Practice patterns of pediatric versus general emergency physicians for pain management of fractures in pediatric patients.
To determine if there are actual differences between pediatric emergency medicine (PEM) physicians and general emergency medicine (GEM) physicians in the management of pain in pediatric patients with fractured extremities. Retrospective chart review of children seen with a forearm or lower extremity fracture over a 2-year period at 3 emergency departments (1 staffed by PEM physicians and 2 staffed by GEM physicians). A severe fracture was defined as a closed fracture with the presence of angulation or displacement. Procedural sedation was defined as the administration of medicine (sedative, analgesic, or dissociative anesthetic) at the time of reduction and/or immobilization of a fracture. Of the 718 charts reviewed, PEM physicians managed 428 patients, and GEM physicians managed 290 patients. There were no significant differences between the patients managed by PEM physicians and GEM physicians with regard to age, sex, site of fracture, and proportion of severe fractures. There were no differences in the administration of analgesic-related medicines between PEM physicians and GEM physicians in the management of all fractures [40% (95% CI 35-45%) vs. 43% (95% CI 37-49%)] or severe fractures [58% (95% CI 51-64%) vs. 66% (95% CI 58-73%)]. In the management of all fractures, procedural sedation was used by PEM physicians in 100 [23% (95% CI 19-27%)] patients and by GEM physicians in 52 [18% (95% CI 14-23%)] patients. When procedural sedation was used, PEM physicians were more likely to use a sedative agent than GEM physicians [94% (95% CI 88-97%) vs. 46% (95% CI 33-59%)], fentanyl as opposed to morphine or meperidine [62% (95% CI 52-71%) vs. 19% (95% CI 33-59%)] and a combination of sedative and analgesic [90% (95% CI 83-94%) vs. 44% (95% CI 31-57%)]. For all fractures, GEM physicians documented recommending pain medications on discharge more often than PEM physicians [66% (95% CI 60-71%) vs. 45% (95% CI 40-50%)], and they prescribed significantly more prescription analgesics than PEM physicians [13% (95% CI 10-17%) vs. 2% (95% CI 1-4%)]. In our study, most children with an extremity fracture and greater than one-third of children with a severe fracture did not receive pain medications in the emergency department. Overall, both PEM physicians and GEM physicians have similar practices of analgesic administration for fracture reduction, with a notable exception in the types of agents used during procedural sedation. GEM physicians documented discharge pain medications and prescribed prescription analgesics more often than PEM physicians.


Data resource profile: cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER).
The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼10(5) patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail firstname.lastname@example.com.


Mortality among workers exposed to carbon disulfide.
Mortality experience was investigated at a plant in Ontario that produced viscose rayon, with carbon disulfide as a main raw material. Work-history records for 279 deceased workers at the plant (plant A) were obtained and compared with those for 511 deceased workers at a pulp and paper plant in the same city (plant B). In a proportional mortality analysis, using as a reference the general population of Ontario, at both plants there were fewer deaths from ischemic heart disease than expected (the proportional mortality ratios [PMRs] were 83 at plant A and 95 at plant B) but more deaths than expected from cerebrovascular disease (PMRs were 115 at plant A and 149 at plant B). In a subgroup of plant A workers who had been employed in high-carbon-disulfide exposure areas, deaths from ischemic heart disease were less than expected (PMR = 82), particularly among those who worked in these areas for more than 5 y. Most deaths occurred among those aged 65 y or more. Mortality from strokes, however, was greater than expected (PMR = 207, p < .05); the excess was confined to workers who died at age 65 y or older (PMR = 229, p = .01). Proportional mortality from strokes was also increased in the pulp workers among those who died at age 65 y or older (PMR = 153). In a case-control analysis, the risk of ischemic heart disease at plant A was slightly less than at plant B (odds ratio (OR] = 0.92, 95% confidence interval [CI] = 0.60-1.42), with no association between risk and years worked in high-carbon-disulfide areas (OR/y = 0.99, 95% CI = 0.94-1.03). Among those who died at age 65 y or older, the risk of stroke in the high-exposure subgroup was (a) increased significantly, compared with other plant A workers (OR = 4.92, 95% CI = 1.66-14.65); and (b) increased slightly, compared with plant B workers (OR = 1.37, 95% CI = 0.83-2.26). These results suggested an unusually low risk of strokes among other plant A workers. The risk of stroke was associated with years in high-carbon-disulfide areas (OR/y = 1.03, 95% CI = 0.96-1.1 0). The observed increase in proportional mortality from strokes may represent a chance finding, but a causal role for exposure cannot be excluded.


Prevalence of obesity, diabetes mellitus, hypertension and associated risk factors in a mining workforce, Democratic Republic of Congo.
The burden of non-communicable diseases (NCDs) is increasing in low and middle-income countries (LMIC). According to the World Health Organization (WHO) the largest increase occurs in Africa. Obesity, diabetes mellitus and hypertension (ODH) are major risk factors for cardiovascular diseases, causing nearly 18 million deaths worldwide. Various risks associated with mining as an occupational activity are implicated in NCDs' occurrence. This study describes the baseline prevalence of ODH and associated risk factors in the workforce of Tenke Fungurume Mining (TFM), in southern Democratic Republic of Congo. A cross-sectional study was conducted on a sample of 2,749 employees' and contractor's occupational health examination files for 2010. Socio-demographic, occupational, medical, anthropometric and behavioral characteristics were collected and assessed. Disease status regards ODH was based on WHO criteria. A multivariate logistic regression model was used. Overall prevalence of ODH was 4.5%, 11.7%, and 18.2% respectively. Proportions of pre-ODH individuals were 19.7%, 16.5%, and 47.8% respectively. Prevalence of ODH increased with age, professional grade, nature of work, gender and reported alcohol use. Smoking 10 or more cigarettes per day increased risk of diabetes and hypertension, while decreasing obesity. Rates of ODH and associated risk factors are higher in the TFM workforce, than in the general DRC population. This is likely reflective of other mining sites in the country and region. It is evident that ODH are associated with various socio-demographic, occupational, anthropometric, biomedical and behavioral risk factors. A NCD prevention program and close monitoring of disease and risk factors trends are needed in this population.


Human Papillomavirus 18 Genetic Variation and Cervical Cancer Risk Worldwide.
Human papillomavirus 18 (HPV18) is the second most carcinogenic HPV type, after HPV16, and it accounts for approximately 12% of squamous cell carcinoma (SCC) as well as 37% of adenocarcinoma (ADC) of the cervix worldwide. We aimed to evaluate the worldwide diversity and carcinogenicity of HPV18 genetic variants by sequencing the entire long control region (LCR) and the E6 open reading frame of 711 HPV18-positive cervical samples from 39 countries, taking advantage of the International Agency for Research on Cancer biobank. A total of 209 unique HPV18 sequence variants were identified that formed three phylogenetic lineages (A, B, and C). A and B lineages each divided into four sublineages, including a newly identified candidate B4 sublineage. The distribution of lineages varied by geographical region, with B and C lineages found principally in Africa. HPV18 (sub)lineages were compared between 453 cancer cases and 236 controls, as well as between 81 ADC and 160 matched SCC cases. In region-stratified analyses, there were no significant differences in the distribution of HPV18 variant lineages between cervical cancer cases and controls or between ADC and SCC. In conclusion, our findings do not support the role of HPV18 (sub)lineages for discriminating cancer risk or explaining why HPV18 is more strongly linked with ADC than SCC. This is the largest and most geographically/ethnically diverse study of the genetic variation of HPV18 to date, providing a comprehensive reference for phylogenetic classification of HPV18 sublineages for epidemiological and biological studies.


Metformin improves vascular and metabolic insulin action in insulin-resistant muscle.
Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague-Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic-hyperinsulinaemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-AKT and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.


The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy.
Disabling neuropathic pain (NeuP) is a common sequel of diabetic peripheral neuropathy (DPN). We aimed to characterise the sensory phenotype of patients with and without NeuP, assess screening tools for NeuP, and relate DPN severity to NeuP. The Pain in Neuropathy Study (PiNS) is an observational cross-sectional multicentre study. A total of 191 patients with DPN underwent neurological examination, quantitative sensory testing, nerve conduction studies, and skin biopsy for intraepidermal nerve fibre density assessment. A set of questionnaires assessed the presence of pain, pain intensity, pain distribution, and the psychological and functional impact of pain. Patients were divided according to the presence of DPN, and thereafter according to the presence and severity of NeuP. The DN4 questionnaire demonstrated excellent sensitivity (88%) and specificity (93%) in screening for NeuP. There was a positive correlation between greater neuropathy severity (r = 0.39, P < 0.01), higher HbA1c (r = 0.21, P < 0.01), and the presence (and severity) of NeuP. Diabetic peripheral neuropathy sensory phenotype is characterised by hyposensitivity to applied stimuli that was more marked in the moderate/severe NeuP group than in the mild NeuP or no NeuP groups. Brush-evoked allodynia was present in only those with NeuP (15%); the paradoxical heat sensation did not discriminate between those with (40%) and without (41.3%) NeuP. The "irritable nociceptor" subgroup could only be applied to a minority of patients (6.3%) with NeuP. This study provides a firm basis to rationalise further phenotyping of painful DPN, for instance, stratification of patients with DPN for analgesic drug trials.


