Colorectal cancer and the Muir-Torre syndrome in a Gypsy family: a review.
The Muir-Torre syndrome (MTS) is characterized by an autosomal dominant predilection to sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas, in concert with the cancer phenotype of hereditary nonpolyposis colorectal cancer (HNPCC). Proof that patients showing a familial aggregation of MTS's cutaneous signs in combination with a specific pattern of visceral cancers which are consonant with an HNPCC diagnosis has been buttressed by the discovery of hMSH2 and hMLH1 germ-line mutations in such families. Our purpose in this investigation was to determine the germ-line mutation in a Gypsy family with MTS in concert with HNPCC cancer features, and to provide genetic counseling. An added objective for this paper is to review the literature on MTS. We describe a Gypsy family with MTS in concert with HNPCC cancer features, as well as the molecular genetic and genetic counseling procedures used in the interest of improved compliance with cancer control recommendations. We review the clinical phenotype, natural history, and molecular genetics involved in the MTS variant HNPCC. An hMSH2 germ-line mutation was identified as the culprit germ-line mutation in this family. The presence of the hMSH2 germ-line mutation in this family provides powerful predictability of colorectal and other HNPCC integral cancers. The gastroenterologist must assume an important role in the diagnosis and management of MTS.


On bus ridership and frequency.
Even before the start of the COVID-19 pandemic, bus ridership in the United States had attained its lowest level since 1973. If transit agencies hope to reverse this trend, they must understand how their service allocation policies affect ridership. This paper is among the first to model ridership trends on a hyper-local level over time. A Poisson fixed-effects model is developed to evaluate the ridership elasticity to frequency on weekdays using passenger count data from Portland, Miami, Minneapolis/St-Paul, and Atlanta between 2012 and 2018. In every agency, ridership is found to be elastic to frequency when observing the variation between individual route-segments at one point in time. In other words, the most frequent routes are already the most productive in terms of passengers per vehicle-trip. When observing the variation within each route-segment over time, however, ridership is inelastic; each additional vehicle-trip is expected to generate less ridership than the average bus already on the route. In three of the four agencies, the elasticity is a decreasing function of prior frequency, meaning that low-frequency routes are the most sensitive to changes in frequency. This paper can help transit agencies anticipate the marginal effect of shifting service throughout the network. As the quality and availability of passenger count data improve, this paper can serve as the methodological basis to explore the dynamics of bus ridership.


Compact polarization beam splitter assisted by subwavelength grating in triple-waveguide directional coupler.
A polarization beam splitter (PBS) is one of the key components for manipulating different polarization states in the areas of optical interconnection and communication. In this paper, a PBS with two coupling regions using a subwavelength grating (SWG) waveguide as a bridge is proposed and investigated on a 340-nm silicon-on-insulator platform. The PBS is designed with a triple-waveguide directional coupler consisting of two identical silicon waveguides and an SWG waveguide sandwiched between them. The tailorable dispersion relation of the SWG waveguide offers a flexible design freedom. With the optimized grating period and duty ratio, the input TE mode will experience efficient coupling between the silicon waveguide and the SWG waveguide, while the TM mode can directly pass through without influence. The results show that with a device length of 6.5 μm, the extinction ratios and insertion losses of the two modes are higher than 27 dB and lower than 0.3 dB at a wavelength of 1550 nm, respectively.


Beef in an Optimal Lean Diet study: effects on lipids, lipoproteins, and apolipoproteins.
A Step I diet with lean beef compared with lean white meat both decrease LDL cholesterol. To our knowledge, no studies have evaluated a low-saturated fatty acid (SFA) (<7% calories) diet that contains lean beef. We studied the effect on LDL cholesterol of cholesterol-lowering diets with varying amounts of lean beef [ie, Dietary Approaches to Stop Hypertension (DASH): 28 g beef/d; Beef in an Optimal Lean Diet (BOLD): 113 g beef/d; and Beef in an Optimal Lean Diet plus additional protein (BOLD+): 153 g beef/d] compared with that of a healthy American diet (HAD). Thirty-six hypercholesterolemic participants (with LDL-cholesterol concentrations >2.8 mmol/L) were randomly assigned to consume each of the 4 diets (HAD: 33% total fat, 12% SFA, 17% protein, and 20 g beef/d), DASH (27% total fat, 6% SFA, 18% protein, and 28 g beef/d), BOLD (28% total fat, 6% SFA, 19% protein, and 113 g beef/d), and BOLD+ (28% total fat, 6% SFA, 27% protein, and 153 g beef/d) for 5 wk. There was a decrease in total cholesterol (TC) and LDL-cholesterol concentrations (P < 0.05) after consumption of the DASH (-0.49 ± 0.11 and -0.37 ± 0.09 mmol/L, respectively), BOLD (-0.48 ± 0.10 and -0.35 ± 0.9 mmol/L, respectively), and BOLD+ (-0.50 ± 0.10 and -0.345 ± 0.09 mmol/L, respectively) diets compared with after consumption of the HAD (-0.22 ± 0.10 and -0.14 ± 0.10 mmol/L, respectively). Apolipoprotein A-I, C-III, and C-III bound to apolipoprotein A1 particles decreased after BOLD and BOLD+ diets compared with after the HAD, and there was a greater decrease in apolipoprotein B after consumption of the BOLD+ diet than after consumption of the HAD (P < 0.05 for both). LDL cholesterol and TC decreased after consumption of the DASH, BOLD, and BOLD+ diets when the baseline C-reactive protein (CRP) concentration was <1 mg/L; LDL cholesterol and TC decreased when baseline CRP concentration was >1 mg/L with the BOLD and BOLD+ diets. Low-SFA, heart-healthy dietary patterns that contain lean beef elicit favorable effects on cardiovascular disease (CVD) lipid and lipoprotein risk factors that are comparable to those elicited by a DASH dietary pattern. These results, in conjunction with the beneficial effects on apolipoprotein CVD risk factors after consumption of the BOLD and BOLD+ diets, which were greater with the BOLD+ diet, provide support for including lean beef in a heart-healthy dietary pattern. This trial was registered at clinicaltrials.gov as NCT00937898.


Gadolinium Complex for the Catch and Release of Phosphate from Water.
The ability of complexes of hard and labile metal ions with one or more open coordination sites to capture phosphates with high affinity and selectivity directly in water at neutral pH and release them under acidic conditions is evaluated with Gadolinium- 2,2',2''-(((nitrilotris(ethane-2,1-diyl))tris(azanediyl))tris(carbonyl))tris(4-oxo-4H-pyran-3-olate) (Gd-TREN-MAM). This model lanthanide complex has two open coordination sites that, at neutral pH, are filled with water molecules. In water at neutral pH, Gd-TREN-MAM binds phosphate with high affinity (Ka = 1.3 × 104) via the formation of a ternary complex in which one phosphate replaces both inner-sphere water molecules. The formation of this complex is highly pH-dependent; the phosphate is completely released from Gd-TREN-MAM below pH 2. Because the GdIII ion remains complexed by its ligand, even under strong acidic conditions, Gd-TREN-MAM can be used at least 10 times in a pH-based recycling scheme that enables the catch and release of one phosphate per cycle. Gd-TREN-MAM is highly selective for phosphate over other anions of environmental concerns, including HCO3-, HCO2-, CH3CO2-, SO42-, NO3-, NO2-, BrO3-, AsO4-, F-, Cl-, and Br- and, to a lesser extent, ClO3-. The development of such receptors that bind phosphate reversibly in a pH-dependent manner opens the possibility to design catch-and-release systems for the purification of surface waters.


Toxoplasma gondii Does Not Inhibit the Assisted Colonization of Eastern Barred Bandicoots (Perameles Gunnii) to Phillip Island, Victoria, Australia.
Eastern barred bandicoots (Perameles gunnii) are thought to be highly susceptible to disease caused by infection with the protozoan parasite Toxoplasma gondii. This study followed a population of 67 P. gunnii introduced onto the Summerland Peninsula, Phillip Island, Australia, where the prevalence of T. gondii infection in the feral cat population was known to be very high. Prior to release, bandicoots were tested for serologic exposure to T. gondii using the modified agglutination test. A subset of bandicoots was tested on four occasions after release onto the peninsula. No seroconversion was detected at any time point. A subset of bandicoots was radiotracked after release and at two additional trapping sessions to help monitor survival. Toxoplasma gondii DNA was not detected by PCR in eight carcasses recovered for necropsy. Fourteen founder bandicoots (21% of founders) were known to be alive at 500 d postrelease. A total of 29 unmarked bandicoots were trapped over the study period, confirming that the bandicoots were successfully reproducing on the island. Body weight, packed cell volume, and total plasma protein were used as measures of individual animal health; population health was inferred from these data. Body weight was significantly associated with trip number, with a general trend of increasing weight after release onto the island. This study showed that eastern barred bandicoots were able to establish a new population despite a probably high environmental load of T. gondii.


A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam.
The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.


Exploring Proxy Measures of Mutuality for Strategic Partnership Development: A Case Study.
Partnerships between academic and clinical-based health organizations are becoming increasingly important in improving health outcomes. Mutuality is recognized as a vital component of these partnerships. If partnerships are to achieve mutuality, there is a need to define what it means to partnering organizations. Few studies have described the elements contributing to mutuality, particularly in new relationships between academic and clinical partners. This study seeks to identify how mutuality is expressed and to explore potential proxy measures of mutuality for an alliance consisting of a hospital system and a School of Public Health. Key informant interviews were conducted with faculty and hospital representatives serving on the partnership steering committee. Key informants were asked about perceived events that led to the development of the Alliance; perceived goals, expectations, and outcomes; and current/future roles with the Alliance. Four proxy measures of mutuality for an academic-clinical partnership were identified: policy directives, community beneficence, procurement of human capital, and partnership longevity. Findings can inform the development of tools for assisting in strengthening relationships and ensuring stakeholders' interests align with the mission and goal of the partnership by operationalizing elements necessary to evaluate the progress of the partnership.


