Maternal dietary glycemic index and glycemic load in early pregnancy are associated with offspring adiposity in childhood: the Southampton Women's Survey.
Maternal hyperglycemia in pregnancy is associated with greater adiposity in offspring. The glycemic index (GI) and glycemic load (GL) describe the glycemic response to carbohydrate ingestion. However, the influence of maternal dietary GI and GL in pregnancy on childhood adiposity is unknown. We examined relations of maternal dietary GI and GL in early and late pregnancy with offspring body composition. A total of 906 mother-child pairs from the prospective cohort the Southampton Women's Survey were included. Children underwent dual-energy X-ray absorptiometry measurements of body composition at birth and 4 and 6 y of age. Log-transformed fat mass and lean mass were standardized with a mean (±SD) of 0 ± 1. Maternal dietary GI and GL were assessed at 11 and 34 wk of gestation by using an administered food-frequency questionnaire. After control for potential confounders, both maternal dietary GI and GL in early pregnancy were positively associated with fat mass at 4 and 6 y of age [fat mass SDs per 10-unit GI increase: β = 0.43 (95% CI: 0.06, 0.80), P = 0.02 at 4 y of age; β = 0.40 (95% CI: 0.10, 0.70), P = 0.01 at 6 y of age; fat mass SDs per 50-unit GL increase: β = 0.43 (95% CI: 0.19, 0.67), P < 0.001 at 4 y of age; β = 0.27 (95% CI: 0.07, 0.47), P = 0.007 at 6 y of age]. In contrast, there were no associations between maternal dietary GI or GL in late pregnancy and offspring fat mass at these ages. Maternal dietary GI and GL were not associated with fat mass at birth or offspring lean mass at any of the ages studied. Higher maternal dietary GI and GL in early pregnancy are associated with greater adiposity in childhood.


Oregon physicians' responses to requests for assisted suicide: a qualitative study.
In 1997, the Oregon Death with Dignity Act was enacted, allowing physicians to prescribe lethal dosages of medication to competent, terminally ill patients who request them. To improve our understanding of physicians' reactions to requests for assisted suicide, we performed semistructured interviews of 35 Oregon physicians who had received requests from patients. Interviews were completed in 2000, and audiotaped, transcribed, and analyzed using qualitative techniques. Requests for assisted suicide had a powerful impact on physicians and their practices. Physicians often felt unprepared, and experienced apprehension and discomfort before and after receiving requests. Prominent sources of discomfort included concerns about adequately managing symptoms and suffering, not wanting to abandon patients, and incomplete understanding of patients' preferences, especially when physicians did not know patients well. Participation in assisted suicide required a large investment of time and was emotionally intense. Regardless of whether they prescribed or not, physicians did not express major regrets about their decisions. Requests often facilitated discussion of important issues, and many physicians felt that the process increased their confidence and assertiveness in discussing end-of-life issues with other patients. Physicians rarely sought support from colleagues; instead, they tended to discuss emotional aspects of their experiences with their spouses.


Patients With Intravitreal Gas Bubbles at Risk of High Intraocular Pressure Without Exceeding Elevation of Surgery: Theoretical Analysis.
The purpose of this study was to show the mechanism responsible for high peak IOP in patients with intravitreal gas bubbles resulting from a descent to low elevation and a return ascent, without exceeding the surgical elevation. A computational model reconstructed four clinical cases, using published elevations, ascent rates, and initial bubble sizes. In each case, patients first underwent surgery (790 m), then went home (790 m, 790 m, 325 m, 240 m). When returning for follow-up visits, patients descended to a low elevation (20 m, 0 m, 25 m, -310 m), then ascended to surgical elevation (790 m). The computational model output bubble size, aqueous humor volume, and IOP during the patients' travels. A parametric study was conducted to investigate the role of each modeling parameter. All four simulated cases showed increased peak IOP (34-50 mm Hg). Intraocular pressure returned to a normal value (15 mm Hg) after prolonged exposure to the surgical elevation. Over the course of the entire path, the gas bubble volume changed approximately 5%, decreasing in size during descent and then increasing during ascent. In our simulations the change of bubble size outpaced the change of aqueous humor volume resulting in a 2-fold risk to patients. First, the bubble size reduction at the low elevation may increase the risk of ocular hypotony and postsurgical retinal detachment. Second, the combined increasing bubble size and accumulated aqueous humor puts patients at risk of high peak IOP after ascent even without exceeding the surgical elevation. The risks are primarily dependent on rates of elevation change and duration spent at the different elevations.


Neuronal organization of the melanin-concentrating hormone system in primitive actinopterygians: evolutionary changes leading to teleosts.
Hypothalamic melanin-concentrating hormone (MCH) neurones occur in all vertebrates and have an apparent neuromodulatory role. In teleost fish, however, MCH is used also as a neurohypophysial hormone, controlling skin color, and as a hypophysiotrophic peptide. This work describes the central location of immunoreactive MCH perikarya and their projections to the pituitary in a range of ancestral fish to determine the phylogenetic stage when the peptide adopted these roles. In all actinopterygians examined, including polypteriformes, chondrosteans, holosteans, and teleosts, immunoreactive fibers were abundant in the median eminence or, in the case of teleosts, within the pars distalis itself, suggesting MCH acquired a hypophysial regulatory role early in vertebrate evolution. MCH fibers appeared to be absent from the posterior neurohypophysis of the polypteriform Calamoichthys but were evident in this region in the chondrostean Acipensor, the holosteans Lepisosteus and Amia, and all teleosts, suggesting its use as a neurohypophysial hormone. The ability of MCH to induce skin pallor seems to have arisen at a later stage, probably in the preholosteans. This hormonal role coincides with the migration of MCH perikarya away from the ventricular surface and their enlargement into magnocellular neurones. In the higher teleosts, magnocellular hypothalamo-neurohypophysial neurones predominate in size and number, whereas smaller periventricular MCH neurones associated with the paraventricular organ, that are prominent in lampreys, early actinopterygians and tetrapods, are reduced in teleosts. The data suggest that, in teleost fish, earlier functions of the peptide may have become subordinate to its novel pigmentary role.


Non-thermal electromagnetic radiation damage to lens epithelium.
High frequency microwave electromagnetic radiation from mobile phones and other modern devices has the potential to damage eye tissues, but its effect on the lens epithelium is unknown at present. The objective of this study was to investigate the non-thermal effects of high frequency microwave electromagnetic radiation (1.1GHz, 2.22 mW) on the eye lens epithelium in situ. Bovine lenses were incubated in organ culture at 35°C for 10-15 days. A novel computer-controlled microwave source was used to investigate the effects of microwave radiation on the lenses. 58 lenses were used in this study. The lenses were divided into four groups: (1) Control lenses incubated in organ culture for 10 to15 days. (2) Electromagnetic radiation exposure group treated with 1.1 GHz, 2.22 mW microwave radiation for 90 cycles of 50 minutes irradiation followed by 10 minutes pause and cultured up to 10 days. (3) Electromagnetic radiation exposure group treated as group 2 with 192 cycles of radiation and cultured for 15 days. (4) Lenses exposed to 39.5°C for 2 hours 3 times with 24 hours interval after each treatment beginning on the second day of the culture and cultured for 11 days. During the culture period, lens optical quality was followed daily by a computer-operated scanning laser beam. At the end of the culture period, control and treated lenses were analyzed morphologically and by assessment of the lens epithelial ATPase activity. Exposure to 1.1 GHz, 2.22 mW microwaves caused a reversible decrease in lens optical quality accompanied by irreversible morphological and biochemical damage to the lens epithelial cell layer. The effect of the electromagnetic radiation on the lens epithelium was remarkably different from those of conductive heat. The results of this investigation showed that electromagnetic fields from microwave radiation have a negative impact on the eye lens. The lens damage by electromagnetic fields was distinctly different from that caused by conductive heat.


The smartphone and the driver's cognitive workload: A comparison of Apple, Google, and Microsoft's intelligent personal assistants.
The goal of this research was to examine the impact of voice-based interactions using 3 different intelligent personal assistants (Apple's Siri, Google's Google Now for Android phones, and Microsoft's Cortana) on the cognitive workload of the driver. In 2 experiments using an instrumented vehicle on suburban roadways, we measured the cognitive workload of drivers when they used the voice-based features of each smartphone to place a call, select music, or send text messages. Cognitive workload was derived from primary task performance through video analysis, secondary-task performance using the Detection Response Task (DRT), and subjective mental workload. We found that workload was significantly higher than that measured in the single-task drive. There were also systematic differences between the smartphones: The Google system placed lower cognitive demands on the driver than the Apple and Microsoft systems, which did not differ. Video analysis revealed that the difference in mental workload between the smartphones was associated with the number of system errors, the time to complete an action, and the complexity and intuitiveness of the devices. Finally, surprisingly high levels of cognitive workload were observed when drivers were interacting with the devices: "on-task" workload measures did not systematically differ from that associated with a mentally demanding Operation Span (OSPAN) task. The analysis also found residual costs associated using each of the smartphones that took a significant time to dissipate. The data suggest that caution is warranted in the use of smartphone voice-based technology in the vehicle because of the high levels of cognitive workload associated with these interactions. (PsycINFO Database Record


Unique associations of the Job Demand-Control-Support model subscales with leisure-time physical activity and dietary energy intake.
Leisure-time physical activity (LTPA) and dietary energy intake are two important health behaviours, which at too low or high levels respectively, are associated with overweight and obesity. This study explores associations between subscales of the Job Demand-Control-Support (JDCS) model, LTPA and dietary energy intake. A cross-sectional design sampled current employees (N=433) from a South Australian cohort using a computer-assisted telephone interview and a self-completed food frequency questionnaire. In analyses adjusted for sex, age, and sociodemographic variables, higher levels of skill discretion were associated with increased odds for attaining sufficient physical activity (OR=2.45; 95% CI=1.10-5.47). Higher levels of decision authority were associated with reduced odds (OR=0.43; 95% CI=0.20-0.93) for being in the highest tertile of daily energy intake. Higher scores for coworker support were associated with increased odds (OR=2.20; 95% CI=1.15-4.23) for being in the highest tertile of daily energy intake. These findings support the consideration of the individual JDCS subscales, since this practice may reveal novel associations with health behaviour outcomes, thereby presenting new opportunities to improve employee health and wellbeing.


