model of addiction; (5) critical thinking skills that improve health literacy; and (6) decision-making and communication skills that help people refuse illegal drugs. The study assigned eligible participants into experimental and control groups on the basis of the parity of their participant numbers. These participants completed web-based baseline and follow-up questionnaires that assessed their knowledge, behavioral intention, self-efficacy, and life skills related to substance use prevention. Knowledge was assessed using 8 questions concerning understanding of substance use harms and the regulation of illicit drugs. Behavioral intention and self-efficacy were assessed using 5-point Likert-type scales. Participants' ability to apply life skills to avoid substance use was assessed using 3 testing scenarios regarding substance use. The study used generalized estimating equations to examine the intervention's effectiveness. A total of 1065 participants (539 control and 526 experimental) completed the intervention and questionnaires in 2019. The average ages of the experimental and control groups were 25.68 (SD 2.71) and 25.66 (SD 2.69) years, respectively. The study observed no significant differences in the demographic variables between the 2 groups. The results of the generalized estimating equation analyses indicated that the intervention significantly improved participants' knowledge (P<.001), behavioral intention (P<.001), and self-efficacy (P<.001) but not their life skills (P=.61) related to substance use prevention. Participants in the experimental group responded to a satisfaction survey with positive feedback on the intervention. The web-based intervention was effective in improving participants' knowledge, behavioral intention, and self-efficacy concerning substance use prevention. The findings support continued efforts to use web-based interventions to prevent substance use among young adults.


Executive function profile of Chinese boys with attention-deficit hyperactivity disorder: different subtypes and comorbidity.
This study examined the executive function (EF) profile of Chinese boys with attention-deficit hyperactivity disorder (ADHD) using a large sample. Executive function performance within the ADHD subtypes and the effects of comorbidity were also investigated. Five hundred Chinese boys (375 with ADHD and 125 controls) aged 6-15 completed a battery of EF tests. Boys with all types of ADHD performed worse in all of the EF tests than age- and intelligence quotient-matched healthy controls. The boys with the inattention ADHD subtype and the combined subtype showed similar impairments across different EF tasks, whereas the boys with the hyperactive-impulsive ADHD subtype primarily displayed deficits in theory of mind and visual memory. Comorbid oppositional defiant disorder/conduct disorder had no additional influence on the EF characteristics of the boys with ADHD only, whereas comorbid learning disorder increased the severity of inhibition and shifting impairments.


[Calculating the diffusion coefficient in the eye lens].
An experimental investigation of the appearance of a cataract under intensive irradiation is carried out. On the basis of the results obtained a model is proposed of calculating the diffusion coefficient which can model the crystalline lens, its individual peculiarities being taken into account.


Anaerobic biodegradation of dissolved ethanol in a pilot-scale sand aquifer: Variability in plume (redox) biogeochemistry.
The use of ethanol in alternative fuels has led to contamination of groundwater with high concentrations of this easily biodegradable organic compound. Previous laboratory and field studies have shown vigorous biodegradation of ethanol plumes, with prevalence of reducing conditions and methanogenesis. The objective of this study was to further our understanding of the dynamic biogeochemistry processes, especially dissolved gas production, that may occur in developing and aging plume cores at sites with ethanol or other organic contamination of groundwater. The experiment performed involved highly-detailed spatial and temporal monitoring of ethanol biodegradation in a 2-dimensional (175cm high×525cm long) sand aquifer tank for 330days, with a vertical shift in plume position and increased nutrient inputs occurring at ~Day 100. Rapid onset of fermentation, denitrification, sulphate-reduction and iron(III)-reduction occurred following dissolved ethanol addition, with the eventual widespread development of methanogenesis. The detailed observations also demonstrate a redox zonation that supports the plume fringe concept, secondary reactions resulting from a changing/moving plume, and time lags for the various biodegradation processes. Additional highlights include: i) the highest dissolved H2 concentrations yet reported for groundwater, possibly linked to vigorous fermentation in the absence of common terminal electron-acceptors (i.e., dissolved oxygen, nitrate, and sulphate, and iron(III)-minerals) and methanogenesis; ii) evidence of phosphorus nutrient limitation, which stalled ethanol biodegradation and perhaps delayed the onset of methanogenesis; and iii) the occurrence of dissimilatory nitrate reduction to ammonium, which has not been reported for ethanol biodegradation to date.