CR3 (CD11b/CD18) activation of nasal neutrophils: a measure of upper airway endotoxin exposure.
Inhaled endotoxin (lipopolysaccharide, LPS) initiates an inflammatory response and leads to the expression of CR3 (CD11b/CD18) receptors on polymorphonuclear leukocytes (PMNs). We determined if PMN activation in nasal lavage fluid (NLF) is a possible biomarker of occupational endotoxin exposure. Seven subjects exposed to endotoxin provided NLF samples that were split into three aliquots (negative control--1 M nicotinamide; sham; positive control--11 etag of exogenous LPS) and PMN activation was measured using a chemiluminometer. Differences in mean PMN activation were apparent, negative control: 548 +/- 15.65 RLU 100 microl(-1); sham: 11469 +/- 2582 RLU 100 microl(-1); positive control: 42026 +/- 16659 RLU 100 microl (n = 7; p <0.05). This technique shows promise as a diagnostic method for measuring upper airway LPS exposure.


Outcomes following cerebrospinal fluid shunting in high-grade glioma patients.
The clinical course of high-grade central nervous system gliomas is occasionally complicated by hydrocephalus. The risks of shunt placement and clinical outcome following CSF diversion in this population are not well defined. The authors retrospectively reviewed the outcomes of patients with pathologically confirmed WHO grade III or IV gliomas with shunt-treated hydrocephalus at their institution. Outcomes of patients in this cohort were compared with those of patients who underwent shunt treatment for normal pressure hydrocephalus (NPH). Hospital-reported outcomes in a national database for malignant primary brain tumor patients undergoing a ventricular shunt procedure were also reviewed. Forty-one patients undergoing CSF shunting between 2001 and 2016 at the authors' institution were identified. Noncommunicating and communicating hydrocephalus occurred at similar rates (51.2% vs 48.8%). Symptomatic improvement after shunting was observed in 75.0% of patients. A major complication occurred in 17.1% of cases, with 2 patients suffering an intracranial hemorrhage. Prior administration of bevacizumab was significantly associated with the incidence of hemorrhage (p = 0.026). Three patients (7.3%) died during admission, and 8 (19.5%) died within 30 days of shunt placement. The presence of ependymal or leptomeningeal enhancement was more common in patients who died within 30 days (75.0% vs 11.1%, p = 0.001). Six patients (18.1%) required readmission to the hospital within 30 days of discharge. Revision surgery was necessary in 7 patients (17.1%). The median time from shunt placement to death was 150.5 days. In comparison with patients with NPH, shunt-treated high-grade glioma patients had increased in-hospital (7.3% vs 0.5%, p = 0.008) and 30-day (19.5% vs 0.8%, p < 0.001) mortality but no difference in the incidence of revision surgery (17.1% vs 17.5%, p = 0.947). Similarly, in the national Vizient Clinical Database Resource Manager, shunt-treated patients with malignant primary brain tumors had an increased length of stay (6.9 vs 3.5 days, p < 0.001), direct cost of admission ($15,755.80 vs $9871.50, p < 0.001), and 30-day readmission rates (20.6% vs 2.4%, p < 0.001) compared with patients without brain tumors who received a shunt for NPH. Shunting can be an effective treatment for the symptoms of hydrocephalus in patients with high-grade gliomas. However, the authors' results suggest that this procedure carries a significant risk of complications in this patient population.


[Graves' disease with associated thyroid nodules (nodular Graves' disease). Clinical, diagnostic and therapeutic considerations].
Sometimes Graveś disease (GD) can appear in association with thyroid nodules, which seems to increase the risk of carcinoma. In this article, we try to establish clinical characteristics, diagnostic means and appropriate treatment for Graves patients with co-existent nodules. A retrospective study was made of 153 consecutive patients who underwent operation for GD between 1967 and 2000. Each patient was subject to a regular protocol including physical examination, diagnostic test, total or subtotal thyroidectomy and follow-up in the long term with the purpose of making a valuation of the postsurgical morbidity, evolution and relapses. Data were processed through computing in order to get the statistical information. 28.1% of GD had thyroid nodules and carcinoma was diagnosed in four patients (9.3%), all of them belonging to papillary variety. Surgery consisted of 57 subtotal thyroidectomies (37.3%) and 94 total thyroidectomies. Parathyroid and recurrent morbidity was established in 4.6 and 3.9%, respectively, a year later since the operation, though it had a strong tendency to decrease from 1980. 96% of cases showed no relapse. Nodular GD is very common in our setting, especially in Graveś patients with late beginning who wait for ages until they are undergone surgery. Initial treatment should be by means of braking therapy with antithyroid drugs and clinical, cytologic and ultrasonographic control. Surgery would be advised, from the outset or during the follow-up, in view of either any suspicion about cancer or presence of local growth. The procedure of choice is total thyroidectomy performed with low morbidity.


Intermittent regime of brain activity at the early, bias-guided stage of perceptual learning.
Perceptual learning improves visual performance. Among the plausible mechanisms of learning, reduction of perceptual bias has been studied the least. Perceptual bias may compensate for lack of stimulus information, but excessive reliance on bias diminishes visual discriminability. We investigated the time course of bias in a perceptual grouping task and studied the associated cortical dynamics in spontaneous and evoked EEG. Participants reported the perceived orientation of dot groupings in ambiguous dot lattices. Performance improved over a 1-hr period as indicated by the proportion of trials in which participants preferred dot groupings favored by dot proximity. The proximity-based responses were compromised by perceptual bias: Vertical groupings were sometimes preferred to horizontal ones, independent of dot proximity. In the evoked EEG activity, greater amplitude of the N1 component for horizontal than vertical responses indicated that the bias was most prominent in conditions of reduced visual discriminability. The prominence of bias decreased in the course of the experiment. Although the bias was still prominent, prestimulus activity was characterized by an intermittent regime of alternating modes of low and high alpha power. Responses were more biased in the former mode, indicating that perceptual bias was deployed actively to compensate for stimulus uncertainty. Thus, early stages of perceptual learning were characterized by episodes of greater reliance on prior visual preferences, alternating with episodes of receptivity to stimulus information. In the course of learning, the former episodes disappeared, and biases reappeared only infrequently.


Methylation of the p73 gene in patients with myelodysplastic syndromes: correlations with apoptosis and prognosis.
The identification of epigenetically inactivated tumor suppressor genes may shed additional light on the pathogenesis of myelodysplastic syndromes (MDS) and lead to the identification of potential therapeutic targets for demethylating agents. In this study, the methylation status of the p73 gene promoter was analyzed by methylation-specific PCR (MS-PCR) in bone marrow (BM) samples from 126 adult patients with de novo MDS. The results of the MS-PCR were confirmed by bisulfite sequencing. In addition, we analyzed p73 expression using real-time PCR. The apoptosis of BM cells was examined by flow cytometry. The methylation of the p73 gene was observed in 36.5 % of cases. There were strong correlations between p73 methylation and the marrow blast levels (p = 0.037) and the WHO classification (p = 0.016). The frequency of p73 methylation was significantly correlated with the International Prognostic Scoring System subgroup ( r = 0.904, p < 0.001). Moreover, a decrease in the transcription of p73 was accompanied by methylation (p = 0.032). Although the level of apoptosis in the BM samples of the methylated group was not significantly lower than that in the unmethylated group (p = 0.094), decitabine treatment restored p73 expression and increased the level of cytarabine (ara-C)-induced apoptosis in vitro. The median survival time of patients with p73 methylation was shorter than that for patients without p73 methylation (15 vs. > 33 months, respectively, p = 0.002). A multivariate analysis also indicated that the p73 methylation status was the independent factor that impacted overall survival. In conclusion, p73 methylation is common in patients with MDS and is associated with poor prognosis. Our results provide further evidence for the involvement of epigenetic dysregulation in the pathogenesis of MDS.


Methods for training collaborative biostatisticians.
The emphasis on team science in clinical and translational research increases the importance of collaborative biostatisticians (CBs) in healthcare. Adequate training and development of CBs ensure appropriate conduct of robust and meaningful research and, therefore, should be considered as a high-priority focus for biostatistics groups. Comprehensive training enhances clinical and translational research by facilitating more productive and efficient collaborations. While many graduate programs in Biostatistics and Epidemiology include training in research collaboration, it is often limited in scope and duration. Therefore, additional training is often required once a CB is hired into a full-time position. This article presents a comprehensive CB training strategy that can be adapted to any collaborative biostatistics group. This strategy follows a roadmap of the biostatistics collaboration process, which is also presented. A TIE approach (Teach the necessary skills, monitor the Implementation of these skills, and Evaluate the proficiency of these skills) was developed to support the adoption of key principles. The training strategy also incorporates a "train the trainer" approach to enable CBs who have successfully completed training to train new staff or faculty.