Using a Low-Risk Population to Estimate the Specificity of the World Heart Federation Criteria for the Diagnosis of Rheumatic Heart Disease.
The 2012 World Heart Federation (WHF) criteria set the minimum standards for echocardiographic diagnosis of rheumatic heart disease (RHD) in a high-risk population without history of acute rheumatic fever. The high sensitivity of the 2012 WHF criteria is well accepted, but the specificity cannot be directly assessed without a confirmatory test. The objective of this study was to estimate the false-positive rate of the WHF criteria through their application in a population at very low risk for RHD. The Children's National Health System echocardiography database was searched for patients (6-15 years of age) with an International Classification of Diseases, Ninth Revision, code for "chest pain." Chart review was performed; children with congenital heart disease or systemic disease were excluded. Patients were classified according to WHF criteria as having normal, borderline, or definite RHD on the basis of mitral and aortic valve morphology and the presence of pathologic mitral and/or aortic regurgitation. A total of 1,251 studies were identified, and 152 were excluded. Fifty studies were randomly chosen from each age, with equal gender distribution, for a total of 500 echocardiograms. No patients met the criteria for definite RHD and four (0.8%) for borderline RHD, both by pathologic mitral regurgitation. No patients met the criteria for borderline RHD on the basis of mitral valve morphology or pathologic aortic regurgitation. In a US pediatric population, no children had findings of definite RHD, and 0.8% had findings of borderline RHD, most likely representing false-positive results. Although there appears to be some overlap between the findings of borderline RHD and those in the normal pediatric population, our data suggest acceptable specificity for all RHD, with excellent specificity for definite RHD.


Cognitive behaviour therapy for adults with chronic fatigue syndrome.
1. To systematically review all randomised controlled trials of cognitive-behaviour therapy (CBT) for adults with chronic fatigue syndrome (CFS); 2. To test the hypothesis that CBT is more effective than orthodox medical management or other interventions in adults with CFS. 1. Electronic searching of bibliographic databases, including Medline, PsycLIT, Biological Abstracts, Embase, SIGLE, Index to Theses, Index to Scientific and Technical Proceedings, and Science Citation Index, using multiple search terms in order to perform a highly sensitive search. 2. Electronic searching of the Trials Register of the Depression, Anxiety and Neurosis group. 3. Citation lists of relevant studies and reviews were perused for other relevant trials. 4. Contact with the principal authors of relevant studies, and with researchers in the field. All randomised controlled trials were included in which - adult patients with CFS; - received CBT or a control intervention, being either orthodox medical management or another intervention; - and whose outcomes were assessed in an appropriate way. CBT could be either type 'A' (encouraging return to 'normal' levels of rest and activity) or type 'B' (encouraging rest and activity which were within levels imposed by the disorder). The two reviewers worked independently throughout the selection of trials and data extraction, comparing findings only when there was disagreement. Relevant trials were allocated to one of three quality categories. Full data extraction, using a standardised data extraction sheet, was performed on studies which were of high or moderate quality. Trials of low quality were excluded from the review. The comparisons made to test the review hypothesis were of type 'A' CBT versus other intervention(s), and of type 'B' CBT versus other intervention(s). Functional outcome was used as the main outcome for comparison, but other appropriate outcomes were compared where possible. Results were synthesised using the Review Manager software. For dichotomous data, the odds ratio was calculated for each study. For continuous data, effect sizes were obtained and the standardised mean difference, with 95% confidence intervals, was calculated. Only three relevant trials of adequate quality were found. These trials demonstrated that CBT significantly benefits physical functioning in adult out-patients with CFS when compared to orthodox medical management or relaxation. It is necessary to treat about two patients to prevent one additional unsatisfactory physical outcome about six months after treatment end. CBT appeared highly acceptable to the patients in these trials. There is no satisfactory evidence for the effectiveness of CBT in patients with the milder forms of CFS found in primary care or in patients who are so disabled that they are unable to attend out-patients. Additionally, there is no satisfactory evidence for the effectiveness of group CBT. Cognitive behaviour therapy appears to be an effective and acceptable treatment for adult out-patients with chronic fatigue syndrome. CFS is a common and disabling disorder. Its sufferers deserve the medical profession to be more aware of the potential of this therapy to bring lasting functional benefit, and health service managers to increase its availability. Further research is needed in this important area. Trials should conform to accepted standards of reporting and methodology. The effectiveness of CBT in more and less severely disabled patients than those usually seen in out-patient clinics needs to be assessed. Trials of group CBT and in-patient CBT compared to orthodox medical management, and of CBT compared to graded activity alone, also need to be conducted.


The effect of different socio-economic and working conditions on body size and proportions: A case study on adults from Samsun, Turkey.
Conditions in the early stages of life shape body size and proportions. This study includes individuals who came from different socio-economic conditions and worked in physically demanding jobs in childhood. By determining the body sizes of these individuals and evaluating the proportional relationships between several groups, the goal was to understand the effect levels of socio-economic levels and working conditions on the body. For this purpose, an anthropometric study was conducted on 623 males and females between the ages of 20 and 45 living in Samsun, Turkey. The study sample consisted of four different groups. It was divided into two main groups of high and low socio-economic level, and the low socio-economic group was divided into two subgroups of heavy-worker and nonheavy-worker. The results demonstrated that socio-economic differences in the size and proportions of the individuals were statistically significant (p<0.05). The high socio-economic group had the highest values in all measures. External factors affected the lower limbs more than the upper limbs. The measurement most affected by these factors was leg length. Longer legs characterized the high socio-economic group, while longer arms characterized both low socio-economic groups. The relative differences observed can be said to derive from the distal limbs. This finding was valid for both sexes. The average values were close to each other in the low socio-economic group, for which the aim was to comprehend the effects of heavy working conditions. However, differences in proportional relationships were more significant. In this context, it was seen that heavy labour also affected growth, in addition to the well-known factors encountered during the growth period, such as nutrition, health, and illness. The observed changes were more significant in males than in females. Thus, it can be said that males were more affected by physiological and physical conditions.


The developmental pattern of stimulus and response interference in a color-object Stroop task: an ERP study.
Several studies have shown that Stroop interference is stronger in children than in adults. However, in a standard Stroop paradigm, stimulus interference and response interference are confounded. The purpose of the present study was to determine whether interference at the stimulus level and the response level are subject to distinct maturational patterns across childhood. Three groups of children (6-7 year-olds, 8-9 year-olds, and 10-12 year-olds) and a group of adults performed a manual Color-Object Stroop designed to disentangle stimulus interference and response interference. This was accomplished by comparing three trial types. In congruent (C) trials there was no interference. In stimulus incongruent (SI) trials there was only stimulus interference. In response incongruent (RI) trials there was stimulus interference and response interference. Stimulus interference and response interference were measured by a comparison of SI with C, and RI with SI trials, respectively. Event-related potentials (ERPs) were measured to study the temporal dynamics of these processes of interference. There was no behavioral evidence for stimulus interference in any of the groups, but in 6-7 year-old children ERPs in the SI condition in comparison with the C condition showed an occipital P1-reduction (80-140 ms) and a widely distributed amplitude enhancement of a negative component followed by an amplitude reduction of a positive component (400-560 ms). For response interference, all groups showed a comparable reaction time (RT) delay, but children made more errors than adults. ERPs in the RI condition in comparison with the SI condition showed an amplitude reduction of a positive component over lateral parietal (-occipital) sites in 10-12 year-olds and adults (300-540 ms), and a widely distributed amplitude enhancement of a positive component in all age groups (680-960 ms). The size of the enhancement correlated positively with the RT response interference effect. Although processes of stimulus interference control as measured with the color-object Stroop task seem to reach mature levels relatively early in childhood (6-7 years), development of response interference control appears to continue into late adolescence as 10-12 year-olds were still more susceptible to errors of response interference than adults.


Dysnatremias in Chronic Kidney Disease: Pathophysiology, Manifestations, and Treatment.
The decreased ability of the kidney to regulate water and monovalent cation excretion predisposes patients with chronic kidney disease (CKD) to dysnatremias. In this report, we describe the clinical associations and methods of management of dysnatremias in this patient population by reviewing publications on hyponatremia and hypernatremia in patients with CKD not on dialysis, and those on maintenance hemodialysis or peritoneal dialysis. The prevalence of both hyponatremia and hypernatremia has been reported to be higher in patients with CKD than in the general population. Certain features of the studies analyzed, such as variation in the cut-off values of serum sodium concentration ([Na]) that define hyponatremia or hypernatremia, create comparison difficulties. Dysnatremias in patients with CKD are associated with adverse clinical conditions and mortality. Currently, investigation and treatment of dysnatremias in patients with CKD should follow clinical judgment and the guidelines for the general population. Whether azotemia allows different rates of correction of [Na] in patients with hyponatremic CKD and the methodology and outcomes of treatment of dysnatremias by renal replacement methods require further investigation. In conclusion, dysnatremias occur frequently and are associated with various comorbidities and mortality in patients with CKD. Knowledge gaps in their treatment and prevention call for further studies.