The Association between Peace and Life Expectancy: An Empirical Study of the World Countries.
Although theoretically peace affects health, few published evidence for such an association was empirically available. This study aimed to explore the association between peace and life expectancy (LE) among the world countries. In an ecological study and using random effects regression model, we examined the association between peace and LE among world countries between 2007 and 2012. The LE at birth and global peace index (GPI: a score between 1 and 5, higher score means lower peace) were selected as outcome and main predictor variables, respectively. We adjusted their association for the gross national income (GNI) per capita and education index (EI). Data were obtained from the Institute for Economics and Peace (IEP) and UNDP (United Nations Development Programme (UNDP). Numbers of included countries were 158 based on the available data. GPI had a negative, considerable, and statistically significant effect on LE (standardized coefficient -0.039; 95% CI: -0.058, -0.019). This association was also significant even after the adjustment for EI (-0.019; 95% CI: -0.035, -0.003), GNI (-0.035; 95% CI: -0.055, -0.015), and both EI and GNI (-0.017; 95% CI: -0.033, -0.001). The full model showed that around 0.61 of the variation of LE among countries may be explained by the GPI, EI and GNI per capita. The contribution of peace as a global determinant of LE was empirically considerable even after the adjustment for the economic and education levels of countries. This implies that governments should make efforts to settle peace through implementing good governance based on interactions with both public and other countries.


The genetics of diabetes susceptibility in mice.
The factors associated with a diabetes-susceptible genotype in mice exhibiting various forms of heritable glucose intolerance syndromes are discussed. Genetic models of insulin-dependent and non-insulin-dependent diabetes in mice are described. Although single gene mutations can be defined for each model that are major contributors to diabetogenic stress, polygenic interactions are required for the expression of a diabetic phenotype, and environmental factors are also contributory. Several strongly penetrant single gene mutations are capable of affecting obesity and insulin-resistant states. Analysis of inbred strain genomic interactions with one of these recessive obesity-producing genes, diabetes (db), suggests that development of a diabetic phenotype is dependent on the strength of an interaction between the db gene and sulfotransferase enzymes. Specifically, diabetes-susceptible vs. resistant inbred strain backgrounds can be distinguished by the extent to which the db mutation elicits an accelerated sequestration by sulfoconjugation of tissue estrogens while androgens remain free. In a male gender- (and Y chromosome-)associated model of transient glucose intolerance, stress as well as a requirement for both adrenal and testicular secretions are each components of the susceptibility background. In the obesity-associated diabetes models, autoimmunity, when it occurs, is a secondary reflection of pancreatic beta cell destruction. The nonobese diabetic (NOD) mouse, in contrast, represents a model in which autoimmunity against beta cells is a primary event in the development of insulin-dependent diabetes. In NOD mice, a gene that is either the unique class II gene in the major histocompatibility complex or is in linkage disequilibrium with this complex makes a major (recessivelike) contribution to diabetes susceptibility. However, diabetogenesis can be mediated only through a multifactorial interaction among this susceptibility locus and multiple unlinked genetic loci regulating immune responsiveness. In addition, the NOD mouse represents one of the best models of diabetes available for demonstrating a critical interaction between heredity and environmental factors. The polygenic nature of the various heritable forms of glucose intolerance syndromes in mice points to a comparable or even greater genetic heterogeneity underlying the major types of diabetes in humans.