Quality of life in alopecia areata: a case-control study.
Although alopecia areata (AA) is typically seen by medical staff as a benign, not life-threatening cosmetic disease, some studies have found significant impairment in quality of life (QL) in AA patients. There are no studies that assess QL in Brazilian AA patients. To evaluate QL in AA patients, using the 36-item Short-Form Health Survey (SF-36). The most affected SF-36 dimensions were compared to two culturally different AA QL studies. We performed a case-control study with 37 AA patients and 49 age- and sex-matched volunteer blood donors. The results of a Turkish and a French study were compared to our results. The dimensions social functioning (P = 0,001), role emotional (P = 0,019), and mental health (P = 0,000) scored statistically lower in the AA group in relation to controls, suggesting a worse QL. Incomparison to the Turkish and French studies, we found: (1) On the dimension role emotional, QL was equally impaired; (2) on the dimension social functioning, it was not different than the Turkish study; (3) social life of French AA patients was more affected; and (4) vitality and mental health dimensions were significantly more affected in French and Turkish patients. Impairment in QL in AA patients affected psychological, emotional, and social aspects of theirlives. Despite the scores of SF-36 dimensions varied significantly among different cultural groups, impairment of QL was found in all three studies; thus, we can suppose that these findings are not linked to a specific culture.


The type I inositol 1,4,5-trisphosphate receptor interacts with protein 4.1N to mediate neurite formation through intracellular Ca waves.
Ca(2+) waves are an important mechanism for encoding Ca(2+) signaling information, but the molecular basis for wave formation and how this regulates neuronal function is not entirely understood. Using nerve growth factor-differentiated PC12 cells as a model system, we investigated the interaction between the type I inositol 1,4,5-trisphosphate receptor (IP3R1) and the cytoskeletal linker, protein 4.1N, to examine the relationship between Ca(2+) wave formation and neurite development. This was examined using RNAi and overexpressed dominant negative binding regions of each protein. Confocal microscopy was used to monitor neurite formation and Ca(2+) waves. Knockdown of IP3R1 or 4.1N attenuated neurite formation, as did binding regions of IP3R1 and 4.1N, which colocalized with endogenous 4.1N and IP3R1, respectively. Upon stimulation with the IP3-producing agonist carbachol, both RNAi and dominant negative molecules shifted signaling events from waves to homogeneous patterns of Ca(2+) release. These findings provide evidence that IP3R1 localization, via protein 4.1N, is necessary for Ca(2+) wave formation, which in turn mediates neurite formation.


HELP! Problems in executing a pragmatic, randomized, stepped wedge trial on the Hospital Elder Life Program to prevent delirium in older patients.
A pragmatic, stepped wedge trial design can be an appealing design to evaluate complex interventions in real-life settings. However, there are certain pitfalls that need to be considered. This paper reports on the experiences and lessons learned from the conduct of a cluster randomized, stepped wedge trial evaluating the effect of the Hospital Elder Life Program (HELP) in a Dutch hospital setting to prevent older patients from developing delirium. We evaluated our trial which was conducted in eight departments in two hospitals in hospitalized patients aged 70 years or older who were at risk for delirium by reflecting on the assumptions that we had and on what we intended to accomplish when we started, as compared to what we actually realized in the different phases of our study. Lessons learned on the design, the timeline, the enrollment of eligible patients and the use of routinely collected data are provided accompanied by recommendations to address challenges. The start of the trial was delayed which caused subsequent time schedule problems. The requirement for individual informed consent for a quality improvement project made the inclusion more prone to selection bias. Most units experienced major difficulties in including patients, leading to excluding two of the eight units from participation. This resulted in failing to include a similar number of patients in the control condition versus the intervention condition. Data on outcomes routinely collected in the electronic patient records were not accessible during the study, and appeared to be often missing during analyses. The stepped wedge, cluster randomized trial poses specific risks in the design and execution of research in real-life settings of which researchers should be aware to prevent negative consequences impacting the validity of their results. Valid conclusions on the effectiveness of the HELP in the Dutch hospital setting are hampered by the limited quantity and quality of routine clinical data in our pragmatic trial. Executing a stepped wedge design in a daily practice setting using routinely collected data requires specific attention to ethical review, flexibility, a spacious time schedule, the availability of substantial capacity in the research team and early checks on the data availability and quality. Netherlands Trial Register, identifier: NTR3842 . Registered on 24 January 2013.


Near surface swimming of Salmonella Typhimurium explains target-site selection and cooperative invasion.
Targeting of permissive entry sites is crucial for bacterial infection. The targeting mechanisms are incompletely understood. We have analyzed target-site selection by S. Typhimurium. This enteropathogenic bacterium employs adhesins (e.g. fim) and the type III secretion system 1 (TTSS-1) for host cell binding, the triggering of ruffles and invasion. Typically, S. Typhimurium invasion is focused on a subset of cells and multiple bacteria invade via the same ruffle. It has remained unclear how this is achieved. We have studied target-site selection in tissue culture by time lapse microscopy, movement pattern analysis and modeling. Flagellar motility (but not chemotaxis) was required for reaching the host cell surface in vitro. Subsequently, physical forces trapped the pathogen for ∼1.5-3 s in "near surface swimming". This increased the local pathogen density and facilitated "scanning" of the host surface topology. We observed transient TTSS-1 and fim-independent "stopping" and irreversible TTSS-1-mediated docking, in particular at sites of prominent topology, i.e. the base of rounded-up cells and membrane ruffles. Our data indicate that target site selection and the cooperative infection of membrane ruffles are attributable to near surface swimming. This mechanism might be of general importance for understanding infection by flagellated bacteria.


Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water.
The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and 4-N-(Nomega-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), led to the discovery of a conserved structural water molecule that was hydrogen bonded between the two heme propionates and the inhibitors (Figure 2). On the basis of this observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of 2 or to the secondary amine nitrogen of 1, the inhibitor molecules could displace the structural water molecule and obtain a direct interaction with the heme cofactor. To test this hypothesis, peptidomimetic analogues 3-5, which have either an N-hydroxyl (3 and 5) or N-amino (4) donor group, were designed and synthesized. X-ray crystal structures of nNOS with inhibitors 3 and 5 bound verified that the N-hydroxyl group had, indeed, displaced the structural water molecule and provided a direct interaction with the heme propionate moiety (Figures 5 and 6). Surprisingly, in vitro activity assay results indicated that the addition of a hydroxyl group (3) only increased the potency slightly against the neuronal isoform over the parent compound (1). Rationalizations for the small increase in potency are consistent with other changes in the crystal structures.


Mutations in the NPH1 locus of Arabidopsis disrupt the perception of phototropic stimuli.
The phototropic response is an important component of seedling establishment in higher plants because it orients the young seedlings for maximal photosynthetic light capture. Despite their obvious importance, little is known about the mechanisms underlying the perception and transduction of the light signals that induce phototropic curvatures. Here, we report the isolation of eight mutants of Arabidopsis that lack or have severely impaired phototropic responses. These nph (for nonphototropic hypocotyl) mutants comprise four genetic loci: nph1, nph2, nph3, and nph4. Physiological and biochemical characterization of the nph1 allele series indicated that the NPH1 locus may encode the apoprotein for a dual-chromophoric or multichromophoric holoprotein photoreceptor capable of absorbing UV-A, blue, and green light and that this photoreceptor regulates all the phototropic responses of Arabidopsis. It appears that the NPH1 protein is most likely a 120-kD plasma membrane-associated phosphoprotein because all of the nph1 mutations negatively affected the abundance of this protein. In addition, the putative NPH1 photoreceptor protein is genetically and biochemically distinct from the HY4 protein, which most likely acts as a photoreceptor for blue light-mediated hypocotyl growth inhibition. Furthermore, the NPH1 and HY4 proteins are not functionally redundant because mutations in either gene alone affect only one physiological response but not the other, thus providing strong support for the hypothesis that more than one blue light photoreceptor is required for the normal growth and development of a seedling.


Elastic properties of single amylose chains in water: a quantum mechanical and AFM study.
Recent single-molecule atomic force microscopy (AFM) experiments have revealed that some polysaccharides display large deviations from force-extension relationships of other polymers which typically behave as simple entropic springs. However, the mechanism of these deviations has not been fully elucidated. Here we report the use of novel quantum mechanical methodologies, the divide-and-conquer linear scaling approach and the self-consistent charge density functional-based tight binding (SCC-DFTB) method, to unravel the mechanism of the extensibility of the polysaccharide amylose, which in water displays particularly large deviations from the simple entropic elasticity. We studied the deformations of maltose, a building block of amylose, both in a vacuum and in solution. To simulate the deformations in solution, the TIP3P molecular mechanical model is used to model the solvent water, and the SCC-DFTB method is used to model the solute. The interactions between the solute and water are treated by the combined quantum mechanical and molecular mechanical approach. We find that water significantly affects the mechanical properties of maltose. Furthermore, we performed two nanosecond-scale steered molecular dynamics simulations for single amylose chains composed of 10 glucopyranose rings in solution. Our SCC-DFTB/MM simulations reproduce the experimentally measured force-extension curve, and we find that the force-induced chair-to-boat transitions of glucopyranose rings are responsible for the characteristic plateau in the force-extension curve of amylose. In addition, we performed single-molecule AFM measurements on carboxymethyl amylose, and we found that, in contrast to the results of an earlier work by others, these side groups do not significantly affect amylose elasticity. By combining our experimental and modeling results, we conclude that the nonentropic elastic behavior of amylose is governed by the mechanics of pyranose rings themselves and their force-induced conformational transitions.