Mice exposed to diagnostic ultrasound in utero are less social and more active in social situations relative to controls.
Clinical use of diagnostic ultrasound imaging during pregnancy has a long history of safety and diagnostic utility, as supported by numerous human case reports and epidemiological studies. However, there exist in vivo studies linking large but clinically relevant doses of ultrasound applied to mouse fetuses in utero to altered learning, memory, and neuroanatomy of those mice. Also, there exists a well-documented significant increase in the likelihood of non-right-handedness in boys exposed to diagnostic ultrasound in utero, potentially relevant given the increased prevalence of autism in males, and reports of excess non-right-handedness in this population. Motivated by these observations, we applied 30 minutes of diagnostic ultrasound to pregnant mice at embryonic day 14.5 and assayed the social behavior of their male pups 3 weeks after their birth. The ultrasound-exposed pups were significantly (P < 0.01) less interested in social interaction than sham-exposed pups in a three-chamber sociability test. In addition, they demonstrated significantly (P < 0.05) more activity relative to the sham-exposed pups, but only in the presence of an unfamiliar mouse. These results suggest that fetal exposure to diagnostic ultrasound applied in utero can alter typical social behaviors in young mice that may be relevant for autism. There exist meaningful differences between the exposure of diagnostic ultrasound to mice versus humans that require further exploration before this work can usefully inform clinical practice. Future work should address these differences as well as clarify the extent, mechanisms, and functional effects of diagnostic ultrasound's interaction with the developing brain.


A Turner syndrome neurocognitive phenotype maps to Xp22.3.
Turner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions. Subjects were recruited from North American genetics and endocrinology clinics. Phenotype assessment included measures of stature, ovarian function, and detailed neurocognitive testing. The neurocognitive phenotype was measured as a quantitative trait, the Turner Syndrome Cognitive Summary (TSCS) score, derived from discriminant function analysis. Genetic analysis included karyotyping, X inactivation studies, fluorescent in situ hybridization, microsatellite marker genotyping, and array comparative genomic hybridization. We report statistical evidence that deletion of Xp22.3, an interval containing 31 annotated genes, is sufficient to cause the neurocognitive phenotype described by the TSCS score. Two other cardinal TS features, ovarian failure and short stature, as well as X chromosome inactivation pattern and subject's age, were unrelated to the TSCS score. Detailed mapping suggests that haploinsufficiency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is responsible for a TS neurocognitive phenotype. This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1). Haploinsufficiency of the short stature gene SHOX in PAR1 probably does not cause this TS neurocognitive phenotype. Two genes proximal to PAR1 within the 8.3 Mb critical region, STS and NLGN4X, are attractive candidates for this neurocognitive phenotype.


TOUCHSTONEX: protein structure prediction with sparse NMR data.
TOUCHSTONEX, a new method for folding proteins that uses a small number of long-range contact restraints derived from NMR experimental NOE (nuclear Overhauser enhancement) data, is described. The method employs a new lattice-based, reduced model of proteins that explicitly represents C(alpha), C(beta), and the sidechain centers of mass. The force field consists of knowledge-based terms to produce protein-like behavior, including various short-range interactions, hydrogen bonding, and one-body, pairwise, and multibody long-range interactions. Contact restraints were incorporated into the force field as an NOE-specific pairwise potential. We evaluated the algorithm using a set of 125 proteins of various secondary structure types and lengths up to 174 residues. Using N/8 simulated, long-range sidechain contact restraints, where N is the number of residues, 108 proteins were folded to a C(alpha)-root-mean-square deviation (RMSD) from native below 6.5 A. The average RMSD of the lowest RMSD structures for all 125 proteins (folded and unfolded) was 4.4 A. The algorithm was also applied to limited experimental NOE data generated for three proteins. Using very few experimental sidechain contact restraints, and a small number of sidechain-main chain and main chain-main chain contact restraints, we folded all three proteins to low-to-medium resolution structures. The algorithm can be applied to the NMR structure determination process or other experimental methods that can provide tertiary restraint information, especially in the early stage of structure determination, when only limited data are available.


Patient-reported utilization patterns of fentanyl transdermal system and oxycodone hydrochloride controlled-release among patients with chronic nonmalignant pain.
Although use of long-acting opioid analgesics has increased for chronic nonmalignant pain management, little is known about patient-reported utilization patterns. To assess patient-reported utilization patterns of fentanyl transdermal system and oxycodone hydrochloride (HCl) controlled-release among patients with chronic nonmalignant pain and to compare these patterns to standard dose administration guidelines recommended in the manufacturers. prescribing information (PI). Cross-sectional, observational, multicenter study of English-speaking patients who were seeking chronic nonmalignant pain management from 6 outpatient pain clinics. The inclusion criteria for the study were (1) diagnosis of chronic nonmalignant pain, (2) prescription for and current use of either transdermal fentanyl or oxycodone HCl controlled-release, and (3) duration of use for either transdermal fentanyl or oxycodone HCl controlled-release of at least 6 weeks. Patients completed either an oxycodone HCl controlled-release or transdermal fentanyl utilization questionnaire. A conversion table was used to standardize opioid analgesic doses from transdermal fentanyl or oxycodone HCl controlled-release to daily oral morphine equivalents. The principal outcome measures were the average interval between oxycodone HCl controlled-release administrations, the number of days the current transdermal fentanyl patch would be worn, and the percentage of oxycodone HCl controlled-release and transdermal fentanyl patients whose administration frequency exceeded the standard recommendation in the manufacturer.s PI (every 12 hours for oxycodone HCl controlled-release or every 72 hours for transdermal fentanyl). Other outcome measures included the number of oxycodone HCl controlled-release tablets per administration, the daily dose of long-acting opioid, the duration of adequate pain relief, and the difference in daily oral morphine equivalents between transdermal fentanyl and oxycodone HCl controlled-release patients, after adjusting in a multivariate regression model for demographic and clinical characteristics. A total of 690 patients were enrolled in this study; 437 (63.4%) received oxycodone HCl controlled-release and 253 (36.6%) received transdermal fentanyl. Oxycodone HCl controlled-release patients reported taking a median of 1 tablet 3 times per day or a median of 3 tablets per day. A mean of 1.6 tablets per administration and 4.6 tablets per day were taken. The average interval between administrations of oxycodone HCl controlled-release was 7.8 hours, and the median daily dose was 80.0 mg (mean 155.6 mg). Among oxycodone HCl controlled-release patients, 17.5% had an average interval between administrations of 12 or more hours, whereas 1.9% reported the duration of pain relief as 12 or more hours. Transdermal fentanyl patients reported wearing the patch, on average, for 2.5 days (median 2.5),and 41.2% reported wearing the patch for at least 3 days, whereas 14.1% reported the duration of pain relief as at least 3 days. The median daily dosage strength of transdermal fentanyl was 75.0 mcg/hour. In the multivariate regression analysis, oxycodone HCl controlled-release patients had, on average, roughly 22 mg additional oral morphine equivalents per day relative to transdermal fentanyl patients (not statistically significant); the probability that oxycodone HCl controlled-release patients had higher oral morphine equivalents was 82.6%, which suggests a trend toward higher oral morphine equivalents per day in the oxycodone HCl controlled-release group. Transdermal fentanyl and oxycodone HCl controlled-release both appear to be used by patients in a manner that is inconsistent with the standard recommendation in the manufacturers' PI;however, the difference between patient-reported utilization and the PI recommendation is more pronounced with oxycodone HCl controlled-release.


Widely used, commercially available Chlamydia pneumoniae antigen contaminated with mycoplasma.
Mycoplasma contamination was detected in a widely used commercially available Chlamydia pneumoniae antigen preparation. Contamination was studied with a mycoplasma group-specific 16S rRNA polymerase chain reaction (PCR) and sequence analysis. Several lots of the purified C. pneumoniae antigen from the Washington Research Foundation appeared to be contaminated with the same Mycoplasma species, which appeared to be closely related to M. arginini. Antigen slides prepared for the detection of chlamydia antibodies by MRL Diagnostics were contaminated with the same Mycoplasma sp. Chlamydia antigen slides from Labsystems OY and two chlamydia complement fixation reagents (Virion International Distribution Ltd and Behring Werke) were not contaminated. It is concluded that commercially available C. pneumoniae antigens may contain mycoplasma antigens as well. Although the impact of such mycoplasma contamination on the results of chlamydia serology may not be significant, routine screening of all antigen preparations obtained by tissue culture before their distribution and use is recommended.


The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial.
In the Women's Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.