Suppression of murine cytomegalovirus (MCMV) replication with a DNA vaccine encoding MCMV M84 (a homolog of human cytomegalovirus pp65).
The cytotoxic T-lymphocyte (CTL) response against the murine cytomegalovirus (MCMV) immediate-early gene 1 (IE1) 89-kDa phosphoprotein pp89 plays a major role in protecting BALB/c mice against the lethal effects of the viral infection. CTL populations specific to MCMV early-phase and structural antigens are also generated during infection, but the identities of these antigens and their relative contributions to overall immunity against MCMV are not known. We previously demonstrated that DNA vaccination with a pp89-expressing plasmid effectively generated a CTL response and conferred protection against infection (J. C. Gonzalez Armas, C. S. Morello, L. D. Cranmer, and D. H. Spector, J. Virol. 70:7921-7928, 1996). In this report, we have sought (i) to identify other viral antigens that contribute to immunity against MCMV and (ii) to determine whether the protective response is haplotype specific. DNA immunization was used to test the protective efficacies of plasmids encoding MCMV homologs of human cytomegalovirus (HCMV) tegument (M32, M48, M56, M82, M83, M69, and M99), capsid (M85 and M86), and nonstructural antigens (IE1-pp89 and M84). BALB/c (H-2(d)) and C3H/HeN (H-2(k)) mice were immunized by intradermal injection of either single plasmids or cocktails of up to four expression plasmids and then challenged with sublethal doses of virulent MCMV administered intraperitoneally. In this way, we identified a new viral gene product, M84, that conferred protection against viral replication in the spleens of BALB/c mice. M84 is expressed early in the infection and encodes a nonstructural protein that shares significant amino acid homology with the HCMV UL83-pp65 tegument protein, a major target of protective CTLs in humans. Specificity of the immune response to the M84 protein was confirmed by showing that immunization with pp89 DNA, but not M84 DNA, protected mice against subsequent infection with an MCMV deletion mutant lacking the M84 gene. The other MCMV genes tested did not generate a protective response even when mice were immunized with vaccinia viruses expressing the viral proteins. However, the M84 plasmid was protective when injected in combination with nonprotective plasmids, and coimmunization of BALB/c mice with pp89 and M84 provided a synergistic level of protection in the spleen. Viral titers in the salivary glands were also reduced, but not to the same extent as observed in the spleen, and the decrease was seen only when the BALB/c mice were immunized with pp89 plus M84 or with pp89 alone. The experiments with the C3H/HeN mice showed that the immunity conferred by DNA vaccination was haplotype dependent. In this strain of mice, only pp89 elicited a protective response as measured by a reduction in spleen titer. These results suggest that DNA immunization with the appropriate combination of CMV genes may provide a strategy for improving vaccine efficacy.


Body donation in India: social awareness, willingness, and associated factors.
With the attendant rise of the number of medical colleges in India over past few decades, the demand for cadavers used in medical education and research is growing. However, there is an insufficient supply of donated cadavers available for dissection. This study was undertaken to assess the general population's awareness of body donation programs and willingness to donate in the State of Maharashtra, India. The willingness of participants to donate was compared with age, gender, and education of the respondents. A total of 625 adult individuals from the State of Maharashtra participated in a survey composed of questions about age, sex, education, awareness of body donation programs, and willingness to donate. It was found that 90.9% of the medical colleges surveyed reported an inadequate supply of cadavers. Of the general population, 32.1% of respondents were aware of body donation, compared to 95.83% of health care professionals. However, only 19.5% of the general population and 44.9% of health care professionals were willing to donate their bodies for anatomical education. Younger age groups, males, graduates, and postgraduates were found more willing to donate their bodies. Organ donation was preferred over body donation. A lack of awareness about body donation was the main factor responsible for respondents' "no body donation" response in the general population, along with firm religious beliefs and customs, the fear that the donated body will not be treated with respect and dignity, and the unacceptability of the dissection of one's own body. To overcome the current shortage of donated cadavers, efforts should be undertaken to change the mindset of the wider Indian society toward body donation. The authors believe this is possible through awareness campaigns and that prospective donors' concerns should be addressed appropriately. Proper guidance and assistance regarding body donation should be easily available for potential donors.