High-dose cyclophosphamide, carmustine, and etoposide followed by allogeneic bone marrow transplantation in patients with lymphoid malignancies who had received prior dose-limiting radiation therapy.
To evaluate a high-dose chemotherapy regimen without total-body irradiation (TBI) followed by allogeneic (allo) bone marrow transplantation (BMT) in patients with lymphoid malignancies who had received prior dose-limiting radiotherapy. Fifty-six patients with non-Hodgkin's lymphoma (NHL, n = 26), Hodgkin's disease (HD, n = 17), or acute lymphoblastic leukemia (ALL, n = 13) with a history of previous radiation therapy were treated with cyclophosphamide (7.2 g/m2), carmustine (300 mg/m2 or 600 mg/m2), and etoposide (2,400 mg/m2; CBV) followed by allo BMT. Nine of 56 patients are alive and disease-free a median of 1,091 (range, 512 to 1,784) days post-transplant. The probabilities of transplant-related mortality, relapse, and event-free survival at 2 years for the entire group of 56 patients were .62, .59, and .17, respectively. Patients who received 600 mg/m2 of carmustine had a higher incidence of grade 3 or 4 regimen-related toxicities (RRTs) (14 of 22) than did patients who received 300 mg/m2 (12 of 33; P < .04), whereas there was no difference in relapse (.34 and .53, respectively, P = .73). Fourteen of 16 patients who received allo BMT for advanced disease (n = 12) or less-advanced disease (n = 4) but who were also eligible for auto BMT relapsed (n = 4) or died of transplant-related complications (n = 10). Allo BMT following a high-dose CBV regimen resulted in long-term disease-free survival in 17% of patients with lymphoid malignancies who had received prior dose-limiting radiotherapy. A high incidence of transplant-related complications, especially fatal idiopathic pneumonia syndrome (IPS) and a high relapse rate limited success. Morbidity and mortality associated with carmustine 600 mg/m2 were high and were not associated with a decrease in relapse. The number of patients in this study eligible for either allo or auto BMT was limited and precluded meaningful analysis of relative effectiveness.


Improving Pressure Injury Prevention by Using Wearable Sensors to Cue Critical Care Patient Repositioning.
Repositioning patients at regular intervals is the standard of care for pressure injury prevention, yet compliance with routine repositioning schedules can be hard to achieve in busy critical care environments. Cueing technology may help improve repositioning compliance. To determine whether using wearable patient sensors to cue nurses about patients' repositioning needs could improve compliance with an every-2-hour repositioning protocol. A sequential pretest-posttest study design was used in a 12-bed medical intensive care unit. The study occurred in 2 phases. In phase 1, eligible patients wore a triaxial accelerometer-based sensor; nurses were blinded to the data. In phase 2, the sensor technology provided staff with visual cues about patients' positions and repositioning needs. The primary measure was repositioning protocol compliance, which was compared between phase 1 and phase 2 with weighted t tests. Unit staff members were surveyed before the start of phase 1 and at the end of phase 2. In phase 1, 25 patients met the inclusion criteria. Phase 2 began 1 day after phase 1 and included 29 patients. In phase 1, repositioning compliance was 55%, and the mean repositioning interval was 3.8 hours. In phase 2, repositioning protocol compliance increased to 89%, and the mean repositioning interval was 2.3 hours. Nursing staff survey results showed improved teamwork in phase 2. Visual cueing about patients' mobility needs is associated with increased compliance with the facility repositioning protocol.


Inertial motion capture in conjunction with an artificial neural network can differentiate the gait patterns of hemiparetic stroke patients compared with able-bodied counterparts.
Clinical gait analysis has proven to reduce uncertainties in selecting the appropriate quantity and type of treatment for patients with neuromuscular disorders. However, gait analysis as a clinical tool is under-utilised due to the limitations and cost of acquiring and managing data. To overcome these obstacles, inertial motion capture (IMC) recently emerged to counter the limitations attributed to other methods. This paper investigates the use of IMC for training and testing a back-propagation artificial neural network (ANN) for the purpose of distinguishing between hemiparetic stroke and able-bodied ambulation. Routine gait analysis was performed on 30 able-bodied control subjects and 28 hemiparetic stroke patients using an IMC system. An ANN was optimised to classify the two groups, achieving a repeatable network accuracy of 99.4%. It is concluded that an IMC system and appropriate computer methods may be useful for the planning and monitoring of gait rehabilitation therapy of stroke victims.


Early mortality after modern total hip arthroplasty.
Because of improvements in surgical technique, anesthesia, and rehabilitation, mortality after hip arthroplasty may be on the decline. The purpose of this study was to determine the 90-day mortality rate after uncemented total hip arthroplasty (THA) performed under regional anesthesia. We retrospectively reviewed 7478 consecutive patients undergoing cementless primary or revision THA between January 2000 and July 2006. Patient survivorship was established and causes of death were obtained by accessing the Social Security Death Index, Centers for Disease Control and Prevention National Death Index, and State Departments of Vital Statistics. There were two intraoperative deaths from cardiac arrest. The overall 30- and 90-day mortality rates were 0.24% (18 of 7478) and 0.55% (41 of 7478), respectively. Thirty-day mortality after primary THA was low at 0.13% (eight of 6272). The most common cause of death was cardiovascular-related. Mortality after modern THA seems to have remained very low despite the availability of this procedure to patients of all ages and comorbidities. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.


Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct.
Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date.Objective: We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study.Design: We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution.Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates.Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.


Structural phylogenetics and the reconstruction of ancient language history.
The contribution of language history to the study of the early dispersals of modern humans throughout the Old World has been limited by the shallow time depth (about 8000 +/- 2000 years) of current linguistic methods. Here it is shown that the application of biological cladistic methods, not to vocabulary (as has been previously tried) but to language structure (sound systems and grammar), may extend the time depths at which language data can be used. The method was tested against well-understood families of Oceanic Austronesian languages, then applied to the Papuan languages of Island Melanesia, a group of hitherto unrelatable isolates. Papuan languages show an archipelago-based phylogenetic signal that is consistent with the current geographical distribution of languages. The most plausible hypothesis to explain this result is the divergence of the Papuan languages from a common ancestral stock, as part of late Pleistocene dispersals.


Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer.
Osteopontin (OPN) is a secreted phosphoglycoprotein that has been linked to tumor progression and survival in several solid tumors, including head and neck cancers. Previous studies showed that OPN expression is induced by tumor hypoxia, and its plasma levels can serve as a surrogate marker for tumor hypoxia and treatment outcome in head and neck cancer patients. In this study, we investigate the transcriptional mechanism by which hypoxia enhances OPN expression. We found that OPN is induced in head and neck squamous cell carcinoma (HNSCC) cell lines and in NIH3T3 cells by hypoxia at both mRNA and protein levels in a time-dependent manner. Actinomycin D chase experiments showed that hypoxic induction of OPN was not due to increased mRNA stability. Deletion analyses of the mouse OPN promoter regions indicated that a ras-activated enhancer (RAE) located at -731 to -712 relative to the transcription start site was essential for hypoxia-enhanced OPN transcription. Using electrophoretic mobility shift assays with the RAE DNA sequence, we found that hypoxia induced sequence-specific DNA-binding complexes. Furthermore, hypoxia and ras exposure resulted in an additive induction of OPN protein and mRNA levels that appeared to be mediated by the RAE. Induction of OPN through the RAE element by hypoxia is mediated by an Akt-kinase signaled pathway as decreasing Akt levels with dominant negative constructs resulted in inhibition of OPN induction by hypoxia. Taken together, these results have identified a new hypoxia responsive transcriptional enhancer that is regulated by Akt signaling.


Arginine vasotocin concentrations in the supraoptic nucleus of the lizard Anolis carolinensis are associated with reproductive state but not oviposition.
Arginine vasotocin (AVT) is a neuropeptide involved in reproductive function in many nonmammalian vertebrates. We determined brain and plasma AVT concentrations during the estrous cycle and oviposition in the lizard Anolis carolinensis. There were no differences in AVT concentrations in the plasma or any brain region during the ovipositional sequence. However, we found that females with an egg in each oviduct and a large pre-ovulatory follicle (diameter > 4.5 mm) in one-ovary had significantly higher AVT concentrations in the supraoptic nucleus (SON) of the hypothalamus than did females with small pre-ovulatory follicles in both ovaries. In a second study, females with an egg in each oviduct and a large pre-ovulatory follicle had significantly greater AVT concentrations in the SON than females with only one oviductal egg and a large pre-ovulatory follicle or females with an egg in each oviduct and a small pre-ovulatory follicle in each ovary. Concentrations of AVT in other brain regions and in the plasma did not differ among these groups. Changes in steroid profiles during estrous and/or direct neural communication between the uterus, ovary, and brain may account for the changes in AVT concentrations seen in the supraoptic nucleus during the estrous cycle of Anolis carolinensis.


