Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption.
Abaloparatide, a novel PTH1 receptor agonist, increased bone formation in osteopenic ovariectomized cynomolgus monkeys while increasing cortical and trabecular bone mass. Abaloparatide increased bone strength and maintained or enhanced bone mass-strength relationships, indicating preserved or improved bone quality. Abaloparatide is a selective PTH1R activator that is approved for the treatment of postmenopausal osteoporosis. The effects of 16 months of abaloparatide administration on bone formation, resorption, density, and strength were assessed in adult ovariectomized (OVX) cynomolgus monkeys (cynos). Sixty-five 9-18-year-old female cynos underwent OVX surgery, and 15 similar cynos underwent sham surgery. After a 9-month period without treatments, OVX cynos were allocated to four groups that received 16 months of daily s.c. injections with either vehicle (n = 17) or abaloparatide (0.2, 1, or 5 μg/kg/day; n = 16/dose level), while Sham controls received s.c. vehicle (n = 15). Bone densitometry (DXA, pQCT, micro-CT), qualitative bone histology, serum calcium, bone turnover markers, bone histomorphometry, and bone strength were among the key measures assessed. At the end of the 9-month post-surgical bone depletion period, just prior to the treatment phase, the OVX groups exhibited increased bone turnover markers and decreased bone mass compared with sham controls. Abaloparatide administration to OVX cynos led to increased bone formation parameters, including serum P1NP and endocortical bone formation rate. Abaloparatide administration did not influence serum calcium levels, bone resorption markers, cortical porosity, or eroded surfaces. Abaloparatide increased bone mass at the whole body, lumbar spine, tibial diaphysis, femoral neck, and femoral trochanter. Abaloparatide administration was associated with greater lumbar vertebral strength, and had no adverse effects on bone mass-strength relationships for the vertebrae, femoral neck, femoral diaphysis, or humeral cortical beams. Abaloparatide administration was associated with increases in bone formation, bone mass and bone strength, and with maintenance of bone quality in OVX cynos, without increases in serum calcium or bone resorption parameters.


Predicting accrual achievement: monitoring accrual milestones of NCI-CTEP-sponsored clinical trials.
The need to increase the number oncology clinical trials with sufficient enrollments is a well-known issue, particularly for trials targeting therapeutic applications. It is critical to identify early predictors of eventual study accrual achievement. All nonpediatric phase I, I/II, II, and III therapeutic studies supported by the National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) between 2000 and 2007 (n = 764) were analyzed for accrual performance. Accrual achievement is defined as those enrolling 100% or more of the stated minimum accrual goal at the time of trial closure. Two accrual milestones were analyzed per trial: time to first patient enrollment and expected time to accrual goal. Multivariate logistic regression analysis was used to calculate the OR with respect to the likelihood of clinical trial accrual achievement. A total of 81.5% (n = 623) of the trials did not achieve the projected accrual goals within the anticipated accruing period. Furthermore, 37.2% (n = 284) of trials failed to achieve the minimum projected accrual at study closure regardless of time the trial was open. Trials that accrue the first enrollment beyond 2 months (n = 379, 49.6%) are significantly less likely to achieve the accrual performance than those trials that enroll patients under 2 months (OR: 0.637, 95% CI: 0.464-0.875, P = 0.005). Of the studies that are open beyond the anticipated enrollment period (n = 603), those do not achieve at least 60.0% of the projected minimum accrual (n = 391, 64.8%) have a significantly less likelihood of achieving final accruals by study closure (OR: 0.190, 95% CI: 0.055-0.652, P = 0.008). The time to first patient enrollment and expected time to accrual goal are shown to be valid measures to evaluate the likelihood of achieving the minimum projected accrual.


The association of Klotho gene polymorphism with the mortality of patients on maintenance dialysis.
Despite medical progress, high morbidity and mortality rates have persisted in patients with end-stage renal disease (ESRD). The role in atherosclerosis and cardiovascular disease of klotho, an aging process-related gene, has been highlighted. Genetic variation in klotho has been reported to be a risk factor for coronary artery disease and ischemic stroke. Regarding the significance of cardiovascular disease for the outcome of ESRD patients, we investigated whether genetic variation of klotho was associated with mortality in ESRD patients on hemodialysis. 478 patients on maintenance hemodialysis for more than 3 months at dialysis facilities affiliated with the Western Dialysis Physician Association were enrolled in September 2004. Patient survival was checked annually until September 2007. Genotypings of klotho in terms of G395A in the promoter region, C1818T in exon 4, and KL-VS was performed. 45 deaths (11.2%) occurred over 3 years. Mortality was higher in the GA+AA group than in the GG group (18.9% vs. 6.7%, respectively, p < 0.001). Kaplan-Meier analysis also revealed that the survival of the GA+AA group was worse than that of GG group (p = 0.002). Cox's proportional hazards regression analysis showed that age, A allele carrier status in G395A of klotho, hemoglobin, albumin and HDL cholesterol levels were the significant factors affecting survival of hemodialysis patients. The A allele of the G395A polymorphism of klotho may be associated with the risk of mortality in Korean hemodialysis patients. Age, hemoglobin, albumin and HDLC were also significant prognostic factors for survival in the present study.


Development and validation of a LC-MS/MS method for the in vitro analysis of 1-hydroxymidazolam in human liver microsomes: application for determining CYP3A4 inhibition in complex matrix mixtures.
Complementary and alternative medicines (CAM) can affect the pharmacokinetics of anticancer drugs by interacting with the metabolizing enzyme cytochrome P450 (CYP) 3A4. To evaluate changes in the activity of CYP3A4 in patients, levels of 1-hydroxymidazolam in plasma are often determined with liquid chromatography-quadrupole mass spectrometry (LC-MS/MS). However, validated LC-MS/MS methods to determine in vitro CYP3A4 inhibition in human liver microsomes are scarce and not optimized for evaluating CYP3A4 inhibition by CAM. The latter is necessary because CAM are often complex mixtures of numerous compounds that can interfere with the selective measurement of 1-hydroxymidazolam. Therefore, the aim was to validate and optimize an LC-MS/MS method for the adequate determination of CYP3A4 inhibition by CAM in human liver microsomes. After incubation of human liver microsomes with midazolam, liquid-liquid extraction with tert-butyl methyl ether was applied and dried samples were reconstituted in 50% methanol. These samples were injected onto a reversed-phase chromatography consisting of a Zorbax Extend-C18 column (2.1 × 150 mm, 5.0 µm particle size), connected to a triple quadrupole mass spectrometer with electrospray ionization. The described LC-MS/MS method was validated over linear range of 1.0-500 nm for 1-hydroxymidazolam. The results revealed good inter-assay accuracy (≥85% and ≤115%) and within-day and between-day precisions (coefficient of variation ≤ 4.43%). Furthermore, the applicability of this assay for the determination of CYP3A4 inhibition in complex matrix mixtures was successfully demonstrated in an in vitro experiment in which CYP3A4 inhibition by known CAM (β-carotene, green tea, milk thistle and St. John's wort) was determined.


Insulin rather than glucose homoeostasis in the pathophysiology of diabetes.
Hepatic glucose efflux is very sensitive to changes in plasma-insulin and it is postulated that this provides an important feedback control of insulin secretion. In diabetes this hepatic "insulin sensor" increases the basal plasma-glucose until the impaired beta cells are sufficiently stimulated to secrete normal basal insulin concentrations. Glucose regulation thus becomes of secondary importance to the maintenance of basal insulin secretion, which is teleologically needed for the "anabolic" requirements of cell growth. This hypothesis provides an explanation for the "normal" basal plasma-insulin concentrations found in diabetes in spite of impaired beta-cell function. This maintenance of basal insulin secretion accounts for the discrepancy between the marked hyperglycaemia and minimal ketosis of maturity onset diabetic patients.


Radiographic technique and brackets affect measurements of proximal enamel thickness on mandibular incisors.
To investigate the influence of radiographic film and tube positioning, the presence and the size of brackets on in vitro measurements of proximal enamel thickness of mandibular incisors on periapical radiographs aimed to aid planning of interproximal enamel reduction procedures in orthodontics. Eighty human mandibular incisors were assigned to sets of four and located in a customized base. Periapical radiographs were taken with the film positioned at three different angles (0°, 2°, and 5°) in relation to the frontal plane and the tube head positioned at five angles (0°, -2°, -5°, +2°, and +5°) in relation to the sagittal plane. The proximal enamel width was calculated by means of computerized image analysis and compared with measurements obtained at 0°. Statistical analysis was carried out to compare the enamel measurements on radiographs made with all angular combinations with and without the presence of brackets of different dimensions. A significant difference (P < 0.05) was found between the measurements of proximal enamel width obtained at the different angles in relation to the frontal and sagittal planes for all sets with or without brackets. The presence of brackets significantly affected the measured width only for the enamel side further away from the radiation source at the sagittal plane (P < 0.05). Angular changes in taking periapical radiographs of mandibular incisors and the presence of brackets significantly affect interproximal enamel measurements made with image analysis software.


Specificity in protein-protein interactions: the structural basis for dual recognition in endonuclease colicin-immunity protein complexes.
Bacteria producing endonuclease colicins are protected against their cytotoxic activity by virtue of a small immunity protein that binds with high affinity and specificity to inactivate the endonuclease. DNase binding by the immunity protein occurs through a "dual recognition" mechanism in which conserved residues from helix III act as the binding-site anchor, while variable residues from helix II define specificity. We now report the 1.7 A crystal structure of the 24.5 kDa complex formed between the endonuclease domain of colicin E9 and its cognate immunity protein Im9, which provides a molecular rationale for this mechanism. Conserved residues of Im9 form a binding-energy hotspot through a combination of backbone hydrogen bonds to the endonuclease, many via buried solvent molecules, and hydrophobic interactions at the core of the interface, while the specificity-determining residues interact with corresponding specificity side-chains on the enzyme. Comparison between the present structure and that reported recently for the colicin E7 endonuclease domain in complex with Im7 highlights how specificity is achieved by very different interactions in the two complexes, predominantly hydrophobic in nature in the E9-Im9 complex but charged in the E7-Im7 complex. A key feature of both complexes is the contact between a conserved tyrosine residue from the immunity proteins (Im9 Tyr54) with a specificity residue on the endonuclease directing it toward the specificity sites of the immunity protein. Remarkably, this tyrosine residue and its neighbour (Im9 Tyr55) are the pivots of a 19 degrees rigid-body rotation that relates the positions of Im7 and Im9 in the two complexes. This rotation does not affect conserved immunity protein interactions with the endonuclease but results in different regions of the specificity helix being presented to the enzyme.