Characterization of the Reversible Intersystem Crossing Dynamics of Organic Photocatalysts Using Transient Absorption Spectroscopy and Time-Resolved Fluorescence Spectroscopy.
Thermally activated delayed fluorescence (TADF) emitters are molecules of interest as homogeneous organic photocatalysts (OPCs) for photoredox chemistry. Here, three classes of OPC candidates are studied in dichloromethane (DCM) or N,N-dimethylformamide (DMF) solutions, using transient absorption spectroscopy and time-resolved fluorescence spectroscopy. These OPCs are benzophenones with either carbazole (2Cz-BP and 2tCz-BP) or phenoxazine/phenothiazine (2PXZ-BP and 2PTZ-BP) appended groups and the dicyanobenzene derivative 4DP-IPN. Dual lifetimes of the S1 state populations are observed, consistent with reverse intersystem crossing (RISC) and TADF emission. Example fluorescence lifetimes in DCM are (5.18 ± 0.01) ns and (6.22 ± 1.27) μs for 2Cz-BP, (1.38 ± 0.01) ns and (0.32 ± 0.01) μs for 2PXZ-BP, and (2.97 ± 0.01) ns and (62.0 ± 5.8) μs for 4DP-IPN. From ground state bleach recoveries and time-correlated single photon counting measurements, triplet quantum yields in DCM are estimated to be 0.62 ± 0.16, 0.04 ± 0.01, and 0.83 ± 0.02 for 2Cz-BP, 2PXZ-BP, and 4DP-IPN, respectively. 4DP-IPN displays similar photophysical behavior to the previously studied OPC 4Cz-IPN. Independent of the choice of solvent, 4DP-IPN, 2Cz-BP, and 2tCz-BP are shown to be TADF emitters, whereas emission by 2PXZ-BP and 2PTZ-BP depends on the molecular environment, with TADF emission enhanced in aggregates compared to monomers. Behavior of this type is representative of aggregation-induced emission luminogens (AIEgens).


Comparison of Fasanella-Servat and Small-Incision Techniques for Involutional Ptosis Repair.
To compare the results of the classic Fasanella-Servat internal approach to the newer, small-incision external approach in the repair of involutional ptosis. Retrospective review identified 93 patients (104 surgical procedures) at Northwestern Ophthalmology from June 2005 until October 2011 who underwent either the Fasanella-Servat or the small-incision approaches for involutional ptosis repair. Change in vertical palpebral fissure measurement, change in marginal reflex distance 1 (MRD1) measurement, patient satisfaction, surgical complications, operating time, and postoperative pain were compared between groups. Of the 93 patients, most were female with an average age of 69 years. Of the procedures, 48% were small incision and 52% were Fasanella-Servat approaches. Average postoperative follow up was 34.0 days. Vertical palpebral fissure height increased an average of 3.36 mm (±1.15) in the Fasanella-Servat group and 2.74 mm (±1.18) in the small-incision group (p = 0.003). Preoperative vertical palpebral fissure height was lower in the Fasanella-Servat group, but postoperative vertical palpebral fissure height was similar between the 2 groups (p=0.3). MRD1 increased an average of 3.42 mm (±0.86) in the Fasanella-Servat group and 2.68 mm (±0.93) in the small-incision group (p < 0.01). Preoperative MRD1 was lower in the Fasanella-Servat group, but postoperative MRD1 was similar between the 2 groups (p = 0.15). Average operating time was 53 minutes (±16) in the small-incision group and 27 minutes (±6) in the Fasanella-Servat group (p < 0.01). There were no surgical complications in either group with equivalent patient satisfaction between the 2 groups. More patients reported postoperative pain in the Fasanella-Servat group (p < 0.0001). Both the Fasanella-Servat and small-incision approaches lead to good surgical outcomes with equivalent patient satisfaction, although the Fasanella-Servat approach provides a shorter average operating time with satisfactory postoperative MRD1.


Change in Mesoherbivore Browsing Is Mediated by Elephant and Hillslope Position.
Elephant are considered major drivers of ecosystems, but their effects within small-scale landscape features and on other herbivores still remain unclear. Elephant impact on vegetation has been widely studied in areas where elephant have been present for many years. We therefore examined the combined effect of short-term elephant presence (< 4 years) and hillslope position on tree species assemblages, resource availability, browsing intensity and soil properties. Short-term elephant presence did not affect woody species assemblages, but did affect height distribution, with greater sapling densities in elephant access areas. Overall tree and stem densities were also not affected by elephant. By contrast, slope position affected woody species assemblages, but not height distributions and densities. Variation in species assemblages was statistically best explained by levels of total cations, Zinc, sand and clay. Although elephant and mesoherbivore browsing intensities were unaffected by slope position, we found lower mesoherbivore browsing intensity on crests with high elephant browsing intensity. Thus, elephant appear to indirectly facilitate the survival of saplings, via the displacement of mesoherbivores, providing a window of opportunity for saplings to grow into taller trees. In the short-term, effects of elephant can be minor and in the opposite direction of expectation. In addition, such behavioural displacement promotes recruitment of saplings into larger height classes. The interaction between slope position and elephant effect found here is in contrast with other studies, and illustrates the importance of examining ecosystem complexity as a function of variation in species presence and topography. The absence of a direct effect of elephant on vegetation, but the presence of an effect on mesoherbivore browsing, is relevant for conservation areas especially where both herbivore groups are actively managed.


A common biological basis of obesity and nicotine addiction.
Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.


Divergent antibody responses to vaccines and divergent body weights of chicken lines selected for high and low humoral responsiveness to sheep red blood cells.
Primary and secondary antibody responses to intramuscularly administered proteins of Eschericia coli (F11), Newcastle disease virus (NCD), infectious bronchitis virus (IB), and infectious bursal disease virus (IBD), respectively, were measured at weekly intervals in two chicken lines. The latter had been divergently selected for high and low antibody responses to sheep red blood cells (SRBC), and in a random-bred control line. An oil-based adjuvant was required to induce primary and secondary antibody responses to NCD, IB, and IBD. With respect to F11, elevated antibody responses were found in birds sensitized and boosted to F11 with and without adjuvant. The humoral response to F11 and to all viral antigens was significantly higher in the high (H) line than in the low (L) line, whereas the control (C) line showed intermediate titers. At 5 and 17 weeks of age, L line birds were significantly heavier than birds of the H and the C lines. A negative phenotypic correlation within lines between body weight at 17 weeks of age and antibody titers at 1 week after sensitization was found, but no further correlations between humoral responses and body weight or growth could be established. The present results suggest that selection for enhanced humoral responsiveness to SRBC resulted in enhanced responsiveness to components of several vaccines. Mechanisms underlying the relationship between divergent selection for immune responsiveness and body weight are discussed.


Increased Lysosomal Membrane Permeabilization in Oxidant-exposed Macrophages of Human Fibrotic Lungs.
A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding.


Body composition and testosterone in men: a Mendelian randomization study.
Testosterone is an essential sex hormone that plays a vital role in the overall health and development of males. It is well known that obesity decreases testosterone levels, but it is difficult to determine the causal relationship between body composition and testosterone. To investigate potential causal associations between body composition and testosterone levels by a first time application of Mendelian randomization methods. Exposure variables in men included body composition (fat mass, fat-free mass, and body mass index). In addition to whole body fat and fat-free mass, we examined fat and fat-free mass for each body part (e.g., trunk, left arm, right arm, left leg and right leg) as exposures. Instrumental variables were defined using genome-wide association study data from the UK Biobank. Outcome variables in men included testosterone levels (total testosterone [TT], bioavailable testosterone [BT], and sex hormone-binding globulin [SHBG]). A one-sample Mendelian randomization analysis of inverse-variance weighted and weighted median was performed. The number of genetic instruments for the 13 exposure traits related to body composition ranged from 156 to 540. Genetically predicted whole body fat mass was negatively associated with TT (β=-0.24, P=5.2×10-33), BT (β=-0.18, P=5.8×10-20) and SHBG (β=-0.06, P=8.0×10-9). Genetically predicted whole body fat-free mass was negatively associated with BT (β=-0.04, P=2.1×10-4), but not with TT and SHBG, after multiple testing corrections. When comparing the causal effect on testosterone levels, there was a consistent trend that the effect of fat mass was more potent than that of fat-free mass. There were no differences between body parts. These results show that reducing fat mass may increase testosterone levels.


Behavioral Profiles of Adolescent Alcohol-Preferring/Non-preferring (P/NP) and High/Low Alcohol-Drinking (HAD/LAD) Rats Are Dependent on Line but Not Sex.
Initial contact with alcohol generally occurs during adolescence, and high consumption during this period is associated with increased risk for later alcohol (AUDs) and/or substance use disorders (SUDs). Rodents selectively bred for high or low alcohol consumption are used to identify behavioral characteristics associated with a propensity for high or low voluntary alcohol intake. The multivariate concentric square field™ (MCSF) is a behavioral test developed to study rodents in a semi-naturalistic setting. Testing in the MCSF creates a comprehensive behavioral profile in a single trial. The current aim was to examine the behavioral profiles of adolescent, bidirectionally selectively bred male and female high alcohol-consuming (P and HAD1/2) and low alcohol-consuming (NP and LAD1/2) rat lines, and outbred Wistar rats. Alcohol-naïve rats were tested once in the MCSF at an age between postnatal days 30 and 35. No common behavioral profile was found for either high or low alcohol-consuming rat lines, and the effect of sex was small. The P/NP and HAD2/LAD2 lines showed within pair-dependent differences, while the HAD1/LAD1 lines were highly similar. The P rats displayed high activity and risk-associated behaviors, whereas HAD2 rats displayed low activity, high shelter-seeking behavior, and open area avoidance. The results from P rats parallel clinical findings that denser family history and risk-taking behavior are strong predictors of future AUDs, often with early onset. Contrarily, the HAD2 behavioral profile was similar to individuals experiencing negative emotionality, which also is associated with a vulnerability to develop, often with a later onset, AUDs and/or SUDs.