Test-Retest Reliability and the Effects of Walking Speed on Stride Time Variability During Continuous, Overground Walking in Healthy Young Adults.
Studies have investigated the reliability and effect of walking speed on stride time variability during walking trials performed on a treadmill. The objective of this study was to investigate the reliability of stride time variability and the effect of walking speed on stride time variability, during continuous, overground walking in healthy young adults. Participants completed: (1) 2 walking trials at their preferred walking speed on 1 day and another trial 2 to 4 days later and (2) 1 trial at their preferred walking speed, 1 trial approximately 20% to 25% faster than their preferred walking speed, and 1 trial approximately 20% to 25% slower than their preferred walking speed on a separate day. Data from a waist-mounted accelerometer were used to determine the consecutive stride times for each trial. The reliability of stride time variability outcomes was generally poor (intraclass correlations: .167-.487). Although some significant differences in stride time variability were found between the preferred walking speed, fast, and slow trials, individual between-trial differences were generally below the estimated minimum difference considered to be a real difference. The development of a protocol to improve the reliability of stride time variability outcomes during continuous, overground walking would be beneficial to improve their application in research and clinical settings.


Earliest known hominin activity in the Philippines by 709 thousand years ago.
Over 60 years ago, stone tools and remains of megafauna were discovered on the Southeast Asian islands of Flores, Sulawesi and Luzon, and a Middle Pleistocene colonization by Homo erectus was initially proposed to have occurred on these islands1-4. However, until the discovery of Homo floresiensis in 2003, claims of the presence of archaic hominins on Wallacean islands were hypothetical owing to the absence of in situ fossils and/or stone artefacts that were excavated from well-documented stratigraphic contexts, or because secure numerical dating methods of these sites were lacking. As a consequence, these claims were generally treated with scepticism 5 . Here we describe the results of recent excavations at Kalinga in the Cagayan Valley of northern Luzon in the Philippines that have yielded 57 stone tools associated with an almost-complete disarticulated skeleton of Rhinoceros philippinensis, which shows clear signs of butchery, together with other fossil fauna remains attributed to stegodon, Philippine brown deer, freshwater turtle and monitor lizard. All finds originate from a clay-rich bone bed that was dated to between 777 and 631 thousand years ago using electron-spin resonance methods that were applied to tooth enamel and fluvial quartz. This evidence pushes back the proven period of colonization 6 of the Philippines by hundreds of thousands of years, and furthermore suggests that early overseas dispersal in Island South East Asia by premodern hominins took place several times during the Early and Middle Pleistocene stages1-4. The Philippines therefore may have had a central role in southward movements into Wallacea, not only of Pleistocene megafauna 7 , but also of archaic hominins.


Multiple Čerenkov second-harmonic waves in a two-dimensional nonlinear photonic structure.
We report simultaneous generation of multiple conical second-harmonic waves in a two-dimensional nonlinear photonic structure when illuminated by two overlapping noncollinear fundamental beams. We show that this phenomenon is caused by the nonlinear Čerenkov radiation emitted due to the interaction of photons from each constituent fundamental beam as well as the virtual one propagating along the bisector of the two beams. In addition, by studying the asymmetric geometry of the interaction, we uniquely verify the effects of reciprocal vectors on the Čerenkov-type second-harmonic generation in nonlinear photonic structures.


MMP-2 and TIMP-1 are derived from, not in response to, pancreatic cancer.
Genetic therapy aimed at disturbing the balance between matrix metalloproteinases (MMP) and their natural tissue inhibitors (TIMP) in treatment of pancreatic cancer requires an understanding of whether MMP and TIMP are tumor- or host-derived. This study was undertaken to determine whether production of MMP-2 and TIMP-1 is by, or in response to, pancreatic cancer. PANC-1 (poorly differentiated human pancreatic cancer) or CD-1 (PANC cells transfected to overproduce TIMP-1) cells were implanted into the pancreata of 20 nude mice. After sacrifice, tumors and peritumoral stroma underwent immunohistochemical staining for human and murine MMP-2 and TIMP-1. Normal murine pancreas served as control. All stains were reviewed in a "blinded" manner by a pathologist and graded relative to normal control pancreata. Control pancreata displayed faint murine MMP-2 and TIMP-1 staining and no human MMP-2 or TIMP-1. MMP-2 was most prominent in peritumoral stroma, while TIMP-1 was most prominent in tumors. CD-1 tumors contained very high levels of TIMP-1 compared to PANC-1 tumors and control pancreata. Tumoral and peritumoral MMP-2 were overwhelmingly human. As well, tumoral TIMP-1 was predominantly human. In a murine model for human pancreatic cancer, nearly all TIMP-1 and MMP-2 expression is tumor-derived (i.e., human). Pharmacologic and gene therapy aimed at disturbing the MMP/TIMP balance in pancreatic cancer should be targeted toward tumor-specific mechanisms and warrants continued investigation.


Imaging genetics and psychiatric disorders.
Imaging genetics is an integrated research method that uses neuroimaging and genetics to assess the impact of genetic variation on brain function and structure. Imaging genetics is both a tool for the discovery of risk genes for psychiatric disorders and a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative and mechanistic aspects of brain function implicated in psychiatric disease. Early studies of imaging genetics included association analyses between brain morphology and single nucleotide polymorphisms whose function is well known, such as catechol-Omethyltransferase (COMT) and brain-derived neurotrophic factor (BDNF). GWAS of psychiatric disorders have identified genes with unknown functions, such as ZNF804A, and imaging genetics has been used to investigate clues of the biological function of these genes. The difficulty in replicating the findings of studies with small sample sizes has motivated the creation of largescale collaborative consortiums, such as ENIGMA, CHARGE and IMAGEN, to collect thousands of images. In a genome-wide association study, the ENIGMA consortium successfully identified common variants in the genome associated with hippocampal volume at 12q24, and the CHARGE consortium replicated this finding. The new era of imaging genetics has just begun, and the next challenge we face is the discovery of small effect size signals from large data sets obtained from genetics and neuroimaging. New methods and technologies for data reduction with appropriate statistical thresholds, such as polygenic analysis and parallel independent component analysis (ICA), are warranted. Future advances in imaging genetics will aid in the discovery of genes and provide mechanistic insight into psychiatric disorders.


Biomass responses in a temperate European grassland through 17 years of elevated CO2.
Future increase in atmospheric CO2 concentrations will potentially enhance grassland biomass production and shift the functional group composition with consequences for ecosystem functioning. In the "GiFACE" experiment (Giessen Free Air Carbon dioxide Enrichment), fertilized grassland plots were fumigated with elevated CO2 (eCO2 ) year-round during daylight hours since 1998, at a level of +20% relative to ambient concentrations (in 1998, aCO2 was 364 ppm and eCO2 399 ppm; in 2014, aCO2 was 397 ppm and eCO2 518 ppm). Harvests were conducted twice annually through 23 years including 17 years with eCO2 (1998 to 2014). Biomass consisted of C3 grasses and forbs, with a small proportion of legumes. The total aboveground biomass (TAB) was significantly increased under eCO2 (p = .045 and .025, at first and second harvest). The dominant plant functional group grasses responded positively at the start, but for forbs, the effect of eCO2 started out as a negative response. The increase in TAB in response to eCO2 was approximately 15% during the period from 2006 to 2014, suggesting that there was no attenuation of eCO2 effects over time, tentatively a consequence of the fertilization management. Biomass and soil moisture responses were closely linked. The soil moisture surplus (c. 3%) in eCO2 manifested in the latter years was associated with a positive biomass response of both functional groups. The direction of the biomass response of the functional group forbs changed over the experimental duration, intensified by extreme weather conditions, pointing to the need of long-term field studies for obtaining reliable responses of perennial ecosystems to eCO2 and as a basis for model development.


Modulation transfer spectroscopy for ⁸⁷Rb atoms: theory and experiment.
We conducted a theoretical and experimental study of lineshape in modulation transfer spectroscopy for ⁸⁷Rb atoms. When a linearly polarized pump beam, modulated at an angular frequency of Ω, overlaps in parallel with an unmodulated linearly polarized probe beam, combined modulated probe beams are generated via nonlinear interaction with atoms. The detected modulation transfer signals are calculated by numerically solving the complete optical Bloch equations for the ⁸⁷Rb atoms without the use of any phenomenological parameters. We find that the calculated results are in good agreement with experimental results.


Premenopausal women and low bone density.
To review the evidence and provide an approach to management of low bone density among premenopausal women. QUALITY OF EVIDENCE MEDLINE: was searched from January 1990 to November 2004 and articles graded by level of evidence (I to III). Diagnosis and management recommendations were based on evidence from randomized controlled trials and expert consensus. Bone mineral density (BMD) testing among premenopausal women should be completed only in the presence of approved indications. Current evidence does not support screening for osteoporosis among premenopausal women. Low BMD in premenopausal women is associated with a lower fracture risk than seen in postmenopausal women. In the absence of fragility fractures, low BMD might reflect low peak bone mass based on genetic predisposition, environment, and lifestyle factors. Clinical evaluation enables distinction between low peak bone mass and a systemic disorder resulting in low BMD and skeletal fragility. Common causes of low bone density among premenopausal women include ovulatory disturbances and low body weight. Bone mineral density alone is insufficient for diagnosis of osteoporosis among premenopausal women in the absence of fragility fractures. Antiresorptive therapy has been evaluated and shown to benefit premenopausal women using glucocorticoid therapy or those with primary hyperparathyroidism.