Goal internalization and persistence as a function of autonomous and directive forms of goal support.
Two prospective studies examined the relations of autonomy support and directive support to goal internalization and goal persistence over a year. Study 1 examined the role of support and internalization in semester-long goals set by college students and whether the goals were reset in the following semester. Study 2 examined semester-long goals and long-term developmental goals. Study 1 showed that autonomy support was not only significantly associated with greater internalization and goal success in the fall semester, but it was also significantly associated with actually resetting and subsequently succeeding at goals that one had failed to reach. Study 2 showed that autonomy support was significantly associated with progress for short-term goals over the semester, whereas directive support was unrelated to progress. For long-term goals, autonomy support was significantly related to greater internalization of goals and to greater goal satisfaction, whereas directive support was significantly negatively related to these outcomes. These studies point to the beneficial effects of autonomy support on goal internalization and resilient persistence. The effects of directive support (null vs. negative) were moderated by the timeline of the goals.


Mediterranean diet and Alzheimer disease mortality.
We previously reported that the Mediterranean diet (MeDi) is related to lower risk for Alzheimer disease (AD). Whether MeDi is associated with subsequent AD course and outcomes has not been investigated. To examine the association between MeDi and mortality in patients with AD. A total of 192 community-based individuals in New York who were diagnosed with AD were prospectively followed every 1.5 years. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of mortality in Cox models that were adjusted for period of recruitment, age, gender, ethnicity, education, APOE genotype, caloric intake, smoking, and body mass index. Eighty-five patients with AD (44%) died during the course of 4.4 (+/-3.6, 0.2 to 13.6) years of follow-up. In unadjusted models, higher adherence to MeDi was associated with lower mortality risk (for each additional MeDi point hazard ratio 0.79; 95% CI 0.69 to 0.91; p = 0.001). This result remained significant after controlling for all covariates (0.76; 0.65 to 0.89; p = 0.001). In adjusted models, as compared with AD patients at the lowest MeDi adherence tertile, those at the middle tertile had lower mortality risk (0.65; 0.38 to 1.09; 1.33 years' longer survival), whereas subjects at the highest tertile had an even lower risk (0.27; 0.10 to 0.69; 3.91 years' longer survival; p for trend = 0.003). Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose-response effect.


Effect of preexisting FeLV infection or FeLV and feline immunodeficiency virus coinfection on pathogenicity of the small variant of Haemobartonella felis in cats.
To investigate the effects of preexisting FeLV infection or FeLV and feline immunodeficiency (FIV) coinfection on the pathogenicity of the small variant of Haemobartonella felis (Hfsm, California variant) in cats. 20 FeLV infected, 5 FeLV-FIV coinfected, and 19 retrovirus-free cats. A client-owned cat, coinfected with FeLV and Hfsm, was the source for Hfsm. Inoculum 1 (FeLV free) was obtained by passage of source Hfsm through 4 FeLV-resistant cats. Inoculum 2 was obtained by further passage of Hfsm (inoculum 1) through 2 specific pathogen-free cats. A mild-to-moderate anemia started 21 days after inoculation, with its nadir occurring at 35 to 42 days after inoculation. Infection with Hfsm induced greater decrease in hemoglobin concentration in FeLV infected cats, compared with retrovirus free cats. Reticulocytosis, macrocytosis, and polychromasia of erythrocytes developed in anemic cats regardless of retrovirus infection status. Mean neutrophil counts decreased during the hemolytic episode. For most cats, the anemia was transient. Four FeLV infected cats, 1 of which was also FIV infected, developed fatal FeLV-associated myeloproliferative diseases. Of the surviving cats, 8 died over the next 24 months from other FeLV-related diseases. Hemolysis did not recur after the initial episode. Inoculum 1 induced more severe anemia than inoculum 2. Our results support the clinical observation that cats coinfected with FeLV and H felis develop more severe anemia than cats infected with H felis alone. Infection with Hfsm may induce myeloproliferative disease in FeLV infected cats. The small variant of H felis may lose pathogenicity by passage through FeLV-free cats.


Comparison of sum absolute QRST integral, and temporal variability in depolarization and repolarization, measured by dynamic vectorcardiography approach, in healthy men and women.
Recently we showed the predictive value of sum absolute QRST integral (SAI QRST) and repolarization lability for risk stratification of sudden cardiac death (SCD) in heart failure patients. The goal of this study was to compare SAI QRST and metrics of depolarization and repolarization variability in healthy men and women. Orthogonal ECGs were recorded at rest for 10 minutes in 160 healthy men and women (mean age 39.6±14.6, 80 men). Mean spatial TT' angle, and normalized variances of T loop area, of spatial T vector amplitude, of QT interval and Tpeak-Tend area were measured for assessment of repolarization lability. Normalized variances of spatial QRS vector and QRS loop area characterized variability of depolarization. In addition, variability indices (VI) were calculated to adjust for normalized heart rate variance. SAI QRST was measured as the averaged arithmetic sum of areas under the QRST curve. Men were characterized by shorter QTc (430.3±21.7 vs. 444.7±22.2 ms; P<0.0001) and larger SAI QRST (282.1±66.7 vs. 204.9±58.5 mV*ms; P<0.0001). Repolarization lability negatively correlated with spatial T vector amplitude. Adjusted by normalized heart rate variance, QT variability index was significantly higher in women than in men (-1.54±0.38 vs. -1.70±0.33; P = 0.017). However, in multivariate logistic regression after adjustment for body surface area, QTc, and spatial T vector amplitude, healthy men had 1.5-3 fold higher probability of having larger repolarization lability, as compared to healthy women (T vector amplitude variability index odds ratio 3.88 (95%CI 1.4-11.1; P = 0.012). Healthy men more likely than women have larger repolarization lability.


Isolation of High Quality Murine Atrial and Ventricular Myocytes for Simultaneous Measurements of Ca2+ Transients and L-Type Calcium Current.
Mouse models play a crucial role in arrhythmia research and allow studying key mechanisms of arrhythmogenesis including altered ion channel function and calcium handling. For this purpose, atrial or ventricular cardiomyocytes of high quality are necessary to perform patch-clamp measurements or to explore calcium handling abnormalities. However, the limited yield of high-quality cardiomyocytes obtained by current isolation protocols does not allow both measurements in the same mouse. This article describes a method to isolate high-quality murine atrial and ventricular myocytes via retrograde enzyme-based Langendorff perfusion, for subsequent simultaneous measurements of calcium transients and L-type calcium current from one animal. Mouse hearts are obtained, and the aorta is rapidly cannulated to remove blood. Hearts are then initially perfused with a calcium-free solution (37 °C) to dissociate the tissue at the level of intercalated discs and afterwards with an enzyme solution containing little calcium to disrupt extracellular matrix (37 °C). The digested heart is subsequently dissected into atria and ventricles. Tissue samples are chopped into small pieces and dissolved by carefully pipetting up and down. The enzymatic digestion is stopped, and cells are stepwise reintroduced to physiologic calcium concentrations. After loading with a fluorescent Ca2+-indicator, isolated cardiomyocytes are prepared for simultaneous measurement of calcium currents and transients. Additionally, isolation pitfalls are discussed and patch-clamp protocols and representative traces of L-type calcium currents with simultaneous calcium transient measurements in atrial and ventricular murine myocytes isolated as described above are provided.


Enabling Stroke Rehabilitation in Home and Community Settings: A Wearable Sensor-Based Approach for Upper-Limb Motor Training.
High-dosage motor practice can significantly contribute to achieving functional recovery after a stroke. Performing rehabilitation exercises at home and using, or attempting to use, the stroke-affected upper limb during Activities of Daily Living (ADL) are effective ways to achieve high-dosage motor practice in stroke survivors. This paper presents a novel technological approach that enables 1) detecting goal-directed upper limb movements during the performance of ADL, so that timely feedback can be provided to encourage the use of the affected limb, and 2) assessing the quality of motor performance during in-home rehabilitation exercises so that appropriate feedback can be generated to promote high-quality exercise. The results herein presented show that it is possible to detect 1) goal-directed movements during the performance of ADL with a [Formula: see text]-statistic of 87.0% and 2) poorly performed movements in selected rehabilitation exercises with an [Formula: see text]-score of 84.3%, thus enabling the generation of appropriate feedback. In a survey to gather preliminary data concerning the clinical adequacy of the proposed approach, 91.7% of occupational therapists demonstrated willingness to use it in their practice, and 88.2% of stroke survivors indicated that they would use it if recommended by their therapist.