Cause specific mortality, social position, and obesity among women who had never smoked: 28 year cohort study.
To investigate the relations between causes of death, social position, and obesity in women who had never smoked. Prospective cohort study. Renfrew and Paisley, Scotland. 8353 women and 7049 men aged 45-64 were recruited to the Renfrew and Paisley Study in 1972-6. Of these, 3613 women had never smoked and were the focus of this study. They were categorised by occupational class (I and II, III non-manual, III manual, and IV and V) and body mass index groups (normal weight, overweight, moderately obese, and severely obese). All cause and cause specific mortality during 28 years of follow-up by occupational class and body mass index, using Cox proportional hazards models adjusted for age and other confounders. The women in lower occupational classes who had never smoked were on average shorter and had poorer lung function and higher systolic blood pressure than women in the higher occupational classes. Overall, 43% (n = 1555) were overweight, 14% (n = 515) moderately obese, and 5% (n = 194) severely obese. Obesity rates were higher in lower occupational classes and much higher in all occupational classes than in current smokers in the full cohort. Half the women died, 51% (n = 916) from cardiovascular disease and 27% (n = 487) from cancer. Relative to occupational class I and II, all cause mortality rates were more than a third higher in occupational classes III manual (relative rate 1.35, 95% confidence interval 1.16 to 1.57) and IV and V (1.34, 1.17 to 1.55) and largely explained by differences in obesity, systolic blood pressure, and lung function. Similar upward gradients were seen for cardiovascular disease and respiratory disease but not for cancer. Mortality rates were highest in severely obese women in the lowest occupational classes. Women who had never smoked and were not obese had the lowest mortality rates, regardless of their social position. Where obesity is socially patterned as in this cohort, it may contribute to health inequalities and increase pressure on health and social services serving more disadvantaged populations.


Direct measurement of soluble CD4 binding to human immunodeficiency virus type 1 virions: gp120 dissociation and its implications for virus-cell binding and fusion reactions and their neutralization by soluble CD4.
We have analyzed the binding of soluble CD4 (sCD4) to human immunodeficiency virus type 1 (HIV-1) virions (isolates IIIB and RF) at 4 and 37 degrees C by using a combination of gel exclusion chromatography and enzyme-linked immunosorbent assay detection systems. The sCD4 binding curve at 37 degrees C indicates that the affinity of the interaction of sCD4 with gp120 on the virion surface is indistinguishable from the affinity of sCD4 for the equivalent concentration of soluble gp120. At 4 degrees C, however, the affinity of sCD4 for virion-bound gp120 but not for soluble gp120 is reduced by about 20-fold. Binding of sCD4 (greater than 0.2 microgram/ml) to virions at 37 degrees C but not 4 degrees C induces the rapid dissociation of a major proportion of gp120 from gp41 on the virion surface. This dissociation requires occupancy by sCD4 of multiple (probably two) binding sites on a gp120-gp41 oligomer. At 37 degrees C there are two components to the neutralizing action of sCD4 on HIV-1; reversible, competitive inhibition at low sCD4 concentrations (less than 0.2 microgram/ml) and essentially irreversible inhibition due to gp120 loss at higher sCD4 concentrations. At 4 degrees C, sCD4 neutralizes HIV infectivity by competitive inhibition alone. These findings may have implications for the HIV-CD4+ cell binding and fusion reactions and the mechanism by which sCD4 blocks infectivity.


Bone texture analysis is correlated with three-dimensional microarchitecture and mechanical properties of trabecular bone in osteoporotic femurs.
Fracture of the proximal femur is a major public health problem in elderly persons. It has recently been suggested that combining texture analysis and bone mineral density measurement improves the failure load prediction in human femurs. In this study, we aimed to compare bone texture analysis with three-dimensional (3D) microarchitecture and mechanical properties of trabecular bone in osteoporotic femurs. Eight femoral heads from osteoporotic patients who fractured their femoral neck provided 31 bone cores. Bone samples were studied using a new high-resolution digital X-ray device (BMA™, D3A Medical Systems) allowing for texture analysis with fractal parameter H (mean), and were examined using micro-computed tomography (microCT) for 3D microarchitecture. Finally, uniaxial compression tests to failure were performed to estimate failure load and apparent modulus of bone samples. The fractal parameter H (mean) was strongly correlated with bone volume fraction (BV/TV) (r = 0.84) and trabecular thickness (Tb.Th) (r = 0.91) (p < 0.01). H (mean) was also markedly correlated with failure load (r = 0.84) and apparent modulus (r = 0.71) of core samples (p < 0.01). Bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) demonstrated significant correlations with failure load (r = 0.85 and 0.72, respectively) and apparent modulus (r = 0.72 and 0.64, respectively) (p < 0.01). Overall, the best predictors of failure load were H (mean), bone volume fraction, and trabecular thickness, with r (2) coefficients of 0.83, 0.76, and 0.80 respectively. This study shows that the fractal parameter H (mean) is correlated with 3D microCT parameters and mechanical properties of femoral head bone samples, which suggests that radiographic texture analysis is a suitable approach for trabecular bone microarchitecture assessment in osteoporotic femurs.


Indocyanine green-assisted internal limiting membrane peeling in macular hole surgery: a meta-analysis.
The opinion of application of indocyanine green (ICG) in the macular hole surgery was contradictory. Here we conducted a meta-analysis to evaluate the effect of in internal limiting membrane (ILM) peeling for macular hole surgery. We searched electronic databases for comparative studies published before July 2012 of ILM peeling with and without ICG. Twenty-two studies including 1585 eyes were included. Visual acuity (VA) improvement, including the postoperative rate of ≥20/40 VA gained (OR, 0.65; 95% CI, 0.43 to 0.97; P = 0.033) and increased LogMAR (WMD, -0.09; 95% CI, -0.16 to -0.02; P = 0.011), was less in the ICG group. The risk of visual field defects was greater in the ICG group than in the non-ICG group. There was no significant difference in the rate of anatomical outcomes between ILM peeling procedures performed with and without ICG. RPE changes and other postoperative complications were not significantly different between the ICG and non-ICG groups. An additional analysis showed that the VA improvement of the ICG group was less than the non-ICG group only within the first year of follow up. A subgroup analysis showed that the rate of VA improvement was lower in the ICG group than in other adjuncts group. A higher rate of secondary closure and less VA improvement were observed in a high proportion (>0.1%) of the ICG group. A sensitivity analysis after the randomized-controlled trials were excluded from the meta-analysis demonstrated no differences compared with the overall results. This meta-analysis demonstrated that there is no evidence of clinical superiority in outcomes for ICG-assisted ILM peeling procedure over the non-ICG one. The toxicity of ICG should be considered when choosing the various staining methods.


Gli1 is an inducing factor in generating floor plate progenitor cells from human embryonic stem cells.
Generation of mesencephalic dopamine (mesDA) neurons from human embryonic stem cells (hESCs) requires several stages of signaling from various extrinsic and intrinsic factors. To date, most methods incorporate exogenous treatment of Sonic hedgehog (SHH) to derive mesDA neurons. However, we and others have shown that this approach is inefficient for generating FOXA2+ cells, the precursors of mesDA neurons. As mesDA neurons are derived from the ventral floor plate (FP) regions of the embryonic neural tube, we sought to develop a system to derive FP cells from hESC. We show that forced expression of the transcription factor GLI1 in hESC at the earliest stage of neural induction, resulted in their commitment to FP lineage. The GLI1+ cells coexpressed FP markers, FOXA2 and Corin, and displayed exocrine SHH activity by ventrally patterning the surrounding neural progenitors. This system results in 63% FOXA2+ cells at the neural progenitor stage of hESC differentiation. The GLI1-transduced cells were also able to differentiate to neurons expressing tyrosine hydroxylase. This study demonstrates that GLI1 is a determinant of FP specification in hESC and describes a highly robust and efficient in vitro model system that mimics the ventral neural tube organizer.


Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment.
A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues.


Liquid chromatography/tandem mass spectrometry characterization of oxidized amyloid beta peptides as potential biomarkers of Alzheimer's disease.
Alzheimer's disease is characterized by the deposition of senile plaques that consist primarily of amyloid beta peptides. There is substantial evidence that amyloid beta is oxidized in vivo, which has led to the suggestion that oxidative stress is an important mediator of Alzheimer's disease. Metal-catalyzed oxidation can mimic in vivo oxidation of amyloid beta because the metal ion binds to the amino acid residues at the site of oxidation, which then deliver reactive oxygen species to that site. Based on electrospray mass spectrometry, it has been suggested that metal-catalyzed oxidation occurs on histidines-13 and -14. Unfortunately, the amyloid beta peptides provide complex spectra, so it is difficult to definitively characterize the sites of oxidation. Trypsin digestion of both native and oxidized amyloid beta1-16 and amyloid beta1-40 resulted in the formation of tryptic peptides corresponding to amyloid beta6-16, which could be separated by liquid chromatography (LC). Sites of oxidation were then unequivocally characterized as histidine-13 and histidine-14 by LC/tandem mass spectrometric (MS/MS) analysis of the tryptic peptides. The ability to analyze the specific amyloid beta6-16 tryptic fragments derived from full-length amyloid beta peptides will make it possible to determine whether oxidation in vivo occurs at specific histidine residues and/or at other amino acid residues such as methionine-35. Using methodology based on LC/MS/MS it will also be possible to analyze the relative amounts of oxidized peptides and native peptide in cerebrospinal fluid from patients with Alzheimer's disease as biomarkers of oxidative stress.