Reference equations for 6-min walk test in healthy Indian subjects (25-80 years).
Six-min walk test (6MWT), a simple functional capacity evaluation tool used globally to determine the prognosis and effectiveness of any therapeutic/medical intervention. However, variability in reference equations derived from western population (due to racial and ethnicity variations) hinders from adequate use of 6MWT clinically. Further, there are no valid Indian studies that predict reference values for 6-min walk distance (6MWD) in healthy Indian normal. We aimed for framing individualized reference equations for 6MWT in healthy Indian population. Anthropometric variables (age, weight, height, and body mass index (BMI)) and 6-min walk in a 30 m corridor were evaluated in 125 subjects (67 females) in a cross-sectional trial. 6MWD significantly correlated with age (r = -0.29), height (r = 0.393), weight (r = 0.08), and BMI (r = -0.17). The gender specific reference equations for healthy Indian individuals were: (1) Males: 561.022 - (2.507 × age [years]) + (1.505 × weight [kg]) - (0.055 × height [cm]). R (2) = 0.288. (2) Indian females: 30.325 - (0.809 × age [years]) - (2.074 × weight [kg]) + (4.235 × height [cm]). R (2) = 0.272. Though the equations possess a small coefficient of determination and larger standard error estimate, the former applicability to Indian population is justified. These reference equations are probably most appropriate for evaluating the walked capacity of Indian patients with chronic diseases.


Increasing exposure to the UV filters octocrylene and 2-ethylhexyl salicylate in Germany from 1996 to 2020: Human biomonitoring in 24-h urine samples of the German Environmental Specimen Bank (ESB).
The UV filters octocrylene (OC) and 2-ethylhexyl salicylate (EHS) are commonly used in sunscreens and frequently detected in environmental media. However, knowledge on human exposures is scarce. In this human biomonitoring (HBM) study, we analyzed concentrations of exposure biomarkers specific to OC (CPAA, DOCCA, 5OH-OC) and EHS (5OH-EHS, 5oxo-EHS, 5cx-EPS) in 24-h urine samples (n = 420) from the German Environmental Specimen Bank (ESB). These samples were collected from German students (20-29 years; 30 males/30 females per year) between 1996 and 2020 (4-year intervals; collection in winter). We found continuously increasing OC and EHS exposures (Jonckheere-Terpstra; p < 0.001) documented by very few to no samples with concentrations of the most sensitive biomarkers CPAA and 5cx-EPS above the limit of quantification (LOQ) in 1996 (5 % and 0 %, respectively) and reaching 100 % and 93 % above the LOQ in 2016, with median concentrations of 4.79 and 0.071 µg/L, respectively. In 2020, biomarker concentrations slightly decreased to 3.12 µg/L CPAA (97 %>LOQ) and 0.060 µg/L 5cx-EPS (88 %>LOQ). This general trend was confirmed by the other biomarkers, however at lower detection rates. Based on metabolite excretion in the 24-h urine samples and human toxicokinetic data, we calculated maximum daily intakes (DI) of 17 µg/(kg bw * d) OC and 59 µg/(kg bw * d) EHS. Based on a derived no-effect level (DNEL) of 0.8 mg/(kg bw * d), the OC exposures of individuals in our study did not indicate any health risk. Similarly, for EHS all biomarker concentrations were well below the HBM-I values of 12 µg/L 5OH-EHS and 11 µg/L 5cx-EPS. Our data proves the general applicability of specific OC and EHS metabolites for HBM in the general population and shows clearly increasing exposures. Higher (co-)exposures must be expected in populations with increased sunscreen use such as (summer) vacationers, children and outdoor workers.


Nociceptin/Orphanin FQ Inhibits the Survival and Axon Growth of Midbrain Dopaminergic Neurons Through a p38-MAPK Dependent Mechanism.
Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide that binds and signals through a G-protein-coupled receptor called the N/OFQ peptide (NOP) receptor. N/OFQ and the NOP receptor are expressed in the midbrain and have been implicated in the pathogenesis of Parkinson's disease (PD). Genetic removal of the N/OFQ precursor partially protects midbrain dopaminergic neurons from 1-methyl-4-phenylpyridine-induced toxicity, suggesting that endogenous N/OFQ may be detrimental to dopaminergic neurons. However, whether N/OFQ directly affects the survival and growth of dopaminergic neurons is unknown. Here, we show that N/OFQ has a detrimental effect on the survival of dopaminergic neurons and the growth of their axons in primary cultures of the E14 rat ventral mesencephalon. N/OFQ potentiates the effects of the neurotoxins 6-hydroxydopamine and 1-methyl-4-phenylpyridinium through p38-MAPK signalling. We also show that like α-synuclein, there is a significant reduction in N/OFQ messenger RNA (mRNA) expression in the midbrain of patients with Parkinson's disease. These results demonstrate for the first time that N/OFQ is detrimental to the survival and growth of dopaminergic neurons and that its expression is altered in the midbrain of patients with Parkinson's disease.


Elevated remnant-like lipoprotein particles in impaired glucose tolerance and type 2 diabetic patients.
Impaired glucose tolerance (IGT) in association with insulin resistance is considered to be a risk factor for atherosclerosis. Thus, patients with IGT may have abnormal lipid and lipoprotein profiles. The purpose of this study was to investigate presence of remnant-type hyperlipoproteinemia in patients with IGT. Serum levels of remnant-like lipoprotein particles (RLP) were measured in 541 subjects (362 men and 179 women, age 53 +/- 7.9 years) who visited our health center for routine medical examinations. We measured RLP cholesterol (RLP-C) and RLP triglycerides (RLP-TG) using immunoaffinity gel containing monoclonal anti-human apoproteins A-I (H-12) and B-100 (JI-H) antibodies. After a 75-g oral glucose tolerance test, subjects were divided into three groups: normal, IGT, and type 2 diabetic. After matching for sex, age, and body weight, serum RLP-C in normal, IGT, and diabetic groups were 4.2 +/- 1.7, 6.2 +/- 3.4, and 6.2 +/- 4.2 mg/dl, respectively. The corresponding RLP-TG values were 16.7 +/- 9.2, 28.0 +/- 19.1, and 29.0 +/- 27.2 mg/dl. We found that RLP-C and RLP-TG values were significantly higher in the IGT and diabetic groups compared with the normal group (P < 0.001). In the same order, total serum cholesterol levels were 206 +/- 29, 205 +/- 34, and 206 +/- 34 mg/dl and LDL cholesterol levels were 127 +/- 27, 124 +/- 34, and 123 +/- 34 mg/dl, showing no marked difference in these groups. However, serum levels of triglyceride were higher in the IGT and diabetes groups (155 +/- 76 and 151 +/- 81 mg/dl vs. 106 +/- 41 mg/dl; P < 0.0001). Further, the incidence of remnant hyperlipoproteinemia in normocholesterolemic subjects was up to four times higher in IGT and diabetic groups compared with the normal group. High serum RLP-C and RLP-TG levels in IGT and diabetic patients may represent an increased risk of atherosclerosis in these patients.


Phylogeographic structure in the bogus yucca moth Prodoxus quinquepunctellus (Prodoxidae): comparisons with coexisting pollinator yucca moths.
The pollination mutualism between yucca moths and yuccas highlights the potential importance of host plant specificity in insect diversification. Historically, one pollinator moth species, Tegeticula yuccasella, was believed to pollinate most yuccas. Recent phylogenetic studies have revealed that it is a complex of at least 13 distinct species, eight of which are specific to one yucca species. Moths in the closely related genus Prodoxus also specialize on yuccas, but they do not pollinate and their larvae feed on different plant parts. Previous research demonstrated that the geographically widespread Prodoxus quinquepunctellus can rapidly specialize to its host plants and may harbor hidden species diversity. We examined the phylogeographic structure of P. quinquepunctellus across its range to compare patterns of diversification with six coexisting pollinator yucca moth species. Morphometric and mtDNA cytochrome oxidase I sequence data indicated that P. quinquepunctellus as currently described contains two species. There was a deep division between moth populations in the eastern and the western United States, with limited sympatry in central Texas; these clades are considered separate species and are redescribed as P. decipiens and P. quinquepunctellus (sensu stricto), respectively. Sequence data also showed a lesser division within P. quinquepunctellus s.s. between the western populations on the Colorado Plateau and those elsewhere. The divergence among the three emerging lineages corresponded with major biogeographic provinces, whereas AMOVA indicated that host plant specialization has been relatively unimportant in diversification. In comparison, the six pollinator species comprise three lineages, one eastern and two western. A pollinator species endemic to the Colorado Plateau has evolved in both of the western lineages. The east-west division and the separate evolution of two Colorado Plateau pollinator species suggest that similar biogeographic factors have influenced diversification in both Tegeticula and Prodoxus. For the pollinators, however, each lineage has produced a monophagous species, a pattern not seen in P. quinquepunctellus.