How fatty acids of different chain length enter and leave cells by free diffusion.
Opposing views exist as to how unesterified fatty acids (FA) enter and leave cells. It is commonly believed that for short- and medium-chain FA free diffusion suffices whereas it is questioned whether proteins are required to facilitate transport of long-chain fatty acid (LCFA). Furthermore, it is unclear whether these proteins facilitate binding to the plasma membrane, trans-membrane movement, dissociation into the cytosol and/or transport in the cytosol. In this mini-review we approach the controversy from a different point of view by focusing on the membrane permeability constant (P) of FA with different chain length. We compare experimentally derived values of the P of short and medium-chain FA with values of apparent permeability coefficients for LCFA calculated from their dissociation rate constant (k(off)), flip-flop rate constant (k(flip)) and partition coefficient (Kp) in phospholipid bilayers. It was found that Overton's rule is valid as long as k(flip)<<k(off). With increasing chain length, the permeability increases according to increasing Kp and reaches a maximum for LCFA with chain length of 18 carbons or longer. For fast flip-flop (e.g. k(flip)=15s(-1)), the apparent permeability constant for palmitic acid is very high (P(app)=1.61 cm/s). Even for a slow flip-flop rate constant (e.g. k(flip)=0.3s(-1)), the permeability constant of LCFA is still several orders of magnitude larger than the P of water and other small non-electrolytes. Since polyunsaturated FA have basically the same physico-chemical properties as LCFA, they have similar membrane permeabilities. The implications for theories involving proteins to facilitate uptake of FA are discussed.


Role of ifosfamide in cervical cancer: an overview.
Ifosfamide, a cyclophosphamide analogue, has demonstrated a wide spectrum of activity against numerous neoplasms in different oncologic areas, including paediatric, haematological, breast, lung and testicular cancers, soft tissue sarcomas and gynaecological cancer. In gynaecologic cancers in particular, evidence suggests activity in the treatment of epithelial ovarian cancer, cervical carcinoma, germ cell carcinoma of the ovary. Cervical cancer has long been considered a poorly chemosensitive tumour and for several years the role of chemotherapy in the treatment of this tumour was confined to persistent or recurrent disease after failure of surgery and/or radiotherapy. In the management of cervical cancer, chemotherapy has received increasing attention in the last two decades and is currently used in neoadjuvant regimens, as salvage treatment in patients with disseminated or recurrent disease, or as a radiosensitizer. Over the past 30 years, several agents have been tested but cisplatin and ifosfamide are the agents that have attracted the greater attention. Cisplatin represents the cornerstone of chemotherapy for cervical cancer. Ifosfamide has been studied as a single agent or in combination with other drugs in different studies. In this paper we reviewed the approach with systemic therapy and, in particular, the role of ifosfamide in advanced or recurrent, and less advanced cervical cancer.


Photosynthesis, photoinhibition and low temperature acclimation in cold tolerant plants.
Cold acclimation requires adjustment to a combination of light and low temperature, conditions which are potentially photoinhibitory. The photosynthetic response of plants to low temperature is dependent upon time of exposure and the developmental history of the leaves. Exposure of fully expanded leaves of winter cereals to short-term, low temperature shiftsinhibits whereas low temperature growthstimulates electron transport capacity and carbon assimilation. However, the photosynthetic response to low temperature is clearly species and cultivar dependent. Winter annuals and algae which actively grow and develop at low temperature and moderate irradiance acquire a resistance to irradiance 5- to 6-fold higher than their growth irradiance. Resistance to short-term photoinhibition (hours) in winter cereals is a reflection of the increased capacity to keep QA oxidized under high light conditions and low temperature. This is due to an increased capacity for photosynthesis. These characteristics reflect photosynthetic acclimation to low growth temperature and can be used to predict the freezing tolerance of cereals. It is proposed that the enhanced photosynthetic capacity reflects an increased flux of fixed carbon through to sucrose in source tissue as a consequence of the combined effects of increased storage of carbohydrate as fructans in the vacuole of leaf mesophyll cells and an enhanced export to the crown due to its increased sink activity. Long-term exposure (months) of cereals to low temperature photoinhibition indicates that this reduction of photochemical efficiency of PS II represents a stable, long-term down regulation of PS II to match the energy requirements for CO2 fixation. Thus, photoinhibition in vivo should be viewed as the capacity of plants to adjust photosynthetically to the prevailing environmental conditions rather than a process which necessarily results in damage or injury to plants. Not all cold tolerant, herbaceous annuals use the same mechanism to acquire resistance to photoinhibition. In contrast to annuals and algae, overwintering evergreens become dormant during the cold hardening period and generally remain susceptible to photoinhibition. It is concluded that the photosynthetic response to low temperatures and susceptibility to photoinhibition are consequences of the overwintering strategy of the plant species.


The KEAP1-NRF2 System in Cancer.
Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2. Unregulated NRF2 confers on cancer cells high-level resistance to anticancer drugs and reactive oxygen species (ROS) and directs cancer cells toward metabolic reprogramming. Therefore, NRF2 has been studied as a therapeutic target molecule in cancer. Two strategies have been used to target NRF2 via therapeutic drugs: inhibition of NRF2 and induction of NRF2. NRF2 inhibitors may be effective against NRF2-addicted cancer cells in which NRF2 is aberrantly activated. These inhibitors have not yet been established as NRF2-targeted anticancer drugs for the treatment of human cancers. Diagnosis of NRF2 activation could facilitate the use of NRF2 inhibitors for the treatment of patients with NRF2-addicted cancers. Conversely, NRF2 inducers have been used or are being developed for non-cancer diseases. In addition, NRF2 inducers may be useful for cancer chemotherapy in combination with conventional anticancer agents or even NRF2 inhibitors.


[The fatty acid composition of the venous and arterial blood lipids in the complications in the acute period of myocardial infarct].
Lipid fatty-acid composition was determined as was the level of free cholesterol in serum and red cells of venous and arterial blood in patients with myocardial infarction presenting with certain complications. The most significant changes in fatty-acid composition of blood serum lipids were in pulmonary edema and pneumonia, with those in the cell lipid complex being recordable in cardiogenic shock and ventricular fibrillation. Fatty-acid composition of the arterial blood lipids is more balanced compared to the venous blood in pulmonary edema, cardiogenic shock, ventricular fibrillation; the opposite tendency is observed during the development of pneumonia.


The Khorana Score in Predicting Venous Thromboembolism for Patients With Metastatic Urothelial Carcinoma and Variant Histology Treated With Chemotherapy.
The Khorana score is a predictive risk model for venous thromboembolism (VTE) in patients with cancer planning to receive chemotherapy. Urothelial carcinoma and variant histologies (UC/VH) were underrepresented in the model. We sought to evaluate whether the Khorana score predicts for VTE in a retrospective multinational data set of patients with metastatic UC/VH. Patients diagnosed with metastatic UC/VH who received chemotherapy were eligible. Those with incomplete or miscoded data were excluded. Khorana scores were calculated based on the pretreatment data and categorized into high (≥3) or intermediate (1-2) VTE risk. Other patient-, tumor-, and therapy-related factors were also analyzed. The χ2 and logistic regression analyses were used to assess differences in VTE rates based on the clinical characteristics. Subgroup analyses were performed to evaluate the Khorana score and associated variables for early (<3 months) and late (>3 months) VTE. A total of 943 patients were eligible for analysis. The cumulative VTE rate was 9.9%. There was no statistical difference in overall VTE rate between Khorana high- and intermediate-risk groups ( P = .16). In the multivariate analysis, nonurothelial histology (odds ratio [OR] = 2.56; P = .002) and the presence of cardiovascular disease (CVD) or CVD risk factors (OR = 2.14; P = .002) were associated with increased VTE risk. In the first 3 months from initiation of chemotherapy, Khorana high risk (OR = 2.08; P = .04) was associated with higher VTE rates. White blood cell (WBC) count (OR = 1.05; P = .04) was the only significant Khorana variable for early VTE. The Khorana score stratifies early but not overall VTE risk in patients with metastatic UC/VH. The WBC count drives the increased early VTE risk seen with the Khorana score.


Chicken toll-like receptor 3 recognizes its cognate ligand when ectopically expressed in human cells.
Recognition of pathogens by toll-like receptors (TLRs) causes activation of signaling cascades that trigger cytokine secretion and, ultimately, innate immunity. Genes encoding proteins with substantial homology to mammalian TLR1, TLR2, TLR3, TLR4, TLR5, and TLR7 are present in the chicken genome, whereas orthologs of TLR8, TLR9, and TLR10 seem to be defective or missing. Except for chicken TLR2 (ChTLR2), which was previously shown to recognize lipopeptides and lipopolysaccharides (LPS), the ligand specificity of ChTLRs had not been determined. We found that polyI:C, LPS, R848, S-28463, and ODN2006, which are specifically recognized by TLR3, TLR4, TLR7/8, and TLR9 in mammals, induced substantial amounts of type I interferon (IFN) and interleukin-6 (IL-6) in freshly prepared chicken splenocytes. To determine the ligand specificity of ChTLR3 and ChTLR7, we used a standard reporter assay frequently employed for analysis of mammalian TLRs. Neither S-28463 nor any other TLR ligand induced reporter activity in human 293 cells expressing ChTLR7. However, human 293 cells expressing ChTLR3 strongly and specifically responded to polyI:C, demonstrating that this chicken receptor represents a true ortholog of mammalian TLR3.