The role of exogenous enzymes in promoting growth and improving nutrient digestibility in poultry.
The value of dietary exogenous enzymes in promoting growth and efficiency of feed utilization is well recognized in poultry industry. In a case of high-cost yellow corn, several feed producers are choosing to replace yellow corn with other ingredients that have lower nutritional value like triticale, wheat, barley or sorghum. These crops are rich in non-starch polysaccharides (NSPs), and there is an inverse relationship between the content of NSPs in the feed and its nutritional value. Dietary supplementation of enzymes can enhance the nutritional value of crops containing high contents of soluble NSPs. Numerous studies have shown that supplementation of exogenous enzymes in wheat, barley, sorghum or triticale-based rations can improve performance of poultry to a level compared to that obtained by corn-soya-based rations. Naturally, the gastrointestinal tract of poultry produces enzymes to aid the digestion of nutrients. However, the birds do not have enough enzymes to digest fiber completely and need some commercial exogenous enzymes in the diets to improve the digestion. Enzyme is a biological catalyst composed of proteins, amino acids with minerals and vitamins. The advantages of using commercial enzymes in poultry feeds include improved productive performance and feed utilization, minimized environmental pollution due to reduced nutrient of manure. The present review covers the information on enzyme uses and its applications in poultry production. Furthermore, this article demonstrates that the exogenous enzymes are very important factors in the study of metabolic and physiological mechanisms. Such data will improve our understanding regarding the role of commercial enzymes in poultry feeds.


[Limited change in the quality of the social medical guidance and in the satisfaction of sick-listed patients, after collaborative projects between general practitioners and occupational physicians].
To evaluate whether regional projects for collaboration between general practitioners (GPs) and occupational physicians (OPs) improved the quality of their social medical guidance (SMG) and the satisfaction of their patients. Evaluation study with before and after measurements with respect to the same GPs and OPs. Structured interviews were conducted with 58 GPs and 83 OPs regarding the SMG of their sick-listed patients. Before the project, the SMG of 1109 sick-listed patients was assessed and after the project, 1 or 1.5 years later, the SMG of 1121 sick-listed patients. These patients were sent a questionnaire by means of which their satisfaction could be assessed. After the projects, the quality ofthe diagnosis by the OPs was improved and they also more often adhered to the official guidelines of the KNMG (Royal Netherlands Medical Association) when contacting the GP about a patient. The GPs more often contacted the OP if they needed more information about a patient after reaching a diagnosis. Nevertheless, in half to three-quarters of the patients for whom contact between GPs and OPs was indicated, this contact did not take place. There was no significant increase in patient satisfaction. Before the projects, patients gave their GP a grade of 8.2 on a 10-point scale and after the projects this was 8.5; the OPs were given a grade of 7.5 both times. Further analysis showed that there was no significant relation between the quality ofthe SMG and the patient's satisfaction with the doctor. Although there was some improvement in the quality of the SMG, there was still insufficient cooperation between GPs and OPs compared to the guidelines. An increase in patient satisfaction was not demonstrated.