A new alarm point of transcranial electrical stimulation motor evoked potentials for intraoperative spinal cord monitoring: a prospective multicenter study from the Spinal Cord Monitoring Working Group of the Japanese Society for Spine Surgery and Related Research.
Although multimodal intraoperative spinal cord monitoring provides greater accuracy, transcranial electrical stimulation motor evoked potential (TcMEP) monitoring became the gold standard for intraoperative spinal cord monitoring. However, there is no definite alarm point for TcMEPs because a multicenter study is lacking. Thus, based on their experience with 48 true-positive cases (that is, a decrease in potentials followed by a new neurological motor deficit postoperatively) encountered between 2007 and 2009, the authors set a 70% decrease in amplitude as the alarm point for TcMEPs. A total of 959 cases of spinal deformity, spinal cord tumor, and ossification of the posterior longitudinal ligament (OPLL) treated between 2010 and 2012 are included in this prospective multicenter study (18 institutions). These institutions are part of the Japanese Society for Spine Surgery and Related Research monitoring working group and the study group on spinal ligament ossification. The authors prospectively analyzed TcMEP variability and pre- and postoperative motor deficits. A 70% decrease in amplitude was designated as the alarm point. There were only 2 false-negative cases, which occurred during surgery for intramedullary spinal cord tumors. This new alarm criterion provided high sensitivity (95%) and specificity (91%) for intraoperative spinal cord monitoring and favorable accuracy, except in cases of intramedullary spinal cord tumor. This study is the first prospective multicenter study to investigate the alarm point of TcMEPs. The authors recommend the designation of an alarm point of a 70% decrease in amplitude for routine spinal cord monitoring, particularly during surgery for spinal deformity, OPLL, and extramedullary spinal cord tumor.


Riluzole blocks human muscle acetylcholine receptors.
Riluzole, the only drug available against amyotrophic lateral sclerosis (ALS), has recently been shown to block muscle ACh receptors (AChRs), raising concerns about possible negative side-effects on neuromuscular transmission in treated patients. In this work we studied riluzole's impact on the function of muscle AChRs in vitro and on neuromuscular transmission in ALS patients, using electrophysiological techniques. Human recombinant AChRs composed of α(1)β(1)δ subunits plus the γ or ε subunit (γ- or ε-AChR) were expressed in HEK cells or Xenopus oocytes. In both preparations, riluzole at 0.5 μm, a clinically relevant concentration, reversibly reduced the amplitude and accelerated the decay of ACh-evoked current if applied before coapplication with ACh. The action on γ-AChRs was more potent and faster than on ε-AChRs. In HEK outside-out patches, riluzole-induced block of macroscopic ACh-evoked current gradually developed during the initial milliseconds of ACh presence. Single channel recordings in HEK cells and in human myotubes from ALS patients showed that riluzole prolongs channel closed time, but has no effect on channel conductance and open duration. Finally, compound muscle action potentials (CMAPs) evoked by nerve stimulation in ALS patients remained unaltered after a 1 week suspension of riluzole treatment. These data indicate that riluzole, while apparently safe with regard to synaptic transmission, may affect the function of AChRs expressed in denervated muscle fibres of ALS patients, with biological consequences that remain to be investigated.


A Monte Carlo study of the effect of an ultrasound transducer on surface dose during intrafraction motion imaging for external beam radiation therapy.
The aim of this study was to estimate changes in surface dose due to the presence of the Clarity Autoscan™ ultrasound (US) probe during prostate radiotherapy using Monte Carlo (MC) methods. MC models of the Autoscan US probe were developed using the BEAMnrc/DOSXYZnrc code based on kV and MV CT images. CT datasets were converted to voxelized mass density phantoms using a CT number-to-mass density calibration. The dosimetric effect of the probe, in the contact region (an 8 mm × 12 mm single layer of voxels), was investigated using a phantom set-up mimicking two scenarios (a) a transperineal imaging configuration (radiation beam perpendicular to the central US axial direction), and (b) a transabdominal imaging configuration (radiation beam parallel to the central US axial direction). For scenario (a), the dosimetric effect was evaluated as a function of the probe to inferior radiation field edge distance. Clinically applicable distances from 5 mm separation to 2 mm overlap were determined from the radiotherapy plans of 27 patients receiving Clarity imaging. Overlaps of 3 to 14 (1 to 3 SD) mm were also considered to include the effect of interfraction motion correction. The influence of voxel size on surface dose estimation was investigated. Approved clinical plans from two prostate patients were used to simulate worst-case dosimetric impact of the probe when large couch translations were applied to correct for interfraction prostate motion. The dosimetric impact of both the MV and kV probe models agreed within ±2% for both beam configurations. For scenario (a) and 1 mm voxel model, the probe gave mean dose increases of 1.2% to 4.6% (of the dose at isocenter) for 5 mm separation to 0 mm overlap in the probe-phantom contact region, respectively. This increased to 27.5% for the largest interfraction motion correction considered (14 mm overlap). For separations of ≥ 2 mm dose differences were < 2%. Simulated dose perturbations were found to be superficial; for the 14 mm overlap the dose increase reduced to < 3% at 5.0 mm within the phantom. For scenario (b), dose increases due to the probe were < 5% in all cases. The dose increase was underestimated by up to ~13% when the voxel size was increased from 1 mm to 3 mm. MC simulated dose to the PTV and OARs for the two clinical plans considered showed good agreement with commercial treatment planning system results (within 2%). Mean dose increases due to the presence of the probe, after the maximum interfraction motion correction, were ~16.3% and ~8.0%, in the contact region, for plan 1 and plan 2, respectively. The presence of the probe results in superficial dose perturbations for patients with an overlap between the probe and the radiation field present in either the original treatment plan or due to translation of the radiation field to simulate correction of interfraction internal prostate motion.


Dietary salt induces transcription of the prostaglandin transporter gene in renal collecting ducts.
Prostaglandin E(2) (PGE(2)) plays an important role in maintaining body fluid homeostasis by activating its receptors on the renal collecting duct (CD) to stimulate renal Na(+) and water excretion. The PG carrier prostaglandin transporter (PGT) is expressed on the CD apical membrane, where it mediates PG reuptake as part of the termination of autocrine PG signaling. Here we tested the hypothesis that dietary salt loading regulates PGT gene transcription in renal CDs. We placed green fluorescence protein (GFP) under control of 3.3 kb of the mouse PGT promoter and injected this construct into the pronuclei of fertilized FVB mouse eggs. Four of thirty-eight offspring were GFP positive by genotyping. We extensively characterized one (no. 29) PGT-GFP transgenic mouse line. On microscopic examination, GFP was expressed in CDs as determined by their expression of aquaporin-2. We fed mice a low (0.03% NaCl)-, normal (0.3% NaCl)-, or high-salt (3% NaCl) diet for 2 wk and quantified CD GFP expression. The average number of GFP-positive CD cells per microscopic section varied directly with dietary salt intake. Compared with mice on the control (0.3% sodium) diet, mice on a low-sodium (0.03%) diet had reduced numbers of GFP-positive cells (71% of control, P < 0.001), whereas mice on a high-sodium (3%) diet had increased numbers of GFP-positive cells (139% of control, P < 0.001). This increase in apparent CD PGT transcription resulted in a 51-55% increase (P < 0.001) in whole kidney PGT mRNA levels as determined by real-time PCR. The regulation of PG signal termination via reuptake represents a new pathway for controlling renal Na(+) balance.


Performance of a career development and compensation program at an academic health science center.
The academic physicians of our department developed a novel Career Development and Compensation Program to outline job expectations, enhance career development, and provide a peer-review process to assess performance. The Career Development and Compensation Program was founded on the principle that sustained achievement in education, clinical care, or research should be valued, supported, and rewarded in an equivalent manner and that reward for clinical work should not be limited by the focus of the university on research and education. The objective of this study was to determine whether the principles of the Career Development and Compensation Program were sustained during the initial 7 years of its implementation. The outcome of the 7 triennial reviews that occurred from 1999 to 2005 was evaluated. For the purposes of some analyses, physicians were classified as predominately clinical (clinician-specialists and clinician-teachers), predominately education (clinician-educators), or predominately research (clinician-investigators and clinician-scientists). Each of the job profiles had a similar probability to increase a level within the Career Development and Compensation Program at the time of triennial review. Similarly, all 5 job profiles had a similar rate of increase in their level in relation to the total number of years of experience at an academic health science center. Neither the university academic rank nor gender of the physician affected the probability of increasing a level at the time of the triennial review. The peer-reviewed Career Development and Compensation Program recognizes sustained achievement in each area of education, clinical care, and research in an equivalent manner with no detectable effect of academic rank or gender.


Calcium window currents, periodic forcing, and chaos: understanding single neuron response with a discontinuous one-dimensional map.
Thalamocortical (TC) neurones are known to express the low-voltage activated, inactivating Ca2+ current I(T). The triggering of this current underlies the generation of low threshold Ca2+ potentials that may evoke single or bursts of action potentials. Moreover, this current can contribute to an intrinsic slow (<1 Hz) oscillation whose rhythm is partly determined by the steady state component of I(T) and its interaction with a leak current. This steady state, or window current as it is so often called, has received relatively little theoretical attention despite its importance in determining the electroresponsiveness and input-output relationship of TC neurones. In this paper, we introduce an integrate-and-fire spiking neuron model that includes a biophysically realistic model of I(T). We briefly review the subthreshold bifurcation diagram of this model with constant current injection before moving on to consider its response to periodic forcing. Direct numerical simulations show that as well as the expected mode-locked responses there are regions of parameter space that support chaotic behavior. To reveal the mechanism by which the window current generates a chaotic response to periodic forcing we consider a piecewise linear caricature of the dynamics for the gating variables in the model of I(T). This model can be analyzed in closed form and is shown to support an unstable set of periodic orbits. Trajectories are repelled from these organizing centers until they reach the threshold for firing. By determining the condition for a grazing bifurcation (at the border between a spiking and nonspiking event) we show how knowledge of the unstable periodic orbits (existence and stability) can be combined with the grazing condition to determine an effective one-dimensional map that captures the essentials of the chaotic behavior. This map is discontinuous and has strong similarities with the universal limit mapping in grazing bifurcations derived in the context of impacting mechanical systems [A. B. Nordmark, Phys. Rev. E 55, 266 (1997)].


Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.
Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children. We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment. 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09). We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn. National Institute for Health Research Health Technology Assessment.


In vitro self-assembly of the light harvesting pigment-protein LH2 revealed by ultrafast spectroscopy and electron microscopy.
Controlled ensemble formation of protein-surfactant systems provides a fundamental concept for the realization of nanoscale devices with self-organizing capability. In this context, spectroscopic monitoring of pigment-containing proteins yields detailed structural information. Here we have studied the association behavior of the bacterial light-harvesting protein LH2 from Rhodobacter spheroides in an n,n-dimethyldodecylamine-n-oxide/water environment. Time-resolved studies of the excitation annihilation yielded information about aggregate sizes and packing of the protein complexes therein. The results are compared to transmission electron microscopy images of instantaneously frozen samples. Our data indicate the manifestation of different phases, which are discussed with respect to the thermodynamic equilibrium in ternary protein-surfactant-water systems. Accordingly, by varying the concentration the formation of different types of aggregates can be controlled. Conditions for the appearance of isolated LH2 complexes are defined.


Predicting unfavorable long-term outcome in juvenile idiopathic arthritis: results from the Nordic cohort study.
The aim was to develop prediction rules that may guide early treatment decisions based on baseline clinical predictors of long-term unfavorable outcome in juvenile idiopathic arthritis (JIA). In the Nordic JIA cohort, we assessed baseline disease characteristics as predictors of the following outcomes 8 years after disease onset. Non-achievement of remission off medication according to the preliminary Wallace criteria, functional disability assessed by Childhood Health Assessment Questionnaire (CHAQ) and Physical Summary Score (PhS) of the Child Health Questionnaire, and articular damage assessed by the Juvenile Arthritis Damage Index-Articular (JADI-A). Multivariable models were constructed, and cross-validations were performed by repeated partitioning of the cohort into training sets for developing prediction models and validation sets to test predictive ability. The total cohort constituted 423 children. Remission status was available in 410 children: 244 (59.5%) of these did not achieve remission off medication at the final study visit. Functional disability was present in 111/340 (32.7%) children assessed by CHAQ and 40/199 (20.1%) by PhS, and joint damage was found in 29/216 (13.4%). Model performance was acceptable for making predictions of long-term outcome. In validation sets, the area under the curves (AUCs) in the receiver operating characteristic (ROC) curves were 0.78 (IQR 0.72-0.82) for non-achievement of remission off medication, 0.73 (IQR 0.67-0.76) for functional disability assessed by CHAQ, 0.74 (IQR 0.65-0.80) for functional disability assessed by PhS, and 0.73 (IQR 0.63-0.76) for joint damage using JADI-A. The feasibility of making long-term predictions of JIA outcome based on early clinical assessment is demonstrated. The prediction models have acceptable precision and require only readily available baseline variables. Further testing in other cohorts is warranted.


Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial.
Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 μg, 15 μg, or 45 μg, or one dose of sclamp vaccine at 45 μg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933. Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 μg dose (geometric mean titre [GMT] 6400, 95% CI 3683-11 122), with 15 μg dose (7492, 4959-11 319), and the two 45 μg dose cohorts (8770, 5526-13 920 in the two-dose 45 μg cohort; 8793, 5570-13 881 in the single-dose 45 μg cohort); 4 weeks after the second dose (day 57) with two 5 μg doses (102 400, 64 857-161 676), with two 15 μg doses (74 725, 51 300-108 847), with two 45 μg doses (79 586, 55 430-114 268), only a single 45 μg dose (4795, 2858-8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 μg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 μg doses (GMT 228, 95% CI 146-356), two 15 μg doses (230, 170-312), and two 45 μg doses (239, 187-307). This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.


Iguanid lizard from the upper cretaceous of Brazil.
Pristiguana brasiliensis, new genus and species, from the Upper Cretaceous Baurú Formation of Brazil, is the oldest fossil referable to the living lizard family Iguanidae. It resembles living primitive South American iguanids in some features, but also shows similarity to members of the related family Teiidae. Iguanid fossils do not appear in North America until the early Eocene, probably by waif dispersal from South America during the late Paleocene or early Eocene. A southern continental (Gondwanan) origin of iguanids is more plausible than the northern one often suggested.


Achillea Millefolium L. Hydro- Alcoholic Extract Protects Pancreatic Cells by Down Regulating IL- 1β and iNOS Gene Expression in Diabetic Rats.
Interleukin-1β (IL-1β) has a role in β- cell destruction in autoimmune diabetes by stimulating the expression of inducible nitric oxide synthase (iNOS) that generates the free radical nitric oxide. We aimed to investigate the effect of Achillea millefolium L, as a traditional hypoglycemic agent, on IL-1β and iNOS gene expression of pancreatic tissue in the STZ- induced diabetic rats. Forty adult male Wistar rats were randomly divided into four groups: 1. diabetic control; 2. diabetic rats treated with Achillea millefolium L. extract; 3. normal rats received only extract and 4. negative control (n= 10 each). Diabetes was induced by single i.p. injection of 45 mg/ kg streptozotocin (STZ). Rats in groups 2 and 3 were treated with i.p. injection of Achillea millefolium L. extract (100 mg/ kg/ day) for 14 days. Body weight, serum glucose and insulin levels were assayed at baseline and on days 3, 7, 10 and 14 of the experiment. Finally, the quantity of pancreatic IL-1β and iNOS mRNA was determined by real- time PCR. The mRNA expression level of IL-1β and iNOS genes, was significantly (p<0.001) increased in diabetic rats of group 1. Treatment with Achillea millefolium L. caused a significant (p<0.01) reduction in both IL-1β and iNOS genes expression. Moreover, rats in group 2 had higher insulin level associated with lower glucose level and higher body weight compared to control diabetic group. It seems that beneficial effect of Achillea millefolium L. on STZ- induced diabetes is at least partly due to amelioration of IL-1β and iNOS gene over expression which can have a β-cell protective effect.


Jasmonate-dependent and COI1-independent defense responses against Sclerotinia sclerotiorum in Arabidopsis thaliana: auxin is part of COI1-independent defense signaling.
The jasmonate receptor COI1 is known to facilitate plant defense responses against necrotrophic pathogens, including the ascomycete Sclerotinia sclerotiorum. However, it is not known to what extent jasmonates contribute to defense nor have COI1-independent defense pathways been sufficiently characterized. Here we show that the susceptibility to S. sclerotiorum of the aos mutant, deficient in biosynthesis of jasmonic acid (JA) and its precursor 12-oxophytadienoic acid, was elevated to a level reminiscent of that of hypersusceptible coi1 mutants. In contrast, susceptibility of the JA-deficient opr3 mutant was comparable with that of the wild type. A set of 99 genes responded similarly to infection with S. sclerotiorum in wild-type and coi1 mutant leaves. Expression of this COI1-independent gene set correlated with known differences in gene expression between wild-type plants and a mutant in the transcriptional repressor auxin response factor 2 (arf2). Susceptibility to S. sclerotiorum was reduced in two arf2 mutants early during infection, implicating ARF2 as a negative regulator of defense responses against this pathogen. Hypersusceptibility of an axr1 mutant to S. sclerotiorum confirmed the contribution of auxin action to defense responses against this fungal pathogen.


Nonretinotopic visual processing in the brain.
A basic principle in visual neuroscience is the retinotopic organization of neural receptive fields. Here, we review behavioral, neurophysiological, and neuroimaging evidence for nonretinotopic processing of visual stimuli. A number of behavioral studies have shown perception depending on object or external-space coordinate systems, in addition to retinal coordinates. Both single-cell neurophysiology and neuroimaging have provided evidence for the modulation of neural firing by gaze position and processing of visual information based on craniotopic or spatiotopic coordinates. Transient remapping of the spatial and temporal properties of neurons contingent on saccadic eye movements has been demonstrated in visual cortex, as well as frontal and parietal areas involved in saliency/priority maps, and is a good candidate to mediate some of the spatial invariance demonstrated by perception. Recent studies suggest that spatiotopic selectivity depends on a low spatial resolution system of maps that operates over a longer time frame than retinotopic processing and is strongly modulated by high-level cognitive factors such as attention. The interaction of an initial and rapid retinotopic processing stage, tied to new fixations, and a longer lasting but less precise nonretinotopic level of visual representation could underlie the perception of both a detailed and a stable visual world across saccadic eye movements.