Shoulder arthroplasty with or without resurfacing of the glenoid in patients who have osteoarthritis.
The indications for resurfacing of the glenoid in patients who have osteoarthritis of the shoulder are not clearly defined; some investigators routinely perform hemiarthroplasty whereas others perform total shoulder arthroplasty. Forty-seven patients (fifty-one shoulders) who were scheduled to have a shoulder arthroplasty for the treatment of degenerative osteoarthritis were randomly assigned, according to a random-numbers table, to one of two groups: replacement of the humeral head with resurfacing of the glenoid with a polyethylene component with cement (total shoulder arthroplasty [twenty-seven shoulders]) or replacement of the humeral head without resurfacing of the glenoid (hemiarthroplasty [twenty-four shoulders]). All patients received the same type of humeral component, and all operations were performed by or under the direct supervision of the same surgeon. The patients were followed for a mean of thirty-five months (range, twenty-four to seventy-two months) postoperatively. Evaluation was performed with use of the scoring systems of the University of California at Los Angeles and the American Shoulder and Elbow Surgeons. No difference was observed between the preoperative scores for the two groups of patients. Postoperatively, the mean scores with use of the University of California at Los Angeles system and the American Shoulder and Elbow Surgeons system were 23.2 points (range, 10 to 31 points) and 65.2 points (range, 15 to 94 points), respectively, after hemiarthroplasty and 27.4 points (range, 9 to 34 points) and 77.3 points (range, 3 to 100 points), respectively, after total shoulder arthroplasty. With the numbers available for study, no significant difference was found between the two operative groups with respect to the postoperative score. (Thirty-five subjects per group would be needed, assuming an effect size of 0.60 and a power of 0.80.) Total shoulder arthroplasty provided significantly greater pain relief (p = 0.002) and internal rotation (p = 0.003) than hemiarthroplasty did. Total shoulder arthroplasty also provided superior results in the specific areas of patient satisfaction, function, and strength, although none of these differences were found to be significant, with the numbers available. Total shoulder arthroplasty was associated with increased cost ($1177), operative time (thirty-five minutes), and blood loss (150 milliliters) per patient compared with hemiarthroplasty. To date, none of the total shoulder arthroplasties in the study group have been revised. Hemiarthroplasty yielded equivalent results for elevation and external rotation. Three of the twenty-five patients who had had a hemiarthroplasty needed a subsequent operation for resurfacing of the glenoid. The mean cost for the revision operations was $15,998. Total shoulder arthroplasty provided superior pain relief compared with hemiarthroplasty in patients who had glenohumeral osteoarthritis, but it was associated with an increased cost of $1177 per patient.


Accelerated reepithelialization by triterpenes: proof of concept in the healing of surgical skin lesions.
The acceleration of wound healing is a major surgical concern. A triterpene extract from birch bark (Betulae cortex) experimentally enhances keratinocyte differentiation in vitro and accelerates wound healing ex vivo. We conducted an open, blind-evaluated, controlled, prospective, randomized (1:1) phase II clinical trial in patients requiring split-thickness skin graft transplantation at two university hospitals in Germany. Donor sites on the upper legs were covered with a moist silicone-coated dressing. Oleogel-S10 ointment containing 10% birch bark extract was randomly applied to the distal or proximal half of the wound, with the other half serving as an intraindividual control, for 14 days after the skin graft surgery. The primary efficacy variable was faster reepithelialization as determined from macrophotographs by independent, blinded experts. Twenty-four patients were randomized and completed the trial. After the 14-day test period, the planned interim analysis revealed a highly significant (p < 0.0001) superiority of Oleogel-S10 in the primary efficacy variable and the trial was terminated early due to ethical concerns. The treatment side was also better reepithelialized and more similar to normal skin after 3 months. In conclusion, Oleogel-S10 significantly accelerated reepithelialization at split-thickness skin graft donor sites. Treatment with Oleogel-S10 was safe and well tolerated.


Comparative analysis of genome composition in Triticeae reveals strong variation in transposable element dynamics and nucleotide diversity.
A 454 sequencing snapshot was utilised to investigate the genome composition and nucleotide diversity of transposable elements (TEs) for several Triticeae taxa, including Triticum aestivum, Hordeum vulgare, Hordeum spontaneum and Secale cereale together with relatives of the A, B and D genome donors of wheat, Triticum urartu (A), Aegilops speltoides (S) and Aegilops tauschii (D). Additional taxa containing the A genome, Triticum monococcum and its wild relative Triticum boeoticum, were also included. The main focus of the analysis was on the genomic composition of TEs as these make up at least 80% of the overall genome content. Although more than 200 TE families were identified in each species, approximately 50% of the overall genome comprised 12-15 TE families. The BARE1 element was the largest contributor to all genomes, contributing more than 10% to the overall genome. We also found that several TE families differ strongly in their abundance between species, indicating that TE families can thrive extremely successfully in one species while going virtually extinct in another. Additionally, the nucleotide diversity of BARE1 populations within individual genomes was measured. Interestingly, the nucleotide diversity in the domesticated barley H. vulgare cv. Barke was found to be twice as high as in its wild progenitor H. spontaneum, suggesting that the domesticated barley gained nucleotide diversity from the addition of different genotypes during the domestication and breeding process. In the rye/wheat lineage, sequence diversity of BARE1 elements was generally higher, suggesting that factors such as geographical distribution and mating systems might play a role in intragenomic TE diversity.


First molecular identification of 'Candidatus mycoplasma haemominutum' from a cat with fatal haemolytic anaemia in Hungary.
Although haemobartonellosis was previously reported in Hungary, until now the diagnosis (based on morphological identification in blood smears) has only been suggestive of the occurrence of the large species, recently reclassified as Mycoplasma haemofelis. However, in July 2007 a cat was presented at a small animal clinic with severe haemolytic anaemia, icterus and haemoglobinuria. While biochemical parameters were within the reference range, the cat had leukocytosis and rapidly decreasing haematocrit values, and eventually died 7 days after the sudden onset of aggravating clinical signs. From blood samples of the cat 'Candidatus Mycoplasma haemominutum' was identified by molecular methods, according to its 100% 16S rRNA gene sequence homology with two Swiss isolates and one isolate from the UK. The rapid termination of the disease and the high pathogenicity of the causative agent observed in this case are unusual, taking into account that PCR results were negative for immunosuppressive viruses. This is the first record of this feline haemoplasma species in Hungary.


Effects of obstetric factors and storage temperatures on the yield of endothelial colony forming cells from umbilical cord blood.
As umbilical cord blood (UCB) is a rich source of endothelial colony-forming cells (ECFC), our aim was twofold: (1) to examine potential obstetric selection criteria for achieving the highest ECFC yields from UCB units, and (2) to determine whether transient storage temperatures of fresh UCB and cryopreservation of UCB units affected ECFC yield and function. ECFC quality was assessed before and after cryopreservation by their clonogenic proliferative potential. Of the 20 factors examined, placental weight was the only statistically significant obstetric factor that predicted ECFC frequency in UCB. Studies on the effects of storage revealed that transient storage of fresh UCB at 4°C reduced ECFC yield compared with storage at 22°C, while cryopreservation of UCB MNCs significantly reduced ECFC recoveries. To our knowledge, this is the first demonstration that placental weight and temperature of storage prior to processing or culture have significant effects on ECFC frequency in UCB. Our studies further support the evidence that cryopreservation of UCB MNCs compromises ECFC recovery.


DNA Methylation Targets Influenced by Bisphenol A and/or Genistein Are Associated with Survival Outcomes in Breast Cancer Patients.
Early postnatal exposures to Bisphenol A (BPA) and genistein (GEN) have been reported to predispose for and against mammary cancer, respectively, in adult rats. Since the changes in cancer susceptibility occurs in the absence of the original chemical exposure, we have investigated the potential of epigenetics to account for these changes. DNA methylation studies reveal that prepubertal BPA exposure alters signaling pathways that contribute to carcinogenesis. Prepubertal exposure to GEN and BPA + GEN revealed pathways involved in maintenance of cellular function, indicating that the presence of GEN either reduces or counters some of the alterations caused by the carcinogenic properties of BPA. We subsequently evaluated the potential of epigenetic changes in the rat mammary tissues to predict survival in breast cancer patients via the Cancer Genomic Atlas (TCGA). We identified 12 genes that showed strong predictive values for long-term survival in estrogen receptor positive patients. Importantly, two genes associated with improved long term survival, HPSE and RPS9, were identified to be hypomethylated in mammary glands of rats exposed prepuberally to GEN or to GEN + BPA respectively, reinforcing the suggested cancer suppressive properties of GEN.


[Corticosteroid induced diabetes mellitus: diagnosis and management].
Steroid diabetes occurs in 20% (range 10-60%) of the persons treated with corticosteroid drugs. Steroid diabetes diagnosis often is omitted or late because the diagnostic sensitivity of fasting blood sugar is low, so the postprandial blood glucose must be monitored and the diagnosis should be made clinically, based on 2 hours after lunch blood glucose or OGTT. Steroid diabetes causes increased hospitalizations for acute diabetic complications; there are few data on the chronic complications. Steroid therapy increases the macrovascular complications in diabetic people, while globally does not increase the mortality. However, in solid organ transplant recipients steroid diabetes causes 60% increase of rejections, 90% of mortality and 150% of the annual costs and considerably worsens the prognosis of AGVHD in bone marrow transplants. The corticosteroids have negative actions on insulin resistance in muscle, liver and adipose tissue and on insulin secretion; hyperglycemia is mainly postprandial, in the afternoon and in the evening, also related to the pharmacokinetics of the drugs. There is insufficient evidence of the efficacy of specific treatments in randomized controlled trials and the treatment is based on pathophysiology, mechanisms of action of drugs and experience. The antidiabetic drug choosing criteria are the body weight, the underlying disease, the type and dose of the corticosteroid drugs, the way of administration, the blood glucose levels, the possible contraindications. New antidiabetic drugs can open therapeutic perspectives, yet still to be explored with ad hoc studies. Insulin is frequently needed, in single or multiple doses with different combinations.