Are Australian rural women aware of coronary heart disease?
Heart disease is the leading cause of morbidity and mortality in Australian women. In 2005, 109 000 women died of heart disease and 27 000 women died of breast cancer. The reported study sought to assess rural women's level of awareness of heart disease as the leading cause of death. A self-enumerated questionnaire designed to collect information on rural women's perception and awareness of heart disease was distributed to women attending a women's health clinic in a regional hospital. Of 65 participants, 13% (n = 8) identified heart disease as the most significant health problem. Sixty-four per cent of women participating in the study reported that breast cancer claims more lives than heart disease. The authors concluded that women do not perceive heart disease as a substantial health concern. Programmes directed at young women to improve their perception of risk for heart disease and to encourage them to make healthy lifestyle choices are required to reduce overall heart disease morbidity and mortality.


Materials processing routes to trap-free halide perovskites.
Photovoltaic devices based on lead iodide perovskite films have seen rapid advancements, recently achieving an impressive 17.9% certified solar power conversion efficiency. Reports have consistently emphasized that the specific choice of growth conditions and chemical precursors is central to achieving superior performance from these materials; yet the roles and mechanisms underlying the selection of materials processing route is poorly understood. Here we show that films grown under iodine-rich conditions are prone to a high density of deep electronic traps (recombination centers), while the use of a chloride precursor avoids the formation of key defects (Pb atom substituted by I) responsible for short diffusion lengths and poor photovoltaic performance. Furthermore, the lowest-energy surfaces of perovskite crystals are found to be entirely trap-free, preserving both electron and hole delocalization to a remarkable degree, helping to account for explaining the success of polycrystalline perovskite films. We construct perovskite films from I-poor conditions using a lead acetate precursor, and our measurement of a long (600 ± 40 nm) diffusion length confirms this new picture of the importance of growth conditions.


Regulation of coremium morphogenesis in Penicillium claviforme.
Coremia of Penicillium claviforme develop in three stages; primordium formation, elongation, and sporulation. Primordium formation was induced by external nutrients, while starvation initiated the differentiation of primordia into coremia with sporeheads. There is strong evidence that external nutrients are not taken up during this differentiation. Continued sporulation by mature coremia again required an external nutrient supply.


Melanoma vaccines, revisited: a review, update.
Melanoma vaccines are usually administered after surgical resection of the tumor with the hope of eradicating the micrometastases, in high-risk patients. As we previously reported, most of the melanoma vaccines failed to show any major impact on the disease, except for the autologous whole cell vaccine. This can be explained by the heterogeneous nature of cutaneous melanoma that expresses various levels of melanoma antigens, peptides and has various genetic profiles among different patients. From an immunological point of view, it is illogic to eliminate the tumor and its specific antigens then apply allogenic type of therapy and expect a tumor response. Therefore, it is more logical is to utilize the tumor site as a source for the tumor-specific antigens. In the meantime, patients with in-transit metastases can give us an excellent opportunity to evaluate the local and systemic effects of intralesional (intratumoral) therapy, and various agents have been utilized with equivocal results. On the other hand, intralesional administration of 2 cytokines seemed to process the tumor antigens and activates thymic-derived lymphocytes (T cells). This can induce an antitumor immune response in vivo, i.e., autoimmunization (auto-vaccination), specific to each patient, and overcome tumor heterogeneity regardless to its antigenic or genetic profiles.


Reactivation in post-traumatic chronic osteomyelitis: ultrasonographic findings.
To describe the ultrasound (US) features of reactivation in post-traumatic chronic osteomyelitis in adults. Twelve patients with clinical suspicion of reactivation of chronic osteomyelitis, secondary to trauma, surgery, and who were investigated with US were selected for the study. The following US features were assessed: periosseous fluid collection, bone changes (periosteal reactions, cortical irregularity, callus, sequestrum and cloaca) and soft-tissue changes (cellulitis and sinus tracts). US findings were correlated with plain radiography (n = 11), computed tomography (n = 3) and magnetic resonance imaging (n = 2). US detected fluid collections in all patients (12 periosseous and 3 in soft tissues), bone changes in 10 and sinus tracts and cellulitis in 5 patients each. Bone changes detected were cortical irregularity (n = 10), discontinuity of cortex (n = 7), sequestrum (n = 2), callus (n = 2), periosteal reaction (n = 1) and cloaca (n = 1). Cellulitis was seen in 5 patients and sinus tracts in 5. Reactivation was confirmed at surgery in all patients. US is a reliable noninvasive imaging modality for the diagnosis of reactivation of post-traumatic chronic osteomyelitis in adults.


[Combined endoscopic treatment of patients with prostatic adenoma].
We studied efficacy of combined surgical treatment of patients with prostatic adenoma (PA) including laser vaporization (LV) and transurethral electroresection (TUER). A total of 294 PA patients entered the trial. Photoselective LV was made with GreenLight PVP laser (80 W) in 180 patients and Dornier Urobeam laser on the basis of diode laser (940 nm) in 34 patients. The other 60 and 20 patients after photoselective LV (GreenLight PVP 80-W laser) and (Dornier Urobeam laser), respectively, have undergone TUER of coagulative-necrotic scab after vaporization. The analysis of the treatment results show that laser vaporization on both lasers is followed with dysuria in 26.6 and 32.4% patients, respectively, while in combination of LV with TUER - in 11.25% patients. Thus, the above combined endoscopic treatment can be recommended as most effective as it rapidly improves quality of life of the patients.


Expression of urease by Haemophilus influenzae during human respiratory tract infection and role in survival in an acid environment.
Nontypeable Haemophilus influenzae is a common cause of otitis media in children and lower respiratory tract infection in adults with chronic obstructive pulmonary disease (COPD). Prior studies have shown that H. influenzae expresses abundant urease during growth in the middle ear of the chinchilla and in pooled human sputum, suggesting that expression of urease is important for colonization and infection in the hostile environments of the middle ear and in the airways in adults. Virtually nothing else is known about the urease of H. influenzae, which was characterized in the present study. Analysis by reverse transcriptase PCR revealed that the ure gene cluster is expressed as a single transcript. Knockout mutants of a urease structural gene (ureC) and of the entire ure operon demonstrated no detectable urease activity indicating that this operon is the only one encoding an active urease. The ure operon is present in all strains tested, including clinical isolates from otitis media and COPD. Urease activity decreased as nitrogen availability increased. To test the hypothesis that urease is expressed during human infection, purified recombinant urease C was used in ELISA with pre acquisition and post infection serum from adults with COPD who experienced infections caused by H. influenzae. A total of 28% of patients developed new antibodies following infection indicating that H. influenzae expresses urease during airway infection. Bacterial viability assays performed at varying pH indicate that urease mediates survival of H. influenzae in an acid environment. The H. influenzae genome contains a single urease operon that mediates urease expression and that is present in all clinical isolates tested. Nitrogen availability is a determinant of urease expression. H. influenzae expresses urease during human respiratory tract infection and urease is a target of the human antibody response. Expression of urease enhances viability in an acid environment. Taken together, these observations suggest that urease is important for survival and replication of H. influenzae in the human respiratory tract.


Comparative study of the modeling of three-dimensional photonic bandgap structures.
A comparative study of theoretical models of different three-dimensional photonic bandgap (3D-PBG) structures has been performed, taking into account instability and convergence problems. Some rules for solving these problems and for reducing the computational time by finding symmetries in the structures are also explained. Finally, some applications produced by defects in 3D structures are shown by studying the creation of a complete bandgap in one of them and the variation of partial bandgaps in several 3D-PBG structures when several parameters of the defects, such as the number of layers stacked at each side of the defect, its thickness, and the real and imaginary parts of its index of refraction, are changed.


Nonparenchymal fluid is the source of increased mean diffusivity in preclinical Alzheimer's disease.
Although increased mean diffusivity of the white matter has been repeatedly linked to Alzheimer's disease pathology, the underlying mechanism is not known. Here, we used ADNI-3 multishell diffusion magnetic resonance imaging data to separate the diffusion signal of the parenchyma from less hindered fluid pools within the white matter such as perivascular space fluid and fluid-filled cavities. We found that the source of the pathological increase of the mean diffusivity is the increased nonparenchymal fluid, often found in lacunes and perivascular spaces. In this cohort, the cognitive decline was significantly associated with the fluid increase and not with the microstructural changes of the white matter parenchyma itself. The white matter fluid increase was dominantly observed in the sagittal stratum and anterior thalamic radiation. These findings are positive steps toward understanding the pathophysiology of white matter alteration and its role in the cognitive decline.


Intradural cervical disc herniation and Brown-Séquard's syndrome. Report of three cases and review of the literature.
Although cervical disc herniation commonly requires surgical intervention, the intradural sequestration of a herniated cervical disc fragment is rare. In searching the world literature on this topic, the authors found six case reports. They report three new cases of intradural cervical disc herniation in which the patients presented with Brown-Séquard's syndrome and they review the literature. Although Brown-Séquard's syndrome is a rare clinical finding in extradural disc herniation, six of the nine patients with intradural cervical disc herniation (our cases and those from the literature) presented with symptoms of this syndrome. The remaining patients presented with para- or quadriparesis. This suggests that intradural disc herniation should be considered preoperatively in patients in whom there is magnetic resonance imaging or myelographic evidence of cervical disc herniation and Brown-Séquard's syndrome. In patients who underwent anterior cervical discectomy for the treatment of intradural cervical disc herniations, better outcomes were demonstrated than in those in whom posterior procedures were performed.