Pneumococcal Colonization Rates in Patients Admitted to a United Kingdom Hospital with Lower Respiratory Tract Infection: a Prospective Case-Control Study.
Current diagnostic tests are ineffective for identifying the etiological pathogen in hospitalized adults with lower respiratory tract infections (LRTIs). The association of pneumococcal colonization with disease has been suggested as a means to increase the diagnostic precision. We compared the pneumococcal colonization rates and the densities of nasal pneumococcal colonization by (i) classical culture and (ii) quantitative real-time PCR (qPCR) targetinglytAin patients with LRTIs admitted to a hospital in the United Kingdom and control patients. A total of 826 patients were screened for inclusion in this prospective case-control study. Of these, 38 patients were recruited, 19 with confirmed LRTIs and 19 controls with other diagnoses. Nasal wash (NW) samples were collected at the time of recruitment. Pneumococcal colonization was detected in 1 patient with LRTI and 3 controls (P= 0.6) by classical culture. By qPCR, pneumococcal colonization was detected in 10 LRTI patients and 8 controls (P= 0.5). Antibiotic usage prior to sampling was significantly higher in the LRTI group than in the control group (19 versus 3;P< 0.001). With a clinically relevant cutoff of >8,000 copies/ml on qPCR, pneumococcal colonization was found in 3 LRTI patients and 4 controls (P> 0.05). We conclude that neither the prevalence nor the density of nasal pneumococcal colonization (by culture and qPCR) can be used as a method of microbiological diagnosis in hospitalized adults with LRTI in the United Kingdom. A community-based study recruiting patients prior to antibiotic therapy may be a useful future step.


Functional cortex and subcortical white matter located within gliomas.
Some neurosurgeons state that intra-axial tumors may be resected with a low risk of neurological deficit if the tumor removal stays within the confines of the grossly abnormal tissue. This is thought to be so even when the lesion is presumably located in a functional area, providing that the adjacent normal-appearing cortex and subcortical white matter are not disturbed. This retrospective analysis presents evidence that this view is not always correct, because functioning motor, sensory, or language tissue can be located within a grossly obvious tumor or the surrounding infiltrated brain. Intraoperative stimulation mapping techniques identified 28 patients, ranging in age between 22 and 73 years, who showed evidence of functional tissue within the boundaries of infiltrative gliomas, as identified by correlation with computed tomography and magnetic resonance imaging scans, intraoperative ultrasound, gross visualization, and histological confirmation. Direct stimulation mapping of cortical and subcortical portions of the tumor during resections identified motor, sensory, naming, reading, or speech arrest function. Nineteen patients had new or worsened neurological deficits immediately after the operation, but after 3 months, only 6 continued to show new deficits whereas 18 showed no deficits and 2 improved. These results demonstrate that regardless of the degree of tumor infiltration, swelling, apparent necrosis, and gross distortion by the mass, functional cortex and subcortical white matter may be located within the tumor or the adjacent infiltrated brain. Therefore, to safely maximize glioma resection in these functional areas, intraoperative stimulation mapping may be used to identify functional cortical or subcortical tissue within, as well as adjacent to, the tumor, thus avoiding permanent injury.


Dissociation between face perception and face memory in adults, but not children, with developmental prosopagnosia.
Cognitive models propose that face recognition is accomplished through a series of discrete stages, including perceptual representation of facial structure, and encoding and retrieval of facial information. This implies that impaired face recognition can result from failures of face perception, face memory, or both. Studies of acquired prosopagnosia, autism spectrum disorders, and the development of normal face recognition support the idea that face perception and face memory are distinct processes, yet this distinction has received little attention in developmental prosopagnosia (DP). To address this issue, we tested the face perception and face memory of children and adults with DP. By definition, face memory is impaired in DP, so memory deficits were present in all participants. However, we found that all children, but only half of the adults had impaired face perception. Thus, results from adults indicate that face perception and face memory are dissociable, while the results from children provide no evidence for this division. Importantly, our findings raise the possibility that DP is qualitatively different in childhood versus adulthood. We discuss theoretical explanations for this developmental pattern and conclude that longitudinal studies are necessary to better understand the developmental trajectory of face perception and face memory deficits in DP.


Alcoholics Anonymous and other 12-step programs for alcohol use disorder.
Alcohol use disorder (AUD) confers a prodigious burden of disease, disability, premature mortality, and high economic costs from lost productivity, accidents, violence, incarceration, and increased healthcare utilization. For over 80 years, Alcoholics Anonymous (AA) has been a widespread AUD recovery organization, with millions of members and treatment free at the point of access, but it is only recently that rigorous research on its effectiveness has been conducted. To evaluate whether peer-led AA and professionally-delivered treatments that facilitate AA involvement (Twelve-Step Facilitation (TSF) interventions) achieve important outcomes, specifically: abstinence, reduced drinking intensity, reduced alcohol-related consequences, alcohol addiction severity, and healthcare cost offsets. We searched the Cochrane Drugs and Alcohol Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, CINAHL and PsycINFO from inception to 2 August 2019. We searched for ongoing and unpublished studies via ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 15 November 2018. All searches included non-English language literature. We handsearched references of topic-related systematic reviews and bibliographies of included studies. We included randomized controlled trials (RCTs), quasi-RCTs and non-randomized studies that compared AA or TSF (AA/TSF) with other interventions, such as motivational enhancement therapy (MET) or cognitive behavioral therapy (CBT), TSF treatment variants, or no treatment. We also included healthcare cost offset studies. Participants were non-coerced adults with AUD. We categorized studies by: study design (RCT/quasi-RCT; non-randomized; economic); degree of standardized manualization (all interventions manualized versus some/none); and comparison intervention type (i.e. whether AA/TSF was compared to an intervention with a different theoretical orientation or an AA/TSF intervention that varied in style or intensity). For analyses, we followed Cochrane methodology calculating the standard mean difference (SMD) for continuous variables (e.g. percent days abstinent (PDA)) or the relative risk (risk ratios (RRs)) for dichotomous variables. We conducted random-effects meta-analyses to pool effects wherever possible. We included 27 studies containing 10,565 participants (21 RCTs/quasi-RCTs, 5 non-randomized, and 1 purely economic study). The average age of participants within studies ranged from 34.2 to 51.0 years. AA/TSF was compared with psychological clinical interventions, such as MET and CBT, and other 12-step program variants. We rated selection bias as being at high risk in 11 of the 27 included studies, unclear in three, and as low risk in 13. We rated risk of attrition bias as high risk in nine studies, unclear in 14, and low in four, due to moderate (> 20%) attrition rates in the study overall (8 studies), or in study treatment group (1 study). Risk of bias due to inadequate researcher blinding was high in one study, unclear in 22, and low in four. Risks of bias arising from the remaining domains were predominantly low or unclear. AA/TSF (manualized) compared to treatments with a different theoretical orientation (e.g. CBT) (randomized/quasi-randomized evidence) RCTs comparing manualized AA/TSF to other clinical interventions (e.g. CBT), showed AA/TSF improves rates of continuous abstinence at 12 months (risk ratio (RR) 1.21, 95% confidence interval (CI) 1.03 to 1.42; 2 studies, 1936 participants; high-certainty evidence). This effect remained consistent at both 24 and 36 months. For percentage days abstinent (PDA), AA/TSF appears to perform as well as other clinical interventions at 12 months (mean difference (MD) 3.03, 95% CI -4.36 to 10.43; 4 studies, 1999 participants; very low-certainty evidence), and better at 24 months (MD 12.91, 95% CI 7.55 to 18.29; 2 studies, 302 participants; low-certainty evidence) and 36 months (MD 6.64, 95% CI 1.54 to 11.75; 1 study, 806 participants; low-certainty evidence). For longest period of abstinence (LPA), AA/TSF may perform as well as comparison interventions at six months (MD 0.60, 95% CI -0.30 to 1.50; 2 studies, 136 participants; low-certainty evidence). For drinking intensity, AA/TSF may perform as well as other clinical interventions at 12 months, as measured by drinks per drinking day (DDD) (MD -0.17, 95% CI -1.11 to 0.77; 1 study, 1516 participants; moderate-certainty evidence) and percentage days heavy drinking (PDHD) (MD -5.51, 95% CI -14.15 to 3.13; 1 study, 91 participants; low-certainty evidence). For alcohol-related consequences, AA/TSF probably performs as well as other clinical interventions at 12 months (MD -2.88, 95% CI -6.81 to 1.04; 3 studies, 1762 participants; moderate-certainty evidence). For alcohol addiction severity, one study found evidence of a difference in favor of AA/TSF at 12 months (P < 0.05; low-certainty evidence). AA/TSF (non-manualized) compared to treatments with a different theoretical orientation (e.g. CBT) (randomized/quasi-randomized evidence) For the proportion of participants completely abstinent, non-manualized AA/TSF may perform as well as other clinical interventions at three to nine months follow-up (RR 1.71, 95% CI 0.70 to 4.18; 1 study, 93 participants; low-certainty evidence). Non-manualized AA/TSF may also perform slightly better than other clinical interventions for PDA (MD 3.00, 95% CI 0.31 to 5.69; 1 study, 93 participants; low-certainty evidence). For drinking intensity, AA/TSF may perform as well as other clinical interventions at nine months, as measured by DDD (MD -1.76, 95% CI -2.23 to -1.29; 1 study, 93 participants; very low-certainty evidence) and PDHD (MD 2.09, 95% CI -1.24 to 5.42; 1 study, 286 participants; low-certainty evidence). None of the RCTs comparing non-manualized AA/TSF to other clinical interventions assessed LPA, alcohol-related consequences, or alcohol addiction severity. Cost-effectiveness studies In three studies, AA/TSF had higher healthcare cost savings than outpatient treatment, CBT, and no AA/TSF treatment. The fourth study found that total medical care costs decreased for participants attending CBT, MET, and AA/TSF treatment, but that among participants with worse prognostic characteristics AA/TSF had higher potential cost savings than MET (moderate-certainty evidence). There is high quality evidence that manualized AA/TSF interventions are more effective than other established treatments, such as CBT, for increasing abstinence. Non-manualized AA/TSF may perform as well as these other established treatments. AA/TSF interventions, both manualized and non-manualized, may be at least as effective as other treatments for other alcohol-related outcomes. AA/TSF probably produces substantial healthcare cost savings among people with alcohol use disorder.