Physicochemical characterization of the cytoplasmic domain of the epidermal growth factor receptor and evidence for conformational changes associated with its activation by ammonium sulphate.
The physiochemical properties of the purified cytoplasmic domain of the epidermal growth factor (EGF) receptor, its self-phosphorylation and peptide phosphorylation activities, and its activation by ammonium sulphate have been studied. Highly efficient purification procedures for the isolation of the recombinant cytoplasmic domain (Met644-Ala1186) of the EGF receptor, expressed in the baculovirus/insect cell system, are described. Physicochemical characterization of the protein included investigation of its isoelectric and hydrodynamic properties, stability, oligomeric status, and secondary structure using far-u.v. circular dichroism. The recombinant protein was not recognized by anti-phosphotyrosine antibodies, unless first self-phosphorylated in vitro. Tryptic phosphopeptide maps of self-phosphorylated recombinant cytoplasmic domain and the EGF-stimulated A431-membrane receptor were very similar, suggesting that the recombinant had similar self-phosphorylation capacity and specificity. The preparations were characterized by high specific activity towards peptide tyrosine phosphorylation. Although the cytoplasmic domain was isolated as a homogeneously monomeric protein, storage at 4 degrees C led to slow, spontaneous aggregation with reduction in specific activity. Both high activity and monomeric state were maintained by storage below 0 degree C. The dependence of the initial rate of self-phosphorylation on protein concentration was consistent with cross-phosphorylation but not with the known oligomerization-induced activation of holoreceptor. The peptide phosphorylation activity was stimulated by Mn2+, Mg2+ and (NH4)2SO4 at high concentrations. The substrate specificity of (NH4)2SO4 activation was studied using synthetic peptides. Self-phosphorylation was inhibited by (NH4)2SO4 in the range 0-0.25 M but activated at 1.0-1.5 M, possibly as a result of ionic and hydrophobic protein interactions respectively. Phosphopeptide maps of cytoplasmic domain phosphorylated in the presence of high (NH4)2SO4 showed that the protein was more extensively phosphorylated than in the absence of salt, or than the native receptor. Far-u.v. circular-dichroism spectra of the cytoplasmic domain changed dramatically at 1 M (NH4)2SO4, raising the possibility that (NH4)2SO4 activates the kinase catalytic domain by inducing conformational changes.


Structural Studies Reveal that Endosomal Cations Promote Formation of Infectious Coxsackievirus A9 A-Particles, Facilitating RNA and VP4 Release.
Coxsackievirus A9 (CVA9), an enterovirus, is a common cause of pediatric aseptic meningitis and neonatal sepsis. During cell entry, enterovirus capsids undergo conformational changes leading to expansion, formation of large pores, externalization of VP1 N termini, and loss of the lipid factor from VP1. Factors such as receptor binding, heat, and acidic pH can trigger capsid expansion in some enteroviruses. Here, we show that fatty acid-free bovine serum albumin or neutral endosomal ionic conditions can independently prime CVA9 for expansion and genome release. Our results showed that CVA9 treatment with albumin or endosomal ions generated a heterogeneous population of virions, which could be physically separated by asymmetric flow field flow fractionation and computationally by cryo-electron microscopy (cryo-EM) and image processing. We report cryo-EM structures of CVA9 A-particles obtained by albumin or endosomal ion treatment and a control nonexpanded virion to 3.5, 3.3, and 2.9 Å resolution, respectively. Whereas albumin promoted stable expanded virions, the endosomal ionic concentrations induced unstable CVA9 virions which easily disintegrated, losing their genome. Loss of most of the VP4 molecules and exposure of negatively charged amino acid residues in the capsid's interior after expansion created a repulsive viral RNA-capsid interface, aiding genome release. IMPORTANCE Coxsackievirus A9 (CVA9) is a common cause of meningitis and neonatal sepsis. The triggers and mode of action of RNA release into the cell unusually do not require receptor interaction. Rather, a slow process in the endosome, independent of low pH, is required. Here, we show by biophysical separation, cryogenic electron microscopy, and image reconstruction that albumin and buffers mimicking the endosomal ion composition can separately and together expand and prime CVA9 for uncoating. Furthermore, we show in these expanded particles that VP4 is present at only ~10% of the occupancy found in the virion, VP1 is externalized, and the genome is repelled by the negatively charged, repulsive inner surface of the capsid that occurs due to the expansion. Thus, we can now link observations from cell biology of infection with the physical processes that occur in the capsid to promote genome uncoating.


Campylobacter jejuni in the stomach.
Campylobacter jejuni is the commonest cause of acute bacterial enteritis in the UK. However, in this case a 74-year-old lady underwent gastroscopy for an upper gastrointestinal haemorrhage and was noted to have a gastric ulcer. Gastric biopsy revealed spiral gram-negative bacteria and culture yielded a moderate growth of C. jejuni. Identification was confirmed by growth characteristics, biochemical tests and PCR amplification of the species-specific flagellin gene--fla A. To prevent misidentification, it is important that laboratories routinely culturing gastric biopsies for Helicobacter pylori should perform a rapid urease test and not rely solely on microscopic morphology.