Proxy and self-report agreement on the Stroke and Aphasia Quality of Life Scale-39.
Health related quality of life outcomes are increasingly used to measure the effectiveness of stroke interventions. People with severe aphasia after stroke may be unable to self-report on such measures, necessitating the use of proxy respondents. We explored the level of agreement between people with aphasia (PWA) and their proxies on the Stroke and Aphasia Quality of Life Scale (SAQOL-39) and whether this agreement is influenced by demographic variables and proxy levels of depression and carer strain. People with chronic aphasia (> or = 6 months post stroke) were recruited through the UK national charity for PWA. They were interviewed on the SAQOL-39 and their nominated proxies were interviewed on the SAQOL-39, the General Health Questionnaire and the Caregiver Strain Index. Proxy respondents had to be > or = 18 years of age, see the person with aphasia at least twice a week and have no known severe mental health problems or cognitive decline. 50 of 55 eligible pairs (91%) took part in the study. Proxies rated PWA as more severely affected than PWA rated themselves. The SDs of the difference scores were large and the difference was significant for three of the four SAQOL-39 domains and the overall mean (p < or = 0.01). However, the bias as indicated by effect sizes was small to moderate (0.2-0.5). The strength of the agreement was excellent for the overall SAQOL-39 and the physical domain (intra-class correlation coefficient ICC 0.8), good for the psychosocial and communication domains (0.7) and fair for the energy domain (0.5). Demographic variables and proxy's mood and carer strain did not affect the level of agreement. For group comparisons, proxy respondents who are in frequent contact with people with chronic aphasia can reliably report on their health related quality of life, using the SAQOL-39. Although there are significant differences between PWA and proxy responses, the magnitude of this difference is small to moderate.


Recent Economic Perspectives on Political Economy, Part II.
In recent years some of the best theoretical work on the political economy of political institutions and processes has begun surfacing outside the political science mainstream in high quality economics journals. This two-part paper surveys these contributions from a recent five-year period. In Part I, the focus is on elections, voting and information aggregation, followed by treatments of parties, candidates, and coalitions. In Part II, papers on economic performance and redistribution, constitutional design, and incentives, institutions, and the quality of political elites are discussed. Part II concludes with a discussion of the methodological bases common to economics and political science, the way economists have used political science research, and some new themes and arbitrage opportunities.


Deep Brain Stimulation, Authenticity and Value.
Deep brain stimulation has been of considerable interest to bioethicists, in large part because of the effects that the intervention can occasionally have on central features of the recipient's personality. These effects raise questions regarding the philosophical concept of authenticity. In this article, we expand on our earlier work on the concept of authenticity in the context of deep brain stimulation by developing a diachronic, value-based account of authenticity. Our account draws on both existentialist and essentialist approaches to authenticity, and Laura Waddell Ekstrom's coherentist approach to personal autonomy. In developing our account, we respond to Sven Nyholm and Elizabeth O'Neill's synchronic approach to authenticity, and explain how the diachronic approach we defend can have practical utility, contrary to Alexandre Erler and Tony Hope's criticism of autonomy-based approaches to authenticity. Having drawn a distinction between the authenticity of an individual's traits and the authenticity of that person's values, we consider how our conception of authenticity applies to the context of anorexia nervosa in comparison to other prominent accounts of authenticity. We conclude with some reflections on the prudential value of authenticity, and by highlighting how the language of authenticity can be invoked to justify covert forms of paternalism that run contrary to the value of individuality that seems to be at the heart of authenticity.


Renal function in urinary schistosomiasis in the Natal Province of South Africa.
Renal function was assessed in 101 schoolchildren with active urinary schistosomiasis by measuring serum creatinine, urate, urea, and B2-microglobulin, urinary B2 microglobulin, and the glomerular filtration rate. Glomerular function in all subjects was normal as were serum creatinine, urate, and urea levels. Serum B2-microglobulin was elevated in only 8% of subjects while urinary B2-microglobulin only was raised in 7% of subjects, indicating proximal tubular dysfunction, a previously unreported feature in urinary schistosomiasis. Urinary tract abnormalities were found in 43% of subjects consenting to an excretory urogram but no correlation with biochemical parameters of renal function was noted. Serum angiotensin converting enzyme level measured in 70 subjects was elevated in 11% of subjects and was regarded as a possible measure of increased granulomatous activity.


Myosin II isoforms play distinct roles in adherens junction biogenesis.
Adherens junction (AJ) assembly under force is essential for many biological processes like epithelial monolayer bending, collective cell migration, cell extrusion and wound healing. The acto-myosin cytoskeleton acts as a major force-generator during the de novo formation and remodeling of AJ. Here, we investigated the role of non-muscle myosin II isoforms (NMIIA and NMIIB) in epithelial junction assembly. NMIIA and NMIIB differentially regulate biogenesis of AJ through association with distinct actin networks. Analysis of junction dynamics, actin organization, and mechanical forces of control and knockdown cells for myosins revealed that NMIIA provides the mechanical tugging force necessary for cell-cell junction reinforcement and maintenance. NMIIB is involved in E-cadherin clustering, maintenance of a branched actin layer connecting E-cadherin complexes and perijunctional actin fibres leading to the building-up of anisotropic stress. These data reveal unanticipated complementary functions of NMIIA and NMIIB in the biogenesis and integrity of AJ.


Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease.
The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease.


Exaggerated response to alerting stimuli in spontaneously hypertensive rats.
The startle response, consisting of behavioral and cardiovascular components, was used to study the reaction of the cardiovascular system to a mild environmental stressor. We used tactile air puff startle to study responses in adult Wistar-Kyoto and spontaneously hypertensive rats. In both strains, air puff elicits a transient motor response with rapid habituation over the test session of 30 trials. Spontaneously hypertensive rats exhibit exaggerated motor responses compared with Wistar-Kyoto rats. Similarly, a 2-3-second duration pressor response was significantly greater in spontaneously hypertensive rats than in Wistar-Kyoto rats (47.7 +/- 2.0 versus 37.1 +/- 1.5 mm Hg, respectively). However, spontaneously hypertensive rats and Wistar-Kyoto rats exhibited strikingly dissimilar heart rate responses. Wistar-Kyoto rats exhibited a transient bradycardia (-42 +/- 7 beats/min) on early trials yielding to tachycardia on later trials (35 +/- 11 beats/min). In contrast, spontaneously hypertensive rats exhibited only tachycardia to all stimuli with an absence of bradycardia. Adrenal medullary secretions chronically modulate cardiac responses in both strains. Sinoaortic denervation did not alter the magnitude or profile of the heart rate responses. Spontaneously hypertensive--Wistar-Kyoto rat differences were not secondary to hypertension because renovascular hypertensive Wistar-Kyoto rats show normal responses to air puff. Four-week-old spontaneously hypertensive rats exhibit enhanced pressor and suppressed bradycardia responses relative to age-matched Wistar-Kyoto rats, indicating chronotropic differences precede development of established hypertension. Our results indicate parasympathetic activation by the mild startle stimuli rather than sympathetic withdrawal allows bradycardia to mask a latent tachycardia in Wistar-Kyoto rats. Spontaneously hypertensive rats exhibit a parasympathetic insufficiency in the startle response to novel alerting stimuli. Thus, mild air puff startle identifies a unique and discriminatory phenotypic difference between inbred normotensive and hypertensive rats.


Effects of small-scale clustering of flowers on pollinator foraging behaviour and flower visitation rate.
Plants often grow in clusters of various sizes and have a variable number of flowers per inflorescence. This small-scale spatial clustering affects insect foraging strategies and plant reproductive success. In our study, we aimed to determine how visitation rate and foraging behaviour of pollinators depend on the number of flowers per plant and on the size of clusters of multiple plants using Dracocephalum moldavica (Lamiaceae) as a target species. We measured flower visitation rate by observations of insects visiting single plants and clusters of plants with different numbers of flowers. Detailed data on foraging behaviour within clusters of different sizes were gathered for honeybees, Apis mellifera, the most abundant visitor of Dracocephalum in the experiments. We found that the total number of flower visitors increased with the increasing number of flowers on individual plants and in larger clusters, but less then proportionally. Although individual honeybees visited more flowers in larger clusters, they visited a smaller proportion of flowers, as has been previously observed. Consequently, visitation rate per flower and unit time peaked in clusters with an intermediate number of flowers. These patterns do not conform to expectations based on optimal foraging theory and the ideal free distribution model. We attribute this discrepancy to incomplete information about the distribution of resources. Detailed observations and video recordings of individual honeybees also showed that the number of flowers had no effect on handling time of flowers by honeybees. We evaluated the implications of these patterns for insect foraging biology and plant reproduction.


Survivorship Care Preferences: A Pilot Study of Young Adults With Cancer
Adolescents and young adults (AYAs) face increased risk for physical, social, and cognitive late complications of cancer therapy. Strategies are needed to better engage AYAs in survivorship research. This study aimed to determine the feasibility of enrolling AYAs within six months of diagnosis to a survivorship study and assess their health concerns and survivorship care preferences. Patients aged 15–34 years who were diagnosed with leukemia, lymphoma, or sarcoma at three Connecticut hospitals from 2008–2011 were identified and recruited by mail. Participants and their physicians received a survivorship care plan. Participants completed surveys at 6 months and 18 months after diagnosis. Recruiting AYAs to survivorship research remains challenging, even when approaching them soon after diagnosis. Novel strategies are needed for nurses and other healthcare team members to engage AYAs in survivorship care and research.


Testing for hyperthyroidism in cats.
Hyperthyroidism remains a common endocrine disorder of cats. Although relatively easy to diagnose in classically presenting cats, the increased frequency of testing cats with early or mild disease has had significant implications for the diagnostic performance of many of the routine tests currently used. Further advances in the etiopathogenesis and earlier diagnosis are only likely with the advent of a species specific feline thyroid-stimulating hormone assay.


Asymmetrical prism for beam shaping of laser diode stacks.
A beam-shaping scheme for a laser diode stack to obtain a flattop output intensity profile is proposed. The shaping element consists of an asymmetrical glass prism. The large divergence-angle compression in the direction perpendicular to the junction plane and the small divergence-angle expansion in the parallel direction are performed simultaneously by a single shaping element. The transformation characteristics are presented, and the optimization performance is investigated based on the ray-tracing method. Analysis shows that a flattop intensity profile can be obtained. This beam-shaping system can be fabricated easily and has a large alignment tolerance.