Increased Efficacy of Brentuximab Vedotin (SGN-35) in Combination with Cytokine-Induced Killer Cells in Lymphoma.
Brentuximab vedotin (SGN-35) is an antibody-drug conjugate with a high selectivity against CD30⁺ cell lines and more than 300-fold less activity against antigen-negative cells. In the last years, the results of many in vitro and in vivo studies have led to the fast approval of this drug to treat lymphoma patients. Another innovative method to treat tumor cells including lymphoma cells is the use cytokine-induced killer (CIK) cells, which have also been approved and proven to be a safe treatment with only minor adverse events. In this study, a possible additive effect when combining SGN-35 with CIK cells was investigated. The combinational treatment showed that it reduces the viability of CD30⁺ cell lines significantly in vitro. Additionally, the amount of lymphoma cells was significantly reduced when exposed to CIK cells as well as when exposed to SGN-35. A significant negative effect of SGN-35 on the function of CIK cells could be excluded. These results lead to the assumption that SGN-35 and CIK cells in combination might achieve better results in an in vitro setting compared to the single use of SGN-35 and CIK cells. Further investigations in in vivo models must be conducted to obtain a better understanding of the exact mechanisms of both treatments when applied in combination.


Meal ingestion, amino acids and brain neurotransmitters: effects of dietary protein source on serotonin and catecholamine synthesis rates.
Carbohydrate ingestion raises tryptophan uptake and serotonin synthesis in rat brain. The addition of protein is generally believed only to block such increases. However, some recent evidence suggests dietary protein may not be limited to this action. In the present studies, we fed rats single meals containing one of 5 proteins (zein, wheat gluten, soy protein isolate, casein, lactalbumin, 17% by weight) or no protein, and killed them 2.5 h later, 30 min after the injection of m-hydroxybenzylhydrazine, to allow serotonin and catecholamine synthesis rates to be measured in brain. Blood and cerebral cortex samples were analyzed for tryptophan and other large, neutral amino acids; 5-hydroxytryptophan and dihydroxyphenylalanine were measured in hypothalamus, hippocampus and cerebral cortex as indices of serotonin and catecholamine synthesis, respectively. An 8-fold variation occurred in cortex tryptophan: a marked decline followed zein ingestion, and modest reductions after casein or gluten. A large rise in cortex tryptophan occurred after lactalbumin consumption, and smaller increases after soy protein or carbohydrate (no protein). In the brain regions examined, a 4-8-fold range in serotonin synthesis occurred which closely followed the tryptophan alterations. No effects were observed in regional catecholamine synthesis rates. Cortical concentrations of leucine showed small changes; leucine has been linked to mTOR (mammalian target of rapamycin) signaling in brain circuits regulating food intake. The data suggest that tryptophan concentrations and serotonin synthesis in brain neurons are remarkably sensitive to which protein is present in a meal. Conceivably, this relationship might inform the brain about the nutritional quality of the protein ingested.


Sensing the heat stress by Mammalian cells.
The heat-shock response network controls the adaptation and survival of the cell against environmental stress. This network is highly conserved and is connected with many other signaling pathways. A key element of the heat-shock network is the heat-shock transcription factor-1 (HSF), which is transiently activated by elevated temperatures. HSF translocates to the nucleus upon elevated temperatures, forming homotrimeric complexes. The HSF homotrimers bind to the heat shock element on the DNA and control the expression of the hsp70 gene. The Hsp70 proteins protect cells from thermal stress. Thermal stress causes the unfolding of proteins, perturbing thus the pathways under their control. By binding to these proteins, Hsp70 allows them to refold and prevents their aggregation. The modulation of the activity of the hsp70-promoter by the intensity of the input stress is thus critical for cell's survival. The promoter activity starts from a basal level and rapidly increases once the stress is applied, reaches a maximum level and attenuates slowely back to the basal level. This phenomenon is the hallmark of many experimental studies and of all computational network analysis. The molecular construct used as a measure of the response to thermal stress is a Hsp70-GFP fusion gene transfected in Chinese hamster ovary (CHO) cells. The time profile of the GFP protein depends on the transient activity, Transient(t), of the heat shock system. The function Transient(t) depends on hsp70 promoter activity, transcriptional regulation and the translation initiation effects elicited by the heat stress. The GFP time profile is recorded using flow cytometry measurements, a technique that allows a quantitative measurement of the fluorescence of a large number of cells (104). The GFP responses to one and two heat shocks were measured for 261 conditions of different temperatures and durations. We found that: (i) the response of the cell to two consecutive shocks (i.e., no recovery time in between shocks) depends on the order of the input shocks, that is the shocks do not commute; (ii) the responses may be classified as mild or severe, depending on the temperature level and the duration of the heat shock and (iii) the response is highly sensitive to small variations in temperature. We propose a mathematical model that maps temperature into the transient activity using experimental data that describes the time course of the response to input thermal stress. The model is built on thermotolerance without recovery time, sharp sensitivity to small variations in temperature and the existence of mild and severe classes of stress responses. The theoretical predictions are tested against experimental data using a series of double-shock inputs. The theoretical structure is represented by a sequence of three cascade processes that transform the input stress into the transient activity. The structure of the cascade is nonlinear-linear-nonlinear (NLN). The first nonlinear system (N) from the NLN structure represents the amplification of small changes in the environmental temperature; the linear system (L) represents the thermotolerance without recovery time, whereas the last system (N) represents the transition of the cell's response from a mild to a severe shock.


Regulation of replication fork progression through histone supply and demand.
DNA replication in eukaryotes requires nucleosome disruption ahead of the replication fork and reassembly behind. An unresolved issue concerns how histone dynamics are coordinated with fork progression to maintain chromosomal stability. Here, we characterize a complex in which the human histone chaperone Asf1 and MCM2-7, the putative replicative helicase, are connected through a histone H3-H4 bridge. Depletion of Asf1 by RNA interference impedes DNA unwinding at replication sites, and similar defects arise from overproduction of new histone H3-H4 that compromises Asf1 function. These data link Asf1 chaperone function, histone supply, and replicative unwinding of DNA in chromatin. We propose that Asf1, as a histone acceptor and donor, handles parental and new histones at the replication fork via an Asf1-(H3-H4)-MCM2-7 intermediate and thus provides a means to fine-tune replication fork progression and histone supply and demand.


[Excessive fluoride inducing calcium overload and apoptosis of ameloblasts].
To study the effect of excessive fluoride on calcium overload and apoptosis in cultured rat ameloblasts in vitro. Logarithmic-phase ameloblasts (HAT-7) were treated with 0, 0.4, 0.8, 1.6, 3.2, and 6.4 mmol · L(-1) sodium fluoride (NaF) solution. Cell activities were detected by using a Cell Counting Kit 8 (CCK-8) assay after 48 h of treatment. The effect of fluoride on cell apoptosis was analyzed by using flow cytometry. Excessive fluoride-induced calcium concentration and calreticulin expression changes in ameloblasts were detected by using laser scanning confocal microscopy, Western blot analysis, and real-time quantitative polymerase chain reaction. NaF inhibited ameloblast activity at 1.6, 3.2, and 6.4 mmol · L(-1) (dose-dependent) after 48 h of induction. The Ca2+ fluorescence intensity of HAT-7 cells incubated with 1.6 and 3.2 mmol · L(-1) NaF was higher than that in the control group. The fluoride-induced early-stage apoptosis of ameloblasts after 48 h of induction and the early-stage apoptosis rate was positively correlated with fluoride concentration. Calreticulin mRNA expression in HAT-7 cells was higher than that in the control group after 48 h of incubation with 0.8, 1.2, and 1.6 mmol · L(-1) NaF. Excessive fluoride-induced calcium overload in ameloblasts and further caused endoplasmic reticulum stress-mediated apoptosis.


β-catenin/Tcf-4 complex transcriptionally regulates AKT1 in glioma.
Increasing evidence suggests that interplays between Wnt/β-catenin and PI3K/AKT signaling cascades are involved in tumor development and progression. However, the exact mechanism in glioma is not well known. Using aspirin, we found that the expression levels of AKT1 in glioma cells significantly correlated with the transcriptional activity of β-catenin. Similar observations were made when we subjected glioma cells to treatment with Tcf4 siRNA. Moreover, both aspirin and Tcf4 siRNA can suppress the proliferation and induce apoptosis of glioma. In addition, our analysis of the gene promoter of AKT1 revealed multiple putative Tcf-4 binding sites. In support of the concept that β-catenin/Tcf-4 is a transcriptional regulator for AKT1, results from our chromatin immunoprecipitation studies and luciferase assay showed that β-catenin/Tcf-4 binds to the potential binding sites in the gene promoter of AKT1. Furthermore, using immunohistochemistry, we found that Tcf-4 protein expression increased significantly in high-grade glioma in comparison to low-grade glioma and correlated with AKT1 expression. In conclusion, our results support the concept that β-catenin/Tcf-4 directly regulates AKT1 in glioma, and these two proteins may cooperate with each other in exerting their oncogenic effects in glioma.