OsCO3, a CONSTANS-LIKE gene, controls flowering by negatively regulating the expression of FT-like genes under SD conditions in rice.
The photoperiod is an important environmental stress that determines flowering time. The CONSTANS (CO) and Heading date 1 (Hd1) genes are known to be central integrators of the photoperiod pathway in Arabidopsis and rice, respectively. Although they are both members of the CONSTANS-LIKE (COL) family and have two B-boxes and a CCT domain, rice also possesses novel COL genes that are not found in Arabidopsis. Here, we demonstrate that a novel COL gene, OsCO3, containing a single B-box and a CCT domain, modulates photoperiodic flowering in rice. The circadian expression pattern of OsCO3 mRNA oscillated in a different phase from Hd1 and was similar to that of OsCO3 pre-mRNA, suggesting that the diurnal expression pattern of OsCO3 transcripts may be regulated at the transcriptional level. Overexpression of OsCO3 specifically caused late flowering under short day (SD) conditions relative to wild-type rice plants. The expression of Hd3a and FTL decreased in these transgenic plants, whereas the expression of Hd1, Early heading date 1 (Ehd1), OsMADS51, and OsMADS50 did not significantly change. Our results suggest that OsCO3 primarily controls flowering time under SD conditions by negatively regulating Hd3a and FTL expression, independent of the SD-promotion pathway.


Modulating postoperative insulin resistance by preoperative carbohydrate loading.
The concept of preoperative overnight fasting was challenged and proved to have no benefits over allowing patients to drink clear fluids up until 2 h before surgery. This led to changes in the guidelines for preoperative fasting in many countries around the world. This concept has more recently been developed further. Mounting evidence indicates that instead of being operated in the traditional overnight fasted state, undergoing surgery in the carbohydrate-fed state has many clinical benefits. Many of these clinical effects can be related to reduced postoperative insulin resistance by preoperative carbohydrate loading. This article summarises the present understanding of the mechanisms behind the positive clinical effects and gives an overview of the information available regarding the clinical effects of this treatment. Finally, the article summarises the most recently published national guidelines on preoperative fasting routines where preoperative carbohydrates are recommended for use before a major surgery. These are to be considered for all patients allowed to drink clear fluids and undergoing elective surgery.


Robotic and laparoscopic pelvic lymph node dissection for rectal cancer: short-term outcomes of 21 consecutive series.
The aim of this study is to describe our initial experience and assess the feasibility and safety of robotic and laparoscopic lateral pelvic node dissection (LPND) in advanced rectal cancer. Between November 2007 and November 2012, extended minimally invasive surgery for LPND was performed in 21 selected patients with advanced rectal cancer, including 11 patients who underwent robotic LPND and 10 who underwent laparoscopic LPND. Extended lymphadenectomy was performed when LPN metastasis was suspected on preoperative magnetic resonance imaging even after chemoradiation. All 21 procedures were technically successful without the need for conversion to open surgery. The median operation time was 396 minutes (range, 170-581 minutes) and estimated blood loss was 200 mL (range, 50-700 mL). The median length of stay was 10 days (range, 5-24 days) and time to removal of the urinary catheter was 3 days (range, 1-21 days). The median total number of lymph nodes harvested was 24 (range, 8-43), and total number of lateral pelvic lymph nodes was 7 (range, 2-23). Six patients (28.6%) developed postoperative complications; three with an anastomotic leakages, two with ileus and one patient with chyle leakage. Two patients (9.5%) developed urinary incontinence. There was no mortality within 30 days. During a median follow-up of 14 months, two patients developed lung metastasis and there was no local recurrence. Robotic and laparoscopic LPND is technically feasible and safe. Minimally invasive techniques for LPND in selected patients can be an acceptable alternative to an open LPND.


Smoke of cigarettes and little cigars: an analytical comparison.
Chemical data are presented from a comparison study of the smoke of cigarettes and little cigars. The tobacco products and their mainstream smokes were analyzed for a number of toxic constituents in an effort to define "smoke inhalability." This issue has particular public health importance because the difference in the inhalability of cigar and cigarette smoke is generally assumed to account for the differences in the health risk to the individual smoker.


Effects of radial head excision and distal radial shortening on load-sharing in cadaver forearms.
The present study was performed to measure changes in radioulnar load-sharing in the cadaveric forearm following two orthopaedic surgical procedures that often have varying results: radial head excision and distal radial shortening. A better understanding of the biomechanical consequences of those procedures could aid surgeons in obtaining a more satisfactory clinical outcome. Miniature load-cells were inserted into the proximal part of the radius and the distal part of the ulna in twenty fresh-frozen cadaveric forearms. Load-cell forces, radial head displacement relative to the capitellum, and local tension within the central band of the interosseous membrane were measured simultaneously as the wrist was loaded to 133.5 N in neutral pronation-supination and neutral radioulnar deviation. Testing was repeated after incremental distal radial shortening and after removal of the radial head. With the elbow flexed to 90 degrees and in valgus alignment (the radial head in contact with the capitellum), the mean force in the distal part of the ulna was 7.1% of the applied wrist force and the mean force in the interosseous membrane was 4.0%. With the elbow in varus alignment (a mean initial gap of 1.97 mm between the radial head and the capitellum), the respective mean values were 27.9% and 51.2%. After excision of the radial head, the mean force in the distal part of the ulna increased to 42.4% of the applied wrist force and the mean force in the interosseous membrane increased to 58.8%, in both varus and valgus elbow alignment. The mean distal ulnar force increased with progressive distal radial shortening in both varus and valgus elbow alignment; after 6 mm of radial shortening, the distal ulnar force averaged 92.4% (in varus alignment) and 60.9% (in valgus alignment). Equal distal load-sharing between the radius and ulna occurred after approximately 5 mm of radial shortening with the elbow in valgus alignment and after approximately 2 mm of radial shortening with the elbow in varus alignment. In valgus alignment, the force in the interosseous membrane was negligible after all degrees of radial shortening; in varus alignment, the mean force in the interosseous membrane decreased from 51.2% (0 mm of distal radial shortening) to 0% (6 mm of distal radial shortening) because of progressive slackening of the interosseous membrane. Radial head excision shifted the applied wrist force that normally would be transmitted to the elbow, through radial head-capitellar contact, to the interosseous membrane. The resulting proximal radial displacement created an ulnar-positive wrist and increased distal ulnar loading. Radial shortening and ulnar lengthening procedures have been designed to shift the applied wrist force from the distal part of the radius to the distal part of the ulna; it is commonly assumed that these procedures have equivalent biomechanical effects. We found that radial shortening resulted in slackening of the interosseous membrane, thereby negating its ability to transmit load through the forearm. Slackening of the interosseous membrane would not be expected with distal ulnar lengthening procedures. When the radial head has been fractured or excised, the mechanical status of the interosseous membrane is critical to the load-sharing process. If the interosseous membrane remains intact, distal ulnar loads will be limited to less than half of the applied wrist force; if the interosseous membrane has been damaged, nearly the entire applied wrist force will be shifted to the ulna. The amount of radial shortening or ulnar lengthening performed at the time of surgery during joint-leveling procedures has been largely empirical. We found that distal ulnar load increased by approximately 10% for each millimeter of radial shortening.


Sex-reversed correlation between stress levels and dominance rank in a captive non-breeder flock of crows.
Group living has both benefits and costs to individuals; benefits include efficient acquisition of resources, and costs include stress from social conflicts among group members. Such social challenges result in hierarchical dominance ranking among group members as a solution to avoid escalating conflict that causes different levels of basal stress between individuals at different ranks. Stress-associated glucocorticoid (corticosterone in rodents and birds; CORT) levels are known to correlate with dominance rank in diverse taxa and to covary with various social factors, such as sex and dominance maintenance styles. Although there is much evidence for sex differences in the basal levels of CORT in various species, the correlation of sex differences in basal CORT with dominance rank is poorly understood. We investigated the correlation between CORT metabolites (CM) in the droppings and social factors, including rank and sex, in a captive non-breeder group of crows. In this group, all the single males dominated all the single females, and dominance ranks were stable among single males but relatively unstable among single females. CM levels and rank were significantly correlated in a sex-reversed fashion: males at higher rank (i.e., more dominant) had higher CM, whereas females at higher rank exhibited lower CM. This is the first evidence of sex-reversed patterns of CM-rank correlation in birds. The results suggest that different mechanisms of stress-dominance relationships operate on the sexes in non-breeder crow aggregations; in males, stress is associated with the cost of aggressive displays, whereas females experience subordination stress due to males' overt aggression.


Cell wall attachment of a widely distributed peptidoglycan binding domain is hindered by cell wall constituents.
The C-terminal region (cA) of the major autolysin AcmA of Lactococcus lactis contains three highly similar repeated regions of 45 amino acid residues (LysM domains), which are separated by nonhomologous sequences. The cA domain could be deleted without destroying the cell wall-hydrolyzing activity of the enzyme in vitro. This AcmA derivative was capable neither of binding to lactococcal cells nor of lysing these cells while separation of the producer cells was incomplete. The cA domain and a chimeric protein consisting of cA fused to the C terminus of MSA2, a malaria parasite surface antigen, bound to lactococcal cells specifically via cA. The fusion protein also bound to many other Gram-positive bacteria. By chemical treatment of purified cell walls of L. lactis and Bacillus subtilis, peptidoglycan was identified as the cell wall component interacting with cA. Immunofluorescence studies showed that binding is on specific locations on the surface of L. lactis, Enterococcus faecalis, Streptococcus thermophilus, B. subtilis, Lactobacillus sake, and Lactobacillus casei cells. Based on these studies, we propose that LysM-type repeats bind to peptidoglycan and that binding is hindered by other cell wall constituents, resulting in localized binding of AcmA. Lipoteichoic acid is a candidate hindering component. For L. lactis SK110, it is shown that lipoteichoic acids are not uniformly distributed over the cell surface and are mainly present at sites where no MSA2cA binding is observed.