Peptidomic characterization and bioactivity of Protoiurus kraepelini (Scorpiones: Iuridae) venom.
Protoiurus kraepelini is a scorpion species found in parts of Turkey and Greece. In this study, the peptide profile of its venom was determined for the first time. The electrophoretic profile of the crude venom showed a protein distribution from 2 to 130 kDa. MALDI-TOF MS analysis of the venom peptide fraction yielded 27 peptides between 1059 and 4623 Da in mass. Several ion channelblocking and antimicrobial peptides were identified by peptide mass fingerprinting analysis. Cytotoxic and antimicrobial effects of the venom were also demonstrated on Jurkat cells and Escherichia coli, respectively. As the first peptidomic characterization study on P. kraepelini venom, this report lays the foundation for detailed future studies that may lead to the discovery of novel bioactive peptides.


Effects of heat shock and hypoxia on protein synthesis in rainbow trout (Oncorhynchus mykiss) cells.
We examined the effects of heat stress (from 18 degreesC to 26 degreesC) and low oxygen tension (1% O2=1 kPa) on protein synthesis in primary cultures of hepatocytes, gill epithelial cells and fibroblast-like RTG-2 cells of rainbow trout Oncorhynchus mykiss. All these cell types displayed elevated levels of 67, 69 and 92 kDa proteins, whereas a 104 kDa protein was induced only in RTG-2 cells. Hypoxia induced a cell-type-specific response, increasing the synthesis of 36, 39 and 51 kDa proteins in the gill epithelial cells. The regulation of the heat-shock response in fish hepatocytes showed that an HSF1-like factor is involved in the transcriptional induction of the hsp70 gene. Consequently, there was a pronounced accumulation of hsp70 mRNA. Furthermore, the kinetics of activation of DNA binding and the increase in hsp70 gene expression showed a remarkable correlation, indicating that hsp70 expression is regulated at the transcriptional level in these trout cells.


miRandola: extracellular circulating microRNAs database.
MicroRNAs are small noncoding RNAs that play an important role in the regulation of various biological processes through their interaction with cellular messenger RNAs. They are frequently dysregulated in cancer and have shown great potential as tissue-based markers for cancer classification and prognostication. microRNAs are also present in extracellular human body fluids such as serum, plasma, saliva, and urine. Most of circulating microRNAs are present in human plasma and serum cofractionate with the Argonaute2 (Ago2) protein. However, circulating microRNAs have been also found in membrane-bound vesicles such as exosomes. Since microRNAs circulate in the bloodstream in a highly stable, extracellular form, they may be used as blood-based biomarkers for cancer and other diseases. A knowledge base of extracellular circulating miRNAs is a fundamental tool for biomedical research. In this work, we present miRandola, a comprehensive manually curated classification of extracellular circulating miRNAs. miRandola is connected to miRò, the miRNA knowledge base, allowing users to infer the potential biological functions of circulating miRNAs and their connections with phenotypes. The miRandola database contains 2132 entries, with 581 unique mature miRNAs and 21 types of samples. miRNAs are classified into four categories, based on their extracellular form: miRNA-Ago2 (173 entries), miRNA-exosome (856 entries), miRNA-HDL (20 entries) and miRNA-circulating (1083 entries). miRandola is available online at: http://atlas.dmi.unict.it/mirandola/index.html.


Differential role for competitive reverse transcriptase-polymerase chain reaction and intracellular cytokine staining as diagnostic tools for the assessment of intragraft cytokine profiles in rejecting and nonrejecting heart allografts.
The early and reliable diagnosis of allograft rejection is a difficult task and the assessment of cytokine expression in the grafts can be a helpful parameter. We have compared competitive reverse transcriptase-polymerase chain reaction (RT-PCR) with intracellular cytokine staining by flow cytometry as tools to measure cytokine expression in rejecting and nonrejecting murine cardiac allografts. Both techniques gave comparable results for cytokine expression in rejecting allografts and syngeneic controls. Grafts from mice pretreated with anti-CD4 antibody and donor-specific blood transfusion showed a marked reduction in cytokine expression, as assessed by competitive RT-PCR, even though a cellular infiltrate was present in the graft. In contrast, the cytokine production measured by intracellular cytokine staining of the isolated graft-infiltrating cells was high and exceeded even that of the rejecting allografts. We conclude that intracellular cytokine staining of graft-infiltrating leukocytes by flow cytometry does not necessarily reflect accurately the cytokine milieu in the graft. This technique might therefore have a limited clinical application in contrast to competitive RT-PCR for the differentiation between graft acceptance and graft rejection.


Incidence of Thrombotic Events and Outcomes in COVID-19 Patients Admitted to Intensive Care Units.
Introduction While coronavirus disease 2019 (COVID-19) mostly causes respiratory illnesses, emerging evidence has shown that patients with severe COVID-19 can develop complications like venous thromboembolism (VTE) and arterial thrombosis as well. The incidence of thrombosis among critically ill patients in the literature has been highly variable, ranging from 25 to 69%. Similarly, reported mortality among critically ill patients has been highly variable too, and it has ranged from 30 to 97%. In this study, we analyzed data from a large database to address the incidence, the risk factors leading to thrombotic complications, and mortality rates among COVID-19 patients. Material and methods Data were obtained from TriNetX (TriNetX, Inc., Cambridge, MA), a multinational clinical research platform that collects medical records from 42 healthcare organizations (HCOs). All nominal data were compared using the chi-squared test. Alpha of <0.05 was considered statistically significant. We used Benjamini-Hochberg correction with a false discovery rate of 0.1 to correct for multiple comparisons. Results We identified 18,652 COVID-19-positive patients, with a median age of 50.7 years [interquartile range (IQR): 31.8-69.6]; among them, 51.8% (9,672) were males and 48.2% (8,951) were females. Of these patients, 630 [3.37%; median age: 61 years (IQR: 44.9-77.1)] were critically ill, requiring intensive care unit (ICU) care within one month of their diagnosis. Men were over-represented among the ICU patients when compared to women (3.7% vs 3%, p=0.009, Χ2=6.66). African Americans were over-represented among the ICU patients when compared to Caucasians (8.5% vs 4%, p<0.0001, Χ2=76.65). Older patients, i.e., 65 years and older, were over-represented in the ICU compared to patients aged 18-64 years (6.8% vs 2.5%, p<0.0001, Χ2=121.43). The cumulative incidence of thrombotic events in the ICU population was 20.4% (129/630). Thrombotic events were significantly more common in patients who were 65 years and older when compared to patients in the age group of 18-64 years (24.6% vs 17.31%, p=0.02, Χ2=5.38). Mortality among ICU patients was higher in those who were 65 years and older when compared to the age group of 18-64 years (31.9% vs 17.3% p=0.0003, Χ2=18.41). The overall mortality in the study population was higher in patients who were 65 years and older when compared to patients aged 18-64 years (18.55% vs 1.4%, p<0.0001, Χ2=1915). Conclusions Among COVID-19 patients, men, African Americans, and people who are 65 years and older are more likely to have severe disease and require ICU level of care. Patients who are 65 years and older are more likely to have thrombotic events, myocardial infarction (MI), and stroke. Overall mortality and ICU mortality are higher among COVID-19 patients who are 65 years and older.


Assessing air quality index awareness and use in Mexico City.
The Mexico City Metropolitan Area has an expansive urban population and a long history of air quality management challenges. Poor air quality has been associated with adverse pulmonary and cardiac health effects, particularly among susceptible populations with underlying disease. In addition to reducing pollution concentrations, risk communication efforts that inform behavior modification have the potential to reduce public health burdens associated with air pollution. This study investigates the utilization of Mexico's IMECA risk communication index to inform air pollution avoidance behavior among the general population living in the Mexico City Metropolitan Area. Individuals were selected via probability sampling and surveyed by phone about their air quality index knowledge, pollution concerns, and individual behaviors. The results indicated reasonably high awareness of the air quality index (53% of respondents), with greater awareness in urban areas, among older and more educated individuals, and for those who received air quality information from a healthcare provider. Additionally, behavior modification was less influenced by index reports as it was by personal perceptions of air quality, and there was no difference in behavior modification among susceptible and non-susceptible groups. Taken together, these results suggest there are opportunities to improve the public health impact of risk communication through an increased focus on susceptible populations and greater encouragement of public action in response to local air quality indices.


An antiviral defense role of AGO2 in plants.
Argonaute (AGO) proteins bind to small-interfering (si)RNAs and micro (mi)RNAs to target RNA silencing against viruses, transgenes and in regulation of mRNAs. Plants encode multiple AGO proteins but, in Arabidopsis, only AGO1 is known to have an antiviral role. To uncover the roles of specific AGOs in limiting virus accumulation we inoculated turnip crinkle virus (TCV) to Arabidopsis plants that were mutant for each of the ten AGO genes. The viral symptoms on most of the plants were the same as on wild type plants although the ago2 mutants were markedly hyper-susceptible to this virus. ago2 plants were also hyper-susceptible to cucumber mosaic virus (CMV), confirming that the antiviral role of AGO2 is not specific to a single virus. For both viruses, this phenotype was associated with transient increase in virus accumulation. In wild type plants the AGO2 protein was induced by TCV and CMV infection. Based on these results we propose that there are multiple layers to RNA-mediated defense and counter-defense in the interactions between plants and their viruses. AGO1 represents a first layer. With some viruses, including TCV and CMV, this layer is overcome by viral suppressors of silencing that can target AGO1 and a second layer involving AGO2 limits virus accumulation. The second layer is activated when the first layer is suppressed because AGO2 is repressed by AGO1 via miR403. The activation of the second layer is therefore a direct consequence of the loss of the first layer of defense.