The effect of in-patient chest physiotherapy in lung cancer patients.
The aim of our study was to investigate the effect of the in-patient chest physiotherapy (ICP) in patients with lung cancer. Eighteen patients with stage IIIA, IIIB, or IV lung cancer (3 females and 15 males) were included. The demographic characteristics and the clinical history of the patients were recorded. Pain (visual analog scale), pulmonary function (pulmonary function test), functional capacity (6-min walking test, Karnofsky performance status (KPS) scale), and health-related quality of life (Nottingham Health Profile (NHP)) parameters were evaluated. The ICP program, including breathing control, breathing exercises, relaxation training, upper and lower extremity exercises, mobilization, and transcutaneous nerve stimulation, was designed to meet each patient's individual needs. After the exercise program, there was a significant decrease in the severity of the dyspnea, fatigue, and pain symptoms (p < 0.05), improvement in the physical mobility, pain, energy, emotional status and sleep subcategories of the NHP (p < or = 0.05), and increase in the 6-min walking distance (75 +/- 15.95 m, p = 0.003). However, pulmonary function test results and KPS scores did not show statistically significant changes (p > 0.05). ICP programs may be beneficial to lung cancer patients by reducing respiratory symptoms, pain, and improving health-related quality of life and exercise capacity. For this reason, the results of this study suggest that ICP programs, which are prepared by taking the individual requirements of lung cancer patients, should be placed in the treatment of the lung cancer.


Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura.
It was recently reported that autoreactive CD4(+) T cells to glycoprotein IIb-IIIa (GPIIb-IIIa) mediate antiplatelet autoantibody production in patients with immune thrombocytopenic purpura (ITP). To further examine the antigenic specificity of the GPIIb-IIIa-reactive T cells, 6 recombinant fragments encoding different portions of GPIIbalpha or GPIIIa were generated and tested for their ability to stimulate antigen-specific T-cell proliferation and anti-GPIIb-IIIa antibody production in vitro. T cells from the peripheral blood of 25 patients with ITP and 10 healthy donors proliferated in response to recombinant GPIIb-IIIa fragments in various combinations. The amino-terminal portions of both GPIIbalpha and GPIIIa (IIbalpha18-259 and IIIa22-262) were frequently recognized (60% and 64%, respectively) compared with other fragments (4%-28%) in patients with ITP, but this tendency was not detected in healthy donors. In subsequent analyses in patients with ITP, T-cell reactivities to IIbalpha18-259 and IIIa22-262 were consistently detected, whereas those to other fragments were sometimes lost. In vitro antigenic stimulation of peripheral blood mononuclear cells with IIbalpha18-259 or IIIa22-262 promoted the synthesis of anti-GPIIb-IIIa antibodies in patients with ITP, but not in healthy donors. Of 15 CD4(+) T-cell lines specific for platelet-derived GPIIb-IIIa generated from 5 patients with ITP, 13 lines recognized IIbalpha18-259, IIIa22-262, or both. T-cell lines reactive to IIbalpha18-259 or IIIa22-262 promoted the production of anti-GPIIb-IIIa antibodies that were capable of binding to normal platelet surfaces. These results indicate that the immunodominant epitopes recognized by pathogenic CD4(+) T cells in patients with ITP are located within the amino-terminal portions of both GPIIbalpha and GPIIIa.


Cannabis Use, Cannabis Use Disorder, and Comorbid Psychiatric Illness: A Narrative Review.
The landscape of attitudes, legal status and patterns of use of cannabis is rapidly changing in the United States and elsewhere. Therefore, the primary aim of this narrative review is to provide a concise overview of the literature on the comorbidity of cannabis use and cannabis use disorder (CUD) with other substance use and psychiatric disorders, and to use this information to accurately guide future directions for the field. A literature review of PubMed was conducted for studies relating to cannabis use, CUD, and a co-occurring psychiatric disorder. To provide an overview of representative data, the literature review focused on national-level, population-based work from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and National Survey on Drug Use and Health (NSDUH) surveys. Considering rapidly changing cannabis laws, recent (past five-year) studies were addressed. A strong body of literature shows associations between cannabis use and CUD with other drug use, psychosis, mood disorders, anxiety disorders, and personality disorders. The strongest evidence of a potential causal relationship exists between cannabis use and psychotic disorders. While some evidence shows potential directionality between cannabis use and mood and anxiety disorders, results are inconsistent. Studies have established higher rates of CUD among those with personality disorders, but little about the specifics of this relationship is understood. Although the general population in the United States increasingly perceives cannabis to be a harmless substance, empirical evidence shows that cannabis use is associated both with CUD and comorbid psychiatric illness. However, there is mixed evidence regarding the role of cannabis in the etiology, course, and prognosis of a co-occurring disorder across all categories of psychiatric disorders. Future research should expand on the existing body of literature with representative, longitudinal data, in order to better understand the acute and long-term effects of cannabis on comorbid psychiatric illness.


TPL2 meets p38MAPK: emergence of a novel positive feedback loop in inflammation.
The activation of p38(MAPK) by Toll-like receptor signalling is essential for the inflammatory response of innate immunity due to its role in post-transcriptional regulation of TNFα and cytokine biosynthesis. p38(MAPK) activation proceeds by the upstream MAP2Ks, MAPK kinase (MKK)3/6 as well as MKK4, which in turn are substrates for MAP3Ks, such as TGFβ-activated protein kinase-1 (TAK1). In contrast, TPL2 has been described as an exclusive MAP3K of MKK1/2-triggering activation of the classical ERKs, ERK1/2. In the recent issue of the Biochemical Journal, Pattison et al report their screening for TPL2 substrates in LPS-stimulated macrophages and the identification of MKK3/6. Using catalytic-dead TPL2 (Map3k8(D270A/D270A)) knockin macrophages, they demonstrated that activation of MKK3/6 by TPL2 significantly contributes to LPS-dependent TNFα biosynthesis and is also essential for TNF-receptor 1 signalling. Hence, a new signalling pathway from TAK1 via IκB kinase, p105 NFκB and TPL2 to MKK3/6 and p38(MAPK) is established in macrophages. Taking into account that some isoforms of p38(MAPK) are necessary for maintaining functional steady-state levels of TPL2, a positive feedback loop in inflammation emerges.


Exercise training and Parkinson's disease: placebo or essential treatment?
Exercise training is often recommended for patients who have Parkinson's disease. Until the debate about the pathophysiologic cause of impaired movement in parkinsonism is settled, it is difficult to develop a specific exercise treatment for symptoms that include hypokinesia, tremor, and muscular rigidity. Most of the published studies show a benefit of exercise training, and we provide an overview of the most essential studies and present conclusions for a practical approach to exercise training in parkinsonism.


Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation.
The major route of hexobarbital metabolism in humans involves hydroxylation at the 3'-position followed by oxidation to a 3'-keto metabolite. Studies were performed to characterize the form of cytochrome P-450 responsible for the initial oxidation. In vitro studies indicated that P-450MP purified from human livers, involved in the 4-hydroxylation of S-mephenytoin, efficiently catalyzed the 3'-hydroxylation of hexobarbital; moreover, polyclonal antibodies raised to this enzyme extensively inhibited such activity in human liver microsomes. S-Mephenytoin 4- and hexobarbital 3'-hydroxylase activities in microsomes from different livers were significantly correlated, and both activities were essentially absent in fetal liver preparations. Hexobarbital was also found to inhibit S-mephenytoin 4-hydroxylation and vice versa, with Ki values similar to the Km values for the measured pathways. These data suggested that in vivo metabolism of hexobarbital would be determined by the same genetic factor(s) responsible for polymorphic 4-hydroxylation of S-mephenytoin. This prediction was confirmed by the finding that, after oral administration of a single dose of hexobarbital (300 mg), the 24-hr urinary excretion of 3'-hydroxy- and 3'-ketohexobarbital in a "poor-metabolizer" was only one third of that in a subject of the "extensive-metabolizer" phenotype. Also, the plasma level of metabolites at 6 hr after administration was reduced, and that of unchanged drug was increased in the poor metabolizer. Finally, a markedly enhanced sedative effect was associated with the impaired metabolism. Accordingly, several lines of in vitro evidence indicate that hexobarbital 3'-hydroxylation is catalyzed by P-450MP.(ABSTRACT TRUNCATED AT 250 WORDS)


Hemostatic factors and subclinical brain infarction in a community-based sample: the ARIC study.
Previous data are conflicting as to whether imbalance between hemostatic factors is associated with clinical strokes. We evaluated the association between hemostatic factor levels and subclinical lacunar infarcts in a nested sample from a subset of the Atherosclerosis Risk in Communities (ARIC) cohort. 196 cases without clinical strokes had lacunar infarcts by MRI, and 214 controls without radiographic infarcts were frequency-matched by age group and sex. Logistic regression models were fitted to assess the association between levels of hemostatic markers and case status. In age-, race- and sex-adjusted models, von Willebrand factor (vWF) and D-dimer were positively associated with case status, with odds ratios for the highest vs. lowest tertile of 2.0 (95% CI 1.2-3.6) for vWF and 1.76 (95% CI 1.02-3.0) for D-dimer. Plasminogen had nonsignificant inverse associations with presence of silent lacunar infarcts. vWF and D-dimer were positively associated, and plasminogen was nonsignificantly inversely associated with subclinical radiographic infarct. Further studies on the role of these hemostatic factors in the development of silent lacunar infarcts may help elucidate the mechanisms behind this injury and may even point to potential targets for future intervention.