Molecular hydration of propofol dimers in supersonic expansions: formation of active centre-like structures.
Spectroscopic studies of molecular aggregates are a powerful tool to understand the weak interactions between molecules. Here, propofol2(H2O)6,7 clusters were formed in supersonic expansions and their electronic and infrared spectroscopy was explored using several mass-resolved laser-based spectroscopic techniques. Using REMPI, their S1 ← S0 electronic spectrum was obtained with vibrational resolution, while the UV/UV hole burning revealed the presence of a single isomer of propofol2(H2O)6 and of two isomers of propofol2(H2O)7. Employment of IR/UV double resonance yielded the IR spectrum in the OH stretch region. Comparison with the spectra predicted for the structures calculated at the M06-2X/6-31+G(d) level demonstrated that the two propofol molecules interact mainly through C-Hπ contacts between the lipophilic sides of the molecules, while the hydroxyl moieties are in close contact, forming a kind of "active centre" with which the water molecules interact, forming polyhedral structures.


Practice tip. Information scanning for GPs.
Information scanning is a very useful skill for general practitioners to have, whether the aim is to keep up-to-date for clinical reasons or to undertake research. It is both easy to learn and adaptable to your information needs. In this article we use a specific example to describe information scanning as GPs may use it, and then discuss the topic more broadly. We also provide some clues on keeping the information useful and manageable.


The role of cognitive and non-cognitive factors in mathematics achievement: The importance of the quality of the student-teacher relationship in middle school.
There is increasing evidence that several factors, including both cognitive and non-cognitive ones, play an important role in mathematics achievement. Relatively little is known about how socio-emotional features and the quality of the student-teacher relationship correlate with mathematics achievement among adolescents in transition to middle school. The aim of the present study is to examine the role of cognitive factors (general cognitive abilities), non-cognitive factors (math anxiety and self-esteem), and the quality of the student-teacher relationship on mathematics achievement. A large sample of Italian sixth graders was evaluated upon entering middle school. The results showed that general cognitive ability was the best predictor of mathematics achievement. As regards non-cognitive factors, the level of math anxiety was effective in predicting mathematics achievement, after controlling for other measures including self-esteem and the quality of the student-teacher relationship. In particular, we found that the quality of the student-teacher relationship had an indirect influence on mathematics achievement through the mediation of math anxiety. Our findings seem to indicate that the quality of the student-teacher relationship may be related to mathematics achievement, through its effects on math anxiety. This may have important implications for practitioners and educators, as we can suggest that interventions devoted to improving the quality of the student-teacher relationship may play a positive role in both preventing math anxiety and promoting mathematics learning.


Mobile ear-EEG to study auditory attention in everyday life : Auditory attention in everyday life.
Most research investigating auditory perception is conducted in controlled laboratory settings, potentially restricting its generalizability to the complex acoustic environment outside the lab. The present study, in contrast, investigated auditory attention with long-term recordings (> 6 h) beyond the lab using a fully mobile, smartphone-based ear-centered electroencephalography (EEG) setup with minimal restrictions for participants. Twelve participants completed iterations of two variants of an oddball task where they had to react to target tones and to ignore standard tones. A rapid variant of the task (tones every 2 s, 5 min total time) was performed seated and with full focus in the morning, around noon and in the afternoon under controlled conditions. A sporadic variant (tones every minute, 160 min total time) was performed once in the morning and once in the afternoon while participants followed their normal office day routine. EEG data, behavioral data, and movement data (with a gyroscope) were recorded and analyzed. The expected increased amplitude of the P3 component in response to the target tone was observed for both the rapid and the sporadic oddball. Miss rates were lower and reaction times were faster in the rapid oddball compared to the sporadic one. The movement data indicated that participants spent most of their office day at relative rest. Overall, this study demonstrated that it is feasible to study auditory perception in everyday life with long-term ear-EEG.


Lack of effect of clinical doses of cyclosporin A on erythrocyte Na+/K+-ATPase activity.
Cyclosporin A (CsA) may exert its cytotoxic effects by altering the activity of different plasma membrane transport systems. Although CsA may act at the gene level, it has been also suggested that it can directly alter transport processes at the plasma membrane. To examine this possibility in a physiological context, we determined Na(+)/K(+)-ATPase activity in erythrocytes from two groups of subjects receiving CsA treatment: group I consisted of kidney transplant patients, and group II comprised patients with steroid-resistant idiopathic nephrotic syndrome. Group I patients showed a marked decrease (35%) in the activity of the Na(+)/K(+)-ATPase in erythrocytes immediately after surgery, before the initiation of CsA treatment. The activity remained low 2 days after the introduction of CsA, but had recovered to the original (pre-surgery) value 1 month later. Group II patients showed the same pattern of erythrocyte Na(+)/K(+)-ATPase activity as those in group I. When the blood CsA levels from all patients were plotted against the corresponding erythrocyte Na(+)/K(+)-ATPase transport activity, a significant linear correlation was found. Higher levels of CsA in the blood were correlated significantly with increased Na(+)/K(+)-ATPase activities. The blood sodium concentration was also correlated positively with both erythrocyte Na(+)/K(+)-ATPase activity and blood CsA concentration. Thus CsA treatment is not associated with inhibition of the Na(+)/K(+)-ATPase in erythrocytes.


Assessing the diversity and specificity of two freshwater viral communities through metagenomics.
Transitions between saline and fresh waters have been shown to be infrequent for microorganisms. Based on host-specific interactions, the presence of specific clades among hosts suggests the existence of freshwater-specific viral clades. Yet, little is known about the composition and diversity of the temperate freshwater viral communities, and even if freshwater lakes and marine waters harbor distinct clades for particular viral sub-families, this distinction remains to be demonstrated on a community scale.To help identify the characteristics and potential specificities of freshwater viral communities, such communities from two lakes differing by their ecological parameters were studied through metagenomics. Both the cluster richness and the species richness of the Lake Bourget virome were significantly higher that those of the Lake Pavin, highlighting a trend similar to the one observed for microorganisms (i.e. the specie richness observed in mesotrophic lakes is greater than the one observed in oligotrophic lakes). Using 29 previously published viromes, the cluster richness was shown to vary between different environment types and appeared significantly higher in marine ecosystems than in other biomes. Furthermore, significant genetic similarity between viral communities of related environments was highlighted as freshwater, marine and hypersaline environments were separated from each other despite the vast geographical distances between sample locations within each of these biomes. An automated phylogeny procedure was then applied to marker genes of the major families of single-stranded (Microviridae, Circoviridae, Nanoviridae) and double-stranded (Caudovirales) DNA viruses. These phylogenetic analyses all spotlighted a very broad diversity and previously unknown clades undetectable by PCR analysis, clades that gathered sequences from the two lakes. Thus, the two freshwater viromes appear closely related, despite the significant ecological differences between the two lakes. Furthermore, freshwater viral communities appear genetically distinct from other aquatic ecosystems, demonstrating the specificity of freshwater viruses at a community scale for the first time.


Histidine supplementation suppresses food intake and fat accumulation in rats.
Histamine, a derivative of histidine, decreases food intake and body fat by activation of histamine neurons. Our objective was to clarify the effect of dietary histidine, in particular, on food intake and/or body fat accumulation in rats. Male Wistar rats were assigned to one of four groups after acclimation and allowed free access to diets containing 20% casein (0% histidine), 20% casein plus 1.0% histidine, 20% casein plus 2.5% histidine, or 20% casein plus 5% histidine for 8 d. Food intake and body weight were recorded daily and compared between groups. During the experimental period, food intake decreased according to the increases in dietary histidine. There was a negative and significant (P < 0.01) correlation between dietary histidine (grams per 8 d) and retroperitoneal fat pad (grams per 100 g of body weight). Uncoupling protein-1 mRNA in brown adipose tissue increased with increases in dietary histidine. Our results indicate that dietary histidine suppresses food intake and fat accumulation in rats.


Detecting information processing bias toward psychopathology: Interpreting Likert scales at intake assessment.
Since the programmatic Rosenhan study, there is a broad discussion of how to actively construct clinical realities on both "insane" and "sane" perspectives. To inform patients about the output of the psychometric questionnaires assessed at intake is a required task in many clinical routines. Information processing bias toward psychopathology may impact many clinical communications and thus lead to clinical errors. Based on an output of the commonly used Symptom Check List 90, case examples demonstrate various grades of balanced and unbalanced alternatives of how to consider the psychopathological as well as the unproblematic poles of Likert scales in discussing psychometric questionnaires at Session 1. We provide one clinical error related to client information at intake assessments and offer four therapeutic tasks that can serve as observable quality indicators of how to facilitate a balanced picture of the patients' burdens and capabilities: (1) validate individual problems, (2) isolate individual problems, (3) validate individual strengths, and (4) break through black and white thinking. (PsycINFO Database Record


Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown. We conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequency of exacerbations, health status, and spirometric values were also assessed. Of 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P=0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for comparisons between these treatments and placebo). The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients. (ClinicalTrials.gov number, NCT00268216 [ClinicalTrials.gov].).