Angiotensin I-converting enzyme polymorphisms, ACE level and blood pressure among Nigerians, Jamaicans and African-Americans.
The genes in the renin-angiotensin system are important physiologic candidates in studies of the genetic susceptibility to hypertension. Limited information has been available in most studies on the extent of variation in the candidate loci or the modifying effects of different environmental settings. We consequently genotyped 13 polymorphisms at the angiotensin I-converting enzyme (ACE) locus at an average distance of 2 kb in 2776 family members from Nigeria, Jamaica and an African-American community in the US. Allele and haplotype frequencies were similar in the three populations, with modest evidence of European admixture in the US. Two markers were consistently associated with ACE level in the three samples and the proportion of variance accounted for by ACE8 was similar in the three groups. No evidence of consistent association of single markers was noted with blood pressure across the three population samples, however. Likewise, in a haplotype-based analysis, despite significant associations within each population, the findings were not replicated consistently across all three samples. We did observe, however, that the overtransmitted haplotypes among hypertensives were drawn from a single clade, suggesting that susceptibility may cluster in patterns not captured directly by our markers.


Pazopanib radio-sensitization of human sarcoma tumors.
Recent data in our laboratory indicate that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation. Angiogenic factors repressed this activity while a monoclonal antibody targeting VEGF, de-repressed ASMase activity and radiosensitized tumor endothelium when delivered immediately prior to SDRT. In this study, we tested the effect of SDRT in combination with the short-acting anti-angiogenic agent, Pazopanib (anti-VEGFR-1/2/3, PDGF-α/β and c-kit), in two xenograft models of human sarcoma. Pre-treatment with a single dose of Pazopanib increased SDRT-induced ASMase activity and endothelial dysfunction in vitro and in vivo, enhancing SDRT tumor cure, and exhibiting critical dependence on timing relative to SDRT exposure, suggesting a mechanism of action identical to that demonstrated for anti-VEGF/VEGFR2 antibodies. These results demonstrate the ability of Pazopanib to shift the response towards tumor cure and could therefore have a significant impact on clinical trial development in combination with SDRT for sarcoma cancer patients.


In situ development of amorphous Mn-Co-P shell on MnCo2O4 nanowire array for superior oxygen evolution electrocatalysis in alkaline media.
Exploitation of efficient and earth-abundant electrocatalysts for the oxygen evolution reaction (OER) is of great importance. Herein, we report that the formation of an amorphous Mn-Co-P shell on MnCo2O4 can boost its OER activity in alkaline media. The core-shell Mn-Co-P@MnCo2O4 nanowire array on Ti mesh (Mn-Co-P@MnCo2O4/Ti) shows excellent electrochemical catalytic activity and requires an overpotential of 269 mV to drive 10 mA cm-2 in 1.0 M KOH, which is 93 mV less than that for the MnCo2O4 nanoarray. Notably, this catalyst also shows strong long-term electrochemical durability with its activity being maintained for at least 100 h and achieves a high turnover frequency of 1.06 s-1 at an overpotential of 450 mV.


Comparing the risks of frameless stereotactic biopsy in eloquent and noneloquent regions of the brain: a retrospective review of 284 cases.
Frameless stereotactic biopsy has been shown in multiple studies to be a safe and effective tool for the diagnosis of brain lesions. However, no study has directly evaluated its safety in lesions located in eloquent regions in comparison with noneloquent locations. In this study, the authors determine whether an increased risk of neurological decline is associated with biopsy of lesions in eloquent regions of the brain. Medical records, including imaging studies, were reviewed for 284 cases in which frameless stereotactic biopsy procedures were performed by 19 neurosurgeons at 7 institutions between January 2000 and December 2006. Lesion location was classified as eloquent or noneloquent in each patient. The incidence of neurological decline was calculated for each group. During the study period, 160 of the 284 biopsies predominately involved eloquent regions of the brain. In evaluation of the complication rate with respect to biopsy site, neurological decline occurred in 9 (5.6%) of 160 biopsies in eloquent brain areas and 10 (8.1%) of 124 biopsies in noneloquent regions; this difference was not statistically significant (p = 0.416). A higher number of needle passes was associated with the presence of a postoperative hemorrhage at the biopsy site, although not with a change in the result of neurological examination. Frameless stereotactic biopsy of lesions located in eloquent brain regions is as safe and effective as biopsy of lesions in noneloquent regions. Therefore, with careful planning, frameless stereotactic biopsy remains a valuable and safe tool for diagnosis of brain lesions, independent of lesion location.


Estimated cardiovascular relative risk reduction from fixed-dose combination pill (polypill) treatment in a wide range of patients with a moderate risk of cardiovascular disease.
Recent data indicate that fixed-dose combination (FDC) pills, polypills, can produce sizeable risk factor reductions. There are very few published data on the consistency of the effects of a polypill in different patient populations. It is unclear for example whether the effects of the polypill are mainly driven by the individuals with high individual risk factor levels. The aim of the present study is to examine whether baseline risk factor levels modify the effect of polypill treatment on low-density lipoprotein (LDL)-cholesterol, blood pressure (BP), calculated cardiovascular relative risk reduction and adverse events. This paper describes a post-hoc analysis of a randomised, placebo-controlled trial of a polypill (containing aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated five-year risk for cardiovascular disease ≥7.5%. The outcomes considered were effect modification by baseline risk factor levels on change in LDL-cholesterol, systolic BP, calculated cardiovascular relative risk reduction and adverse events. The mean LDL-cholesterol in the polypill group was 0.9 mmol/l (95% confidence interval (CI): 0.8-1.0) lower compared with the placebo group during follow-up. Those with a baseline LDL-cholesterol >3.6 mmol/l achieved a greater absolute LDL-cholesterol reduction with the polypill compared with placebo, than patients with an LDL-cholesterol ≤3.6 mmol/l (-1.1 versus -0.6 mmol/l, respectively). The mean systolic BP was 10 mm Hg (95% CI: 8-12) lower in the polypill group. In participants with a baseline systolic BP >135 mm Hg the polypill resulted in a greater absolute systolic BP reduction with the polypill compared with placebo, than participants with a systolic BP ≤ 135 mm Hg (-12 versus -7 mm Hg, respectively). Calculated from individual risk factor reductions, the mean cardiovascular relative risk reduction was 48% (95% CI: 43-52) in the polypill group. Both baseline LDL-cholesterol and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill. Adverse events did not appear to be related to baseline risk factor levels or the estimated cardiovascular risk. This study demonstrated that the effect of a cardiovascular polypill on risk factor levels is modified by the level of these risk factors. Groups defined by baseline LDL-cholesterol or systolic BP had large differences in risk factor reductions but only moderate differences in estimated cardiovascular relative risk reduction, suggesting also that patients with mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill.


Limb input to the cat vestibular nuclei.
The input from fore- and hindlimbs to the vestibular nuclear complex (VNC) was investigated in awake cats. Electrical stimulus was given to the sciatic, radial and vestibular nerves bilaterally and single unit responses were recorded in the VNC with extracellular technique. The position of the microelectrode was histologically confirmed. All four major vestibular nuclei received fore- as well as hindlimb input. Forty per cent of the neurons with limb input also received vestibular afferents. No major distinguishing features appeared between the different nuclei with regard to response characteristics. Certain differences in laterality of response, quantitative fore-hindlimb ratio and somatosensory-labyrinthine convergence were observed however. Response latencies to sciatic and radial nerve stimuli always exceeded a 3 msec and were grouped around 8 and 16 msec. A third population of vestibular neurons had latencies over 20 msec. Both excitatory and inhibitory responses were recorded, with the latter not always following an activation. The findings illustrate the complex nature of the ascending pathway to the VNC and the integrative properties of this complex.


Age at first use and later substance use disorder: Shared genetic and environmental pathways for nicotine, alcohol, and cannabis.
Behavioral genetic studies have provided insights into why early substance use initiation is associated with increased risk for disorder. Few genetically informative studies, however, have operationalized initiation as the timing of first use and simultaneously modeled the timing of initiation and problematic use of multiple substances. Such research can help capture the risk associated with early initiation and determine the extent to which genetic and environmental risk generalizes across substances. This study utilized a behavior genetic approach to examine the relation between the age of substance use initiation and symptoms of substance use disorder. Participants were 7,285 monozygotic and dizygotic twins (40% male, mean age at interview = 30.6 years) from the Australian Twin Registry who reported on their ages of tobacco, alcohol, and cannabis initiation and symptoms of Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV) nicotine dependence, alcohol use disorder, and cannabis use disorder. Biometric modeling was conducted to (a) determine the structure of genetic and environmental influences on initiation and disorder and (b) examine their genetic and environmental overlap. The latent structure of initiation differed across men and women. The familial covariance between initiation and disorder was genetic among men and genetic and environmental among women, suggesting that the relation between first substance use and disorder is partly explained by a shared liability. After accounting for familial overlap, significant unique environmental correlations were observed, indicating that the age of initiation of multiple drugs may directly increase risk for substance-related problems. Results support the utility of conceptualizing initiation in terms of age and of adopting a multivariate approach. (PsycINFO Database Record


Age-specific sequence of colorectal cancer screening options in Germany: A model-based critical evaluation.
The current organized screening program for colorectal cancer in Germany offers both sexes 5 annual fecal immunochemical tests (FITs) between ages 50 and 54 years, followed by a first screening colonoscopy at age 55 years if all of these FITs were negative. We sought to assess the implications of this approach for key parameters of diagnostic performance. Using a multistate Markov model, we estimated the expected detection rates of advanced neoplasms (advanced adenomas and cancers) and number needed to scope (NNS) to detect 1 advanced neoplasm at a first screening colonoscopy conducted at age 55 after 5 preceding negative FITs and compared them with the corresponding estimates for a first screening colonoscopy at age 55 with no preceding FIT testing. In individuals with 5 consecutive negative FITs undergoing screening colonoscopy at age 55, expected colonoscopy detection rate (NNS) was 3.7% (27) and 0.10% (1,021) for any advanced neoplasm and cancer, respectively, in men, and 2.1% (47) and 0.05% (1,880) for any advanced neoplasm and cancer, respectively, in women. These NNS values for detecting 1 advanced neoplasm are approximately 3-fold higher, and the NNS values for detecting 1 cancer are approximately 8-fold higher, than those for a first screening colonoscopy at age 55 without prior FITs. This study is limited by model simplifying assumptions and uncertainties related to input parameters. Screening colonoscopy at age 55 after 5 consecutive negative FITs at ages 50-54, as currently offered in the German cancer early detection program, is expected to have very low positive predictive value. Our results may inform efforts to enhance the design of screening programs.