Boron-doped graphitic carbon nitride nanosheets for enhanced visible light photocatalytic water splitting.
A new type of boron-doped graphitic carbon nitride (B-g-C3N4) nanosheets was prepared by a benign one-pot thermal polycondensation process. Systematic studies revealed that a B-doping amount of 1 at% into g-C3N4 (1at%B-g-C3N4) showed the best photocatalytic H2 evolution activity of 1880 μmol h-1 g-1 under visible light irradiation (>400 nm), which is more than 12 times that of the pristine g-C3N4 bulk. Detailed characterizations revealed that the high photocatalytic performance could be attributed to the combination of band structure engineering and morphological control. B-doping not only reduces the band gap to absorb more visible light but also exhibits a higher surface area of B-g-C3N4 (49.47 m2 g-1) as compared to that of g-C3N4 bulk (8.24 m2 g-1), which subsequently improve the photocatalytic performance drastically. This work demonstrates a synergistic strategy to prepare efficient metal-free B-g-C3N4 nanosheets as a promising photocatalyst for H2 evolution under visible light with good stability.


Essentiality of mmpL3 and impact of its silencing on Mycobacterium tuberculosis gene expression.
MmpL3 is an inner membrane transporter of Mycobacterium tuberculosis responsible for the export of trehalose momomycolate, a precursor of the mycobacterial outer membrane component trehalose dimycolate (TDM), as well as mycolic acids bound to arabinogalactan. MmpL3 represents an emerging target for tuberculosis therapy. In this paper, we describe the construction and characterization of an mmpL3 knockdown strain of M. tuberculosis. Downregulation of mmpL3 led to a stop in bacterial division and rapid cell death, preceded by the accumulation of TDM precursors. MmpL3 was also shown to be essential for growth in monocyte-derived human macrophages. Using RNA-seq we also found that MmpL3 depletion caused up-regulation of 47 genes and down-regulation of 23 genes (at least 3-fold change and false discovery rate ≤1%). Several genes related to osmoprotection and metal homeostasis were induced, while several genes related to energy production and mycolic acids biosynthesis were repressed suggesting that inability to synthesize a correct outer membrane leads to changes in cellular permeability and a metabolic downshift.


Intravaginally applied oxytocin improves post-menopausal vaginal atrophy.
To explore the efficacy of local oxytocin for the treatment of post-menopausal vaginal atrophy. Double-blinded randomised controlled trial. Healthy post-menopausal women in Stockholm, Sweden. Sixty four post-menopausal women between February and June 2012 at the Karolinska University Hospital Huddinge/Sweden. The efficacy of oxytocin for treatment of vaginal atrophy after seven weeks and cytological evaluation. The percentage of superficial cells in the vaginal smears and the maturation values were significantly increased after seven weeks of treatment with vagitocin 400 IU (p = 0.0288 and p = 0.0002, respectively). The vaginal pH decreased significantly after seven weeks of treatment with vagitocin 100 IU (p = 0.02). The scores of vaginal atrophy, according to the histological evaluation, were significantly reduced after administration of vagitocin 100 IU (p = 0.03). The thickness of the endometrium did not differ between the treatment and placebo groups after seven weeks of treatment. The symptom experienced as the most bothersome was significantly reduced after seven weeks of treatment in the women receiving vagitocin 400 IU compared to women in the placebo group (p = 0.0089). Treatment with intravaginally applied oxytocin could be an alternative to local estrogen treatment in women with post-menopausal vaginal atrophy.


Children and pregnant women.
A review of the literature of the 1980s reveals that women living in rural American are at risk for receiving inadequate prenatal and maternal care. Documented risk factors include poverty and concomitant lack of medical insurance, residence in the most restrictive Medicaid states, and loss of local services including the closure of obstetric units of rural hospitals and the decision by local physicians to discontinue obstetrics. A prominent factor in a physician's decision to stop providing maternity care is the escalating cost of medical liability insurance; however, other forces are also at work, including interference with personal and family activities, disruption of other aspects of professional life (e.g., office schedule), inadequate reimbursement, and an inability to keep up with advancing technology. A research agenda for the 1990s should be consistent with previous recommendations and must stimulate the development of new programs that will induce the maximum number of providers to again offer high quality perinatal care to rural women. Other items on the 1990s research agenda include: (1) the clarification of the impact of lost perinatal services in rural areas, (2) the effects of travel time and distance on perinatal outcomes and cost of care, (3) the effect of loss of obstetric services on other health care services for women and children, and (4) comparisons of regionalized versus centralized systems for the provision of perinatal services.


Estimating the rate of retinal ganglion cell loss in glaucoma.
To present and evaluate a new method of estimating rates of retinal ganglion cell (RGC) loss in glaucoma by combining structural and functional measurements. Observational cohort study. The study included 213 eyes of 213 glaucoma patients followed up for an average of 4.5 ± 0.8 years with standard automated perimetry visual fields and optical coherence tomography. A control group of 33 eyes of 33 glaucoma patients underwent repeated tests over a short period to test the specificity of the method. An additional group of 52 eyes from 52 healthy subjects followed up for an average of 4.0 ± 0.7 years was used to estimate age-related losses of RGCs. Estimates of RGC counts were obtained from standard automated perimetry and optical coherence tomography, and a weighted average was used to obtain a final estimate of the number of RGCs for each eye. The rate of RGC loss was calculated for each eye using linear regression. Progression was defined by a statistically significant slope faster than the age-expected loss of RGCs. From the 213 eyes, 47 (22.1%) showed rates of RGC loss that were faster than the age-expected decline. A larger proportion of glaucomatous eyes showed progression based on rates of RGC loss rather than based on isolated parameters from standard automated perimetry (8.5%) or optical coherence tomography (14.6%; P < .01), while maintaining similar specificities in the stable group. The rate of RGC loss estimated from combining structure and function performed better than either isolated structural or functional measures for detecting progressive glaucomatous damage.


Does presentation at multidisciplinary team meetings improve lung cancer survival? Findings from a consecutive cohort study.
Multidisciplinary team (MDT) presentation in lung cancer has the potential to improve longterm outcomes, although this varies between studies. This study aims to evaluate outcomes including survival, according to MDT presentation and to explore the utility of data obtained from local clinical sources. Prospective cases of lung cancer recorded in our institution's cancer registry were analyzed according to MDT presentation for patient and tumour characteristics, adjusted survival and referral to palliative care. 1197 cases were included, 295 (24.6%) with MDT presentation and 902 (75.4%) without. 60% of patients were male with median (IQR) age at diagnosis of 70 years (62-78). Histopathology distribution (non-small cell lung cancer and small-cell lung cancer) was similar between the two groups. Compared with the non-MDT group, the MDT group had (1) ECOG score recorded more often (71.9% vs. 47.6%), (2) higher proportion of ECOG 0 cases (31.2% vs. 11.9%) and ECOG 1 cases (28.8% vs. 20.3%), (3) higher proportion of early stage disease (stage I - 23.1% vs. 9.7% stage II - 10.2% vs. 4.8%, stage IIIA - 14.6% vs 6.3%) and (4) lower proportion of metastatic disease (stage IV - 39.3% vs. 56.1%). Referral to palliative care was incompletely recorded in both groups (MDT: n = 116/295, 39.3%; non-MDT: n = 430, 47.7%) but did not differ significantly for stage IV cases. Survival analyzed by stage was greater in the MDT group at 1, 2 and 5 years for all stages except stage IIIB at 1 year post-diagnosis. Adjusted survival analysis for the entire cohort showed improved survival at 5 years for the MDT group (HR 0.7 (0.58-0.85), p < 0.001). MDT presentation is associated with improved adjusted survival for lung cancer in this single institutional cohort in an analysis of local clinical cancer registry data.


Food safety knowledge and behavior of expanded food and nutrition education program participants in Arizona.
Consumer education is one of the focus points to reduce foodborne illness within the food safety continuum "from farm to table." A survey was conducted to determine the food safety knowledge and practices of the U.S. Department of Agriculture's Expanded Food and Nutrition Education Program participants in Maricopa and Pima counties of Arizona. Two hundred sixty-eight surveys were completed between 1 January and 31 December 1998. Survey participants consisted of 222 (85%) females and 39 (15%) males with an average age and education level of 31.5 and 11.7 years, respectively. The racial characteristics of this group included 53% whites, 32% Hispanics, 22% African-Americans, and 7% other. A majority of the survey participants (67%) were either unsure or felt it was appropriate to let food cool to room temperature prior to refrigeration. In addition 56% were in disagreement with or unsure about the need to cool foods in shallow containers. Fifty-two percent of respondents reported having no previous formal food safety education; for those who had, work was the most common source. Television news was the primary source of current food safety information for 50% of respondents. The most commonly consumed high-risk (i.e., raw or undercooked animal food or food purchased from unlicensed vendor) food