The causes of esophageal symptoms in human immunodeficiency virus infection. A prospective study of 110 patients.
--To determine the prevalence of infectious agents in patients with human immunodeficiency virus infection and odynophagia or dysphagia; the utility of endoscopic, histologic, cytologic, and virologic testing for the diagnosis of esophagitis; and the yield of blind brushings of the esophagus in this setting. --Prospective clinical case study. --Urban county hospital. --One hundred ten consecutive patients with esophageal symptoms and documented human immunodeficiency virus infection. --Blind brushing of the esophagus via orogastric tube followed by endoscopy with esophageal brushing for fungal stain, Papanicolau smear, and viral cultures and esophageal biopsies for histologic examination and viral culture. --Seventy-two (65%) of the 110 patients had a total of 100 esophageal infections. Thirty-three (30%) had Candida alone, 22 (20%) had Candida and cytomegalovirus, two (1.8%) had Candida with cytomegalovirus and herpes simplex virus, seven (6%) had cytomegalovirus alone, six (5%) had herpes simplex virus alone, and two (1.8%) had both viruses. Fifty of 55 patients with plaques alone had Candida, and two (4%) had only viral infection. Of 19 patients with erosions or ulcers, 11 (58%) had a viral infection, two (11%) had Candida alone, and six (30%) had no etiologic agent identified. The sensitivity of endoscopic brushings (95%) was better than that of histologic examination (70%) in the diagnosis of Candida esophagitis. Likewise, viral cultures of brushings or biopsy specimens were more sensitive (67%) than histologic examination (35%) for viral esophagitis. Blind brushing of the esophagus had a sensitivity and specificity for infectious esophagitis of 84% and 75%, respectively. Oral thrush had a sensitivity of 53% and a positive predictive value of 77% for Candida esophagitis.


Review article: the role of hypotension in perioperative stroke.
A stroke is an uncommon but potentially devastating complication after surgery. Although hypoperfusion is often mentioned as a possible cause of a perioperative stroke, a thorough investigation is needed into the role of intraoperative and/or postoperative hypotension in the occurrence and development of perioperative cerebral ischemia. In this review article, we present an overview of the available literature on the possible role of hypotension in perioperative stroke, and we place these studies in a broader context. Perioperative strokes are most frequently thromboembolic in origin and commonly occur within the first 72 postoperative hours after a symptom-free interval. Case reports have shown a causal relationship between hypotension and perioperative stroke; nevertheless, many other factors contribute to its pathophysiology. Hypotension contributes as a primary factor or likely more frequently as a secondary factor in the development of a perioperative stroke. Among the main difficulties in studying this association is the lack of standardized definitions of perioperative hypotension, baseline blood pressure, and the length of the postoperative period. To guide future research, we propose a selection of problems to address in order to gain more insight into the problem of perioperative cerebral ischemia. Unusually low blood pressure will eventually result in neurological damage; however, the threshold and duration at which an association might be found between a perioperative stroke and hypotension have not been well investigated. Thus, the exact role of hypotension in the etiology of perioperative stroke is still largely unknown.


Chronic wasting disease prions are not transmissible to transgenic mice overexpressing human prion protein.
Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids, including mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD-infected cervids have been reported in 14 USA states, two Canadian provinces and in South Korea. The possibility of a zoonotic transmission of CWD prions via diet is of particular concern in North America where hunting of cervids is a popular sport. To investigate the potential public health risks posed by CWD prions, we have investigated whether intracerebral inoculation of brain and spinal cord from CWD-infected mule deer transmits prion infection to transgenic mice overexpressing human prion protein with methionine or valine at polymorphic residue 129. These transgenic mice have been utilized in extensive transmission studies of human and animal prion disease and are susceptible to BSE and vCJD prions, allowing comparison with CWD. Here, we show that these mice proved entirely resistant to infection with mule deer CWD prions arguing that the transmission barrier associated with this prion strain/host combination is greater than that observed with classical BSE prions. However, it is possible that CWD may be caused by multiple prion strains. Further studies will be required to evaluate the transmission properties of distinct cervid prion strains as they are characterized.


Chance or challenge, spoilt for choice? New recommendations on diagnostic and therapeutic considerations in hereditary transthyretin amyloidosis with polyneuropathy: the German/Austrian position and review of the literature.
Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTRv) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America. By stabilizing the TTR protein or degrading its mRNA, all types of treatment aim at preventing amyloid deposition and stopping the otherwise fatal course. Therefore, it is of utmost importance to recognize both onset and progression of neuropathy as early as possible. To establish recommendations for diagnostic and therapeutic procedures in the follow-up of both pre-symptomatic mutation carriers and patients with manifest ATTRv amyloidosis with polyneuropathy, German and Austrian experts elaborated a harmonized position. This paper is further based on a systematic review of the literature. Potential challenges in the early recognition of disease onset and progression are the clinical heterogeneity and the subjectivity of sensory and autonomic symptoms. Progression cannot be defined by a single test or score alone but has to be evaluated considering various disease aspects and their dynamics over time. The first-line therapy should be chosen based on individual symptom constellations and contra-indications. If symptoms worsen, this should promptly implicate to consider optimizing treatment. Due to the rareness and variability of ATTRv amyloidosis, the clinical course is most importantly directive in doubtful cases. Therefore, a systematic follow-up at an experienced center is crucial to identify progression and reassure patients and carriers.


Acute phenytoin intoxication in a 4-year-old mimicking viral meningoencephalitis.
We report here the case of a 4-year-old female preschooler who presented to the emergency department with generalised tonic-clonic convulsions and history of vomiting, irritability and dysarthria of short duration. On examination she was found to be responsive only to painful stimulus, had terminal neck stiffness and bilateral extensor plantars. In view of her clinical presentation, an initial diagnosis of viral meningoencephalitis was made in the emergency room and the child treated accordingly. On subsequent transfer to the intensive care unit (ICU), the parents revealed additional history of an elder sibling taking phenytoin for seizures. Therefore, a suspicion of acute phenytoin toxicity was made and phenytoin levels sent for confirmation. Her serum phenytoin level was 80 μgm/mL (normal: 10-20). The child was managed conservatively and discharged after 5 days of hospitalisation. We chose to report this case to highlight the unusual presentation of this rare intoxication.


B cell development and regulation after T cell-depleted marrow transplantation.
Antibody secreting B lymphocytes from immunized donors can be adoptively transferred after T cell-depleted marrow transplantation to produce protective levels of antibody in the recipient. We have investigated whether these transferred lymphocytes remain subject to continued clonal selection and subsequently became memory B cells even in the initial absence of T cells. Twenty-eight donor/recipient pairs were randomized pretransplant to be immunized or not with tetanus toxoid (TT). The recipients were then vaccinated with TT at 3, 6, and 12 mo posttransplant, and the anti-TT antibody response (IgG and IgM) was measured. Only when both donor and recipient were immunized pretransplant could the recipient respond to antigen challenge within the first year posttransplant. Examination of the spectrotype pattern of the recipient anti-TT antibody shows that selection of B cell clones continues, so that T cell depletion does not prevent the appearance of oligoclonal antibody responses. However, because the spectrotype pattern of the recipient did not match the donors, B cell regulatory mechanisms in donor and recipient are nonidentical. These data contrast with observations made in recipients of non-T cell-depleted marrow and serve to illustrate the role of T lymphocytes in the induction and regulation of secondary antibody responses in man. The results also suggest that optimal humoral responses to any antigen after T cell depletion can only occur when both donor and recipient are immunized pretransplant, a prediction borne out by studies on the influence of donor cytomegalovirus status on the severity of cytomegalovirus infection in the recipient.


Role of clusterin gene 3'-UTR polymorphisms and promoter hypomethylation in the pathogenesis of pseudoexfoliation syndrome and pseudoexfoliation glaucoma.
Pseudoexfoliation (PEX) is a multifactorial age-related disease characterized by the deposition of extracellular fibrillar aggregates in the anterior ocular tissues. This study aims to identify the genetic and epigenetic contribution of clusterin (CLU) in PEX pathology. CLU is a molecular chaperone upregulated in PEX and genetically associated with the disease. Sequencing of a 2.9 kb region encompassing the previously associated rs2279590 in 250 control and 313 PEX [(207 pseudoexfoliation syndrome (PEXS) and 106 pseudoexfoliation glaucoma (PEXG)] individuals identified three single nucleotide polymorphisms (SNPs), rs9331942, rs9331949 and rs9331950, in the 3'-UTR of CLU of which rs9331942 and rs9331949 were found to be significantly associated with PEXS and PEXG as risk factors. Following in silico analysis, in vitro luciferase reporter assays in human embryonic kidney cells revealed that risk alleles at rs9331942 and rs9331949 bind to miR-223 and miR-1283, respectively, suggesting differential regulation of clusterin in the presence of risk alleles at the SNPs. Further, through bisulfite sequencing, we also identified that CLU promoter is hypomethylated in DNA from blood and lens capsules of PEX patients compared to controls that correlated with decreased expression of DNA methyltransferase 1 (DNMT1). Promoter demethylation of CLU using DNMT inhibitor, 5'-aza-dC, in human lens epithelial cells increased CLU expression. Chromatin immunoprecipitation assays showed that the demethylated CLU promoter provides increased access to the transcription factor, Sp1, which might lead to enhanced expression of CLU. In conclusion, this study highlights the different molecular mechanisms of clusterin regulation in pseudoexfoliation pathology.