Improving survival and storage stability of bacteria recalcitrant to freeze-drying: a coordinated study by European culture collections.
The objective of this study is to improve the viability after freeze-drying and during storage of delicate or recalcitrant strains safeguarded at biological resource centers. To achieve this objective, a joint experimental strategy was established among the different involved partner collections of the EMbaRC project ( www.embarc.eu ). Five bacterial strains considered as recalcitrant to freeze-drying were subjected to a standardized freeze-drying protocol and to seven agreed protocol variants. Viability of these strains was determined before and after freeze-drying (within 1 week, after 6 and 12 months, and after accelerated storage) for each of the protocols. Furthermore, strains were exchanged between partners to perform experiments with different freeze-dryer-dependent parameters. Of all tested variables, choice of the lyoprotectant had the biggest impact on viability after freeze-drying and during storage. For nearly all tested strains, skim milk as lyoprotectant resulted in lowest viability after freeze-drying and storage. On the other hand, best freeze-drying and storage conditions were strain and device dependent. For Aeromonas salmonicida CECT 894(T), best survival was obtained when horse serum supplemented with trehalose was used as lyoprotectant, while Aliivibrio fischeri LMG 4414(T) should be freeze-dried in skim milk supplemented with marine broth in a 1:1 ratio. Freeze-drying Campylobacter fetus CIP 53.96(T) using skim milk supplemented with trehalose as lyoprotectant resulted in best recovery. Xanthomonas fragariae DSM 3587(T) expressed high viability after freeze-drying and storage for all tested lyoprotectants and could not be considered as recalcitrant. In contrary, Flavobacterium columnare LMG 10406(T) did not survive the freeze-drying process under all tested conditions.


Universally applicable model for the quantitative determination of lake sediment composition using fourier transform infrared spectroscopy.
Fourier transform infrared spectroscopy (FTIRS) can provide detailed information on organic and minerogenic constituents of sediment records. Based on a large number of sediment samples of varying age (0-340,000 yrs) and from very diverse lake settings in Antarctica, Argentina, Canada, Macedonia/Albania, Siberia, and Sweden, we have developed universally applicable calibration models for the quantitative determination of biogenic silica (BSi; n = 816), total inorganic carbon (TIC; n = 879), and total organic carbon (TOC; n = 3164) using FTIRS. These models are based on the differential absorbance of infrared radiation at specific wavelengths with varying concentrations of individual parameters, due to molecular vibrations associated with each parameter. The calibration models have low prediction errors and the predicted values are highly correlated with conventionally measured values (R = 0.94-0.99). Robustness tests indicate the accuracy of the newly developed FTIRS calibration models is similar to that of conventional geochemical analyses. Consequently FTIRS offers a useful and rapid alternative to conventional analyses for the quantitative determination of BSi, TIC, and TOC. The rapidity, cost-effectiveness, and small sample size required enables FTIRS determination of geochemical properties to be undertaken at higher resolutions than would otherwise be possible with the same resource allocation, thus providing crucial sedimentological information for climatic and environmental reconstructions.


Low parental tolerance for infant crying: an underlying factor in infant sleep problems?
Parenting behaviours play a major role in the evolution of infant sleep. Sleep problems in infancy have been associated with excessive parental involvement at night-time, and with shorter delays in response to infant night wakings and signalling. Infant crying and sleep problems are linked, yet little is known about the impact of parental responses to crying on infant sleep patterns. This study examined the hypothesis that lower parental tolerance for crying is associated with infant sleep problems. We studied 144 married couples divided into three groups: parents of infants suffering from night-waking problems (i.e. the clinical group), parents of infants without sleep problems and childless couples. Crying tolerance was assessed using questionnaires, audio recordings of crying infants and using a novel paradigm, in which participants were shown a video of a crying infant and asked when they would intervene. Parents in the clinical group demonstrated shorter intervention delays in the crying infant clip (group effect: P < 0.0001), and tended to attribute more distress to the crying infants compared to parents in both control groups (P < 0.05). Additionally, women demonstrated lower tolerance for infant crying on most measures compared to men. Our results suggest that parents of sleep-disturbed infants appear to have lower tolerance for infant crying, which may be a predisposition underlying their excessive involvement in soothing their infants to sleep which may lead to the development of sleep problems. These preliminary findings should be explored further to assess their clinical validity and utility.


Wide field-of-view crossed Dragone optical system using anamorphic aspherical surfaces.
A side-fed crossed Dragone telescope provides a wide field of view. This type of telescope is commonly employed in the measurement of cosmic microwave background polarization, which requires an image-space telecentric telescope with a large focal plane over broadband coverage. We report the design of a wide field-of-view crossed Dragone optical system using anamorphic aspherical surfaces with correction terms up to the 10th order. We achieved a Strehl ratio larger than 0.95 over 32×18 square degrees at 150 GHz. This design is an image-space telecentric and fully diffraction-limited system below 400 GHz. We discuss the optical performance in the uniformity of the axially symmetric point-spread function and telecentricity over the field of view. We also address the analysis to evaluate the polarization properties, including the instrumental polarization, extinction rate, and polarization angle rotation. This work is a part of a program to design a compact multi-color wide-field-of-view telescope for LiteBIRD, which is a next-generation cosmic microwave background (CMB) polarization satellite.


Reappearance of sympathetic skin response below a thoracic level-9 complete spinal cord injury.
Reappearance of sympathetic skin response (SSR) below lesion is reported in a patient with a complete thoracic-9 spinal cord injury 6 months following injury. SSR was elicited by electrical stimulation of supraorbital nerve (SON) and pudendal nerve (PN). SON stimulation induced SSRs only in the hand. SSRs were initially absent below the level of SCI but reappeared only with PN stimulation. This case suggests that 6 months following a complete lesion, the isolated spinal cord can generate a SSR. Possible underlying mechanisms and implications for autonomic plasticity below spinal lesion are discussed in view of the literature.


Intracellular calcium chelator, BAPTA-AM, prevents cocaine-induced ventricular fibrillation.
Cocaine is a potent cardiac stimulant that can provoke lethal cardiac events, including ventricular fibrillation (VF). The cocaine-induced accumulation of intracellular calcium could contribute significantly to the development of these lethal arrhythmias. To test this hypothesis, VF was induced in 12 mongrel dogs by the combination of cocaine (1.0 mg/kg) and a 2-min coronary occlusion during exercise. This test without cocaine failed to induce arrhythmias. Pretreatment with the intracellular calcium-specific chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM; 1.0 mg/kg iv) prevented VF in 8 of 12 animals (P < 0.001) and delayed the onset of lethal arrhythmias in 3 of the remaining animals. Cocaine induced significant increases in left ventricular (LV) systolic pressure (control 154.7 +/- 8.7, cocaine 167.4 +/- 8.4 mmHg), heart rate (control 195.9 +/- 6.1, cocaine 222.3 +/- 10.6 beats/min), and LV maximum rate of pressure development (dP/dtmax; control 5,251 +/- 317.6, cocaine 6,016 +/- 435.1 mmHg/s). BAPTA-AM attenuated the increase in LV dP/dtmax (BAPTA-AM 4,591 +/- 479.3 mmHg/s) and LV systolic pressure (BAPTA-AM 154.5 +/- 6.8 mmHg). Because vascular muscle relaxation could contribute to the cardioprotection, the cocaine and exercise plus ischemia test was repeated after nitroprusside. The nitroprusside prevented cocaine-induced increases in LV systolic pressure but failed to prevent VF. These data suggest that BAPTA-AM may prevent cocaine-induced VF independently of its vascular actions.


Selective renal medullary damage and hypertension in the rat: the role of vasopressin.
The induction of selective renal medullary damage by 2-bromoethylamine hydrobromide (BEA) results in polyuria and raised blood pressure. In view of the likely elevation of plasma vasopressin we have investigated the role of vasopressin (AVP) in the elevated blood pressure in this model. Plasma vasopressin levels in BEA pretreated rats were raised significantly (2 +/- 0.6 pg/ml vs 0.8 +/- 0.1 in normal rat, P less than 0.05) but not to pressor levels. In addition, pressor responsiveness was investigated in renal medullary damaged rats. There was a reduced response to vasopressin and noradrenaline but no alteration with angiotensin II. A specific V1, receptor AVP antagonist [d(CH2)5Tyr(Me)AVP] produced no fall in blood pressure but returned the noradrenaline dose-response curve to normal. This suggests an interaction between vasopressin and the sympathetic nervous system in this model. Thus there is no evidence that vasopressin contributes to the rise in blood pressure produced by chemical renal medullectomy and other mechanisms have to be sought.


T cells regulate lymph node-resident ILC populations in a tissue and subset-specific way.
Innate lymphoid cells (ILCs) have been shown to be significantly affected in the small intestine lamina propria and secondary lymphoid organs (SLOs) of conventional lymphopenic mice. How ILCs are regulated by adaptive immunity in SLOs remains unclear. In T cell-deficient mice, ILC2s are significantly increased in the mesenteric lymph nodes (MLNs) at the expense of CCR6+ ILC3s, which are nonetheless increased in the peripheral lymph nodes (PLNs). Here, we show that T cells regulate lymph node-resident ILCs in a tissue- and subset-specific way. First, reducing microbial colonization from birth restored CCR6+ ILC3s in the MLNs of T cell-deficient mice. In contrast, T cell reconstitution resulted in the contraction of both MLNs ILC2s and PLNs ILC3s, whereas antagonizing microbial colonization from birth had no impact on these populations. Finally, the accumulation of MLNs ILC2s was partly regulated by T cells through stroma-derived IL-33.


Hepatitis C virus itself is a causal risk factor for chronic kidney disease beyond traditional risk factors: a 6-year nationwide cohort study across Taiwan.
Hepatitis C virus (HCV) infection and chronic kidney disease (CKD) have high prevalences in Taiwan and worldwide, but the role of HCV infection in causing CKD remains uncertain. This cohort study aimed to explore this association. This nationwide cohort study examined the association of HCV with CKD by analysis of sampled claims data from Taiwan National Health Insurance Research Database from 1998 to 2004. ICD-9 diagnosis codes were used to identify diseases. We extracted data of 3182 subjects who had newly identified HCV infection and no traditional CKD risk factors and data of randomly selected 12728 matched HCV-uninfected control subjects. Each subject was tracked for 6 years from the index date to identify incident CKD cases. Cox proportional hazard regression was used to determine the risk of CKD in the HCV-infected and control groups. The mean follow-up durations were 5.88 years and 5.92 years for the HCV-infected and control groups, respectively. Among the sample of 15910 subjects, 251 subjects (1.6%) developed CKD during the 6-year follow-up period, 64 subjects (2.0%) from the HCV-infected group and 187 subjects (1.5%) from the control group. The incidence rate of CKD was significantly higher in the HCV-infected group than in the control group (3.42 vs. 2.48 per 1000 person-years, p = 0.02). Multivariate analysis indicated that the HCV-infected group had significantly greater risk for CKD (adjusted hazard ratio: 1.75, 95% CI: 1.25-2.43, p = 0.0009). This relationship also held for a comparison of HCV-infected and HCV-uninfected subjects who were younger than 70 years and had none of traditional CKD risk factors. HCV infection is associated with increased risk for CKD beyond the well-known traditional CKD risk factors. HCV patients should be informed of their increased risk for development of CKD and should be more closely monitored.


In situ X-ray photoelectron and Auger electron spectroscopic characterization of reaction mechanisms during Li-ion cycling.
The complex nature of Li-ion battery reactions along with their sensitivity to environmental exposure necessitates in situ characterization, particularly for surface sensitive methods. In this work, we demonstrate in situ X-ray photoelectron spectroscopy and in situ Auger electron spectroscopy applied to characterize the evolution of bonding and chemistry during cycling of nanoparticle electrodes. We apply the method to study the conversion reaction associated with Li insertion and extraction from CuO nanoparticle electrodes. This approach circumvents the need for ion sputtering and mechanical erosion, previously required to remove solid electrolyte interphase during ex situ measurements. This allows the elucidation of the changes in Cu oxidation state, during initial Li insertion, without the introduction of artifacts that have caused prior disagreement in the published literature.


The acute behavioral syndrome of anterior thalamic infarction: a prospective study of 12 cases.
Using systematic investigations, including neurological and neuropsychological examinations and computed tomography and magnetic resonance imaging analyzed on anatomical maps, we prospectively studied 12 patients (age range, 63+/-19 years) with an isolated anterior thalamic infarct. They had acute, severe, perseverative behavior, which was apparent in thinking, speech, and all memory and executive tasks, combined with increased sensitivity to interference. They also showed superimposition of mental activities normally processed sequentially (e.g., giving biographical information while working on a calculation test), which we called palipsychism (from the Greek palin [again] and the Greek psyche [soul]). In addition, all 12 patients (8 with a left-sided infarct, 4 with a right-sided infarct) had word-finding difficulties, 7 of 12 with impaired naming, 8 of 12 with dysarthria, and 5 of 12 with hypophonia. Comprehension, repetition, written abilities, and reasoning were consistently preserved, but apathy was usual. All patients had anterograde memory impairment, with a delayed recall deficit, primarily verbal in left-sided infarcts and visuospatial in right-sided infarcts. Dysexecutive features such as difficulty in programming motor sequences were always present. Visual neglect or topographic disorientation was found in 3 patients. Magnetic resonance imaging emphasized involvement of the anterior group of thalamic nuclei, the mamillothalamic tract, and the anterior part of the internal medullary lamina, with structural sparing of the dorsomedial and ventrolateral nuclei. Sequential follow-up examinations showed spectacular improvement within a few months, with the only significant persisting abnormalities being memory dysfunction and apathy. The acute behavioral syndrome of anterior thalamic infarction is dominated by palipsychism, which corresponds to an overlap of sequential cognitive processes in two or more domains. Its association with severe perseverative behavior with increased sensitivity to interference, anterograde memory retrieval deficit, intrusions, naming difficulties with dysarthria and hypophonia, and apathy is suggestive of this type of infarct.


Asymmetric total synthesis of (-)-amphidinolide V through effective combinations of catalytic transformations.
An asymmetric total synthesis of (-)-amphidinolide V was accomplished. The synthesis features a base-catalyzed alkynyl silane alcoholysis/ring-closing enyne metathesis sequence for facile construction of a 1,3-diene motif. A diene RCM followed by a ring-contractive allylic transposition of cyclic silyl ethers was incorporated for the stereoselective installation of a functionalized 1,5-diene subunit. An efficient proline-mediated direct cross-aldol condensation of two advanced aldehyde intermediates was utilized for the construction of a key α,β-unsaturated epoxyaldehyde. This total synthesis demonstrates the prowess of metal-catalyzed transformations in complex molecule synthesis.


Environmental pollutants and the thyroid.
Common environmental exposures may affect thyroid function in humans. Foetuses and infants are most vulnerable to these effects because they need thyroid hormone for normal neurodevelopment. Perchlorate, thiocyanate and nitrate are all competitive inhibitors of the sodium/iodine symporter (NIS) in pharmacologic doses, but their effects on human thyroid function at environmental exposure levels remain unclear. Many compounds, including polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs), bisphenol-A (BPA) and triclosan, may have direct actions on the thyroid hormone receptor, but these effects are complex and are not yet well understood. Isoflavones inhibit thyroperoxidase (TPO) activity, and, therefore, may cause goitre and hypothyroidism if ingested at high levels, particularly in iodine-deficient individuals. Organochlorine pesticides and dioxins may decrease serum T(4) half-life by activating hepatic enzymes. Additional studies are needed to further elucidate the risk posed by these and other potentially thyroid-disrupting compounds.


An outbreak of mycobacterial furunculosis associated with footbaths at a nail salon.
In September 2000, a physician in northern California described four patients with persistent, culture-negative boils on the lower extremities. The patients had received pedicures at the same nail salon. We identified and investigated an outbreak of Mycobacterium fortuitum furunculosis among customers of this nail salon. Patients were defined as salon customers with persistent skin infections below the knee. A case-control study was conducted that included the first 48 patients identified, and 56 unaffected friends and family members who had had a pedicure at the same salon served as controls. Selected M. fortuitum isolates, cultured from patients and the salon environment, were compared by pulsed-field gel electrophoresis. We identified 110 customers of the nail salon who had furunculosis. Cultures from 34 were positive for rapidly growing mycobacteria (32 M. fortuitum and 2 unidentified). Most of the affected patients had more than 1 boil (median, 2; range, 1 to 37). All patients and controls had had whirlpool footbaths. Shaving the legs with a razor before pedicure was a risk factor for infection (70 percent of patients vs. 31 percent of controls; adjusted odds ratio, 4.8; 95 percent confidence interval, 2.1 to 11.1). Cultures from all 10 footbaths at the salon yielded M. fortuitum. The M. fortuitum isolates from three footbaths and 14 patients were indistinguishable by electrophoresis. We identified a large outbreak of rapidly growing mycobacterial infections among persons who had had footbaths and pedicures at one nail salon. Physicians should suspect this cause in patients with persistent furunculosis after exposure to whirlpool footbaths.


Hormonal regulation of prostaglandin production by rhesus monkey endometrium.
Although there have been numerous studies on the production of prostaglandins (PGs) by human endometrium in vitro during the menstrual cycle, considerable variation exists in the levels reported during the proliferative vs. the secretory phase. Such variation may be due in part to the difficulty in obtaining endometrium from a precisely known hormonal environment and in part to the use of the different culture systems employed. The aim of the present study was to develop a non-human primate model in which precisely dated endometrial tissue could be obtained reliably. Moreover, PG levels in the endometrium of the rhesus monkey or other primates have not previously been reported during the artificial menstrual cycle. An important objective in establishing such a model was to permit future manipulations of the cycle in vivo [e.g. by omitting the midcycle estradiol (E) peak] to further dissect specific roles of E and progesterone (P) in regulating PG synthesis during the menstrual cycle. Ovariectomized rhesus monkeys were maintained on a standard artificial menstrual cycle via the insertion and removal of Silastic capsules containing E or P. Samples of endometrium (approximately 50 mg) were obtained by hysterotomy under sterile conditions at predetermined stages of separate menstrual cycles: day 9 (midproliferative; n = 5), day 13 (E peak; n = 3), day 14 (1 day post-E peak; n = 5), and day 23 (midsecretory; n = 8). Measurement of the primary PGs in unextracted medium by RIA over 4 days of organ culture indicated PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 greater than thromboxane-B2, PGD2 greater than leukotrienes. PGF2 alpha, the most abundant PG produced on the first day of culture, was low on day 9 and increased dramatically on day 13 (P less than 0.01). On day 14, PGF2 alpha levels fell significantly only 1 day post-E peak (P less than 0.01), while on day 23, after exposure to P in vivo, PGF2 alpha was 10-fold higher (P less than 0.01) than on cycle days 9 and 14. The other PGs measured showed a lower but similar profile at the cycle stages examined. Physiological concentrations of P (5.0 ng/mL) added to cycle day 23 cultures in both the absence and presence of low or high E markedly inhibited the high levels of PGs found in day 23 cultures (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)


The Cardiac Physiome: perspectives for the future.
The Physiome Project, exemplified by the Cardiac Physiome, is now 10 years old. In this article, we review past progress and future challenges in developing a quantitative framework for understanding human physiology that incorporates both genetic inheritance and environmental influence. Despite the enormity of the challenge, which is certainly greater than that facing the pioneers of the human genome project 20 years ago, there is reason for optimism that real and accelerating progress is being made.


Supplementation of fexofenadine therapy with nedocromil sodium 2% ophthalmic solution to treat ocular symptoms of seasonal allergic conjunctivitis.
Ocular symptoms are often under-treated in patients with allergic rhinoconjunctivitis. The efficacy of fexofenadine hydrochloride 60 mg capsules supplemented with nedocromil sodium 2% ophthalmic solution was evaluated to determine the optimal drug regimen for control of ocular allergic symptoms. In this 5-week, open-label, randomized, multicentre comparative study, 89 patients with documented ragweed pollen allergy received fexofenadine b.i.d. with nedocromil rescue, fexofenadine q.d. with nedocromil b.i.d., or fexofenadine rescue with nedocromil b.i.d. during the ragweed pollen season. For all regimens, mean symptom severity scores for itching, burning, tearing, redness, grittiness, discharge, light sensitivity and swelling improved significantly (P < 0.003). Similarly, all groups experienced significant (P < 0.02) improvement in all clinical signs: erythema, oedema, discharge, conjunctival injection and conjunctivitis, as well as quality-of-life scores (P < 0.0001). All regimens reduced overall symptom severity scores after 5 min (P < 0.05) with relief persisting over 12 h (P < 0.03). Improvements in mean symptoms, signs and quality-of-life scores were similar among the treatment groups as were onset and duration of action even though patients in two of the three study arms were taking one-half or less of the recommended fexofenadine dosage. Patients and physicians judged the regimens containing lower fexofenadine dosages (with nedocromil b.i.d.) to be more effective overall than the regimen containing the highest fexo-fenadine dosage (with nedocromil as rescue only). Supplementation of oral fexofenadine therapy with nedocromil sodium 2% ophthalmic solution relieves ocular symptoms of seasonal allergic rhinoconjunctivitis, allowing control of rhinal symptoms with half the recommended dosage of fexofenadine.


Prophylactic Potential of Conventional and Supercritical Garlic Extracts to Alleviate Diet Related Malfunctions.
The present research was tailored to explore the prophylactic role of garlic extracts to mitigate some diet related malfunctions. The recent patents regarding antidiabetic agents (US 20140147528 A1) and garlic compositions (US 20110129580 A1) also helped in the study design. Bioevaluation trials were conducted on Sprague Dawley rats by feeding garlic extracts for a period of sixty days. Accordingly, three studies were carried out comprising of normal, hyperglycemic and hypercholesterolemic rats. Drink & feed intakes and weight gain were measured throughout the trial. After sixty days, collected sera from rats were analyzed for serum cholesterol, LDL, HDL & triglyceride levels and glucose & insulin concentrations. Finally, the data obtained were subjected to statistical modeling. Results concerning the bioevaluation trials revealed that maximum 12.39% reduction was observed in serum cholesterol in Study III (hypercholesterolemic rats) on the provision of garlic supercritical extract (nutraceutical diet) followed by 10.24% decline in rats fed on solvent extract supplemented diet (functional diet). Regarding LDL, maximum decrease (17.02%) was recorded on the administration of diet having garlic supercritical extract to the hypercholesterolemic rats. While in Study II (hyperglycemic rats) maximum decrease of 11.03% in glucose level was recorded in rats fed on supercritical extract containing diet. In the same group maximum increase in insulin (7.95%) was recorded. From the current investigations, it can be concluded that garlic based designer foods possess the prophylactic perspectives to alleviate the risk of metabolic ailments. Thus, it can be used in the diet based therapeutic interventions as an adjuvant to pharmaceuticals.


Anterior subcutaneous internal fixation for treatment of unstable pelvic fractures.
Fractures of the pelvic ring including disruption of the posterior elements in high-energy trauma have both high morbidity and mortality rates. For some injury pattern part of the initial resuscitation includes either external fixation or plate fixation to close the pelvic ring and decrease blood loss. In certain situations--especially when associated with abdominal trauma and the need to perform laparotomies--both techniques may put the patient at risk of either pintract or deep plate infections. We describe an operative approach to percutaneously close and stabilize the pelvic ring using spinal implants as an internal fixator and report the results in a small series of patients treated with this technique during the resuscitation phase. Four patients were treated by subcutaneous placement of an internal fixator. Screw fixation was carried out by minimally invasive placement of two supra-acetabular iliac screws. Afterwards, a subcutaneous transfixation rod was inserted and attached to the screws after reduction of the pelvic ring. All patients were allowed to fully weight-bear. No losses of reduction or deep infections occurred. Fracture healing was uneventful in all cases. Minimally invasive fixation is an alternative technique to stabilize the pelvic ring. The clinical results illustrate that this technique is able to achieve good results in terms of maintenance of reduction the pelvic ring. Also, abdominal surgeries no longer put the patient at risk of infected pins or plates.


Handedness, clumsiness and cognitive ability.
An unselected group of 170 children aged between eight and nine years was given tests of intelligence, reading ability and manual dexterity. A 'target' group of children was selected on the basis of very poor performance with the non-preferred hand. Using an extension of Satz's pathological left-handedness model, it is argued that there should be a higher proportion of left-handers in the target group than in the remainder of the sample: this prediction was confirmed. It was also predicted that the target group should have a higher incidence of neurological disorder, and that left-handers in the target group should have a lower incidence of familial sinistrality than other left-handers. Partial confirmation of these predictions was obtained. The target group was impaired on cognitive tasks. It is argued that skill with the non-preferred hand may be more meaningful than direction of hand preference as a basis for understanding relationships between handedness and ability.


Identification of conserved and HLA promiscuous DENV3 T-cell epitopes.
Anti-dengue T-cell responses have been implicated in both protection and immunopathology. However, most of the T-cell studies for dengue include few epitopes, with limited knowledge of their inter-serotype variation and the breadth of their human leukocyte antigen (HLA) affinity. In order to expand our knowledge of HLA-restricted dengue epitopes, we screened T-cell responses against 477 overlapping peptides derived from structural and non-structural proteins of the dengue virus serotype 3 (DENV3) by use of HLA class I and II transgenic mice (TgM): A2, A24, B7, DR2, DR3 and DR4. TgM were inoculated with peptides pools and the T-cell immunogenic peptides were identified by ELISPOT. Nine HLA class I and 97 HLA class II novel DENV3 epitopes were identified based on immunogenicity in TgM and their HLA affinity was further confirmed by binding assays analysis. A subset of these epitopes activated memory T-cells from DENV3 immune volunteers and was also capable of priming naïve T-cells, ex vivo, from dengue IgG negative individuals. Analysis of inter- and intra-serotype variation of such an epitope (A02-restricted) allowed us to identify altered peptide ligands not only in DENV3 but also in other DENV serotypes. These studies also characterized the HLA promiscuity of 23 HLA class II epitopes bearing highly conserved sequences, six of which could bind to more than 10 different HLA molecules representing a large percentage of the global population. These epitope data are invaluable to investigate the role of T-cells in dengue immunity/pathogenesis and vaccine design.


Chromatin architecture may dictate the target site for DMC1, but not for RAD51, during homologous pairing.
In eukaryotes, genomic DNA is compacted as chromatin, in which histones and DNA form the nucleosome as the basic unit. DMC1 and RAD51 are essential eukaryotic recombinases that mediate homologous chromosome pairing during homologous recombination. However, the means by which these two recombinases distinctly function in chromatin have remained elusive. Here we found that, in chromatin, the human DMC1-single-stranded DNA complex bypasses binding to the nucleosome, and preferentially promotes homologous pairing at the nucleosome-depleted regions. Consistently, DMC1 forms ternary complex recombination intermediates with the nucleosome-free DNA or the nucleosome-depleted DNA region. Surprisingly, removal of the histone tails improperly enhances the nucleosome binding by DMC1. In contrast, RAD51 does not specifically target the nucleosome-depleted region in chromatin. These are the first demonstrations that the chromatin architecture specifies the sites to promote the homologous recombination reaction by DMC1, but not by RAD51.


Phylogenetic analysis of population-based and deep sequencing data to identify coevolving sites in the nef gene of HIV-1.
Rapidly evolving viruses such as HIV-1 display extensive sequence variation in response to host-specific selection, while simultaneously maintaining functions that are critical to replication and infectivity. This apparent conflict between diversifying and purifying selection may be resolved by an abundance of epistatic interactions such that the same functional requirements can be met by highly divergent sequences. We investigate this hypothesis by conducting an extensive characterization of sequence variation in the HIV-1 nef gene that encodes a highly variable multifunctional protein. Population-based sequences were obtained from 686 patients enrolled in the HOMER cohort in British Columbia, Canada, from which the distribution of nonsynonymous substitutions in the phylogeny was reconstructed by maximum likelihood. We used a phylogenetic comparative method on these data to identify putative epistatic interactions between residues. Two interactions (Y120/Q125 and N157/S169) were chosen to further investigate within-host evolution using HIV-1 RNA extractions from plasma samples from eight patients. Clonal sequencing confirmed strong linkage between polymorphisms at these sites in every case. We used massively parallel pyrosequencing (MPP) to reconstruct within-host evolution in these patients. Experimental error associated with MPP was quantified by performing replicates at two different stages of the protocol, which were pooled prior to analysis to reduce this source of variation. Phylogenetic reconstruction from these data revealed correlated substitutions at Y120/Q125 or N157/S169 repeated across multiple lineages in every host, indicating convergent within-host evolution shaped by epistatic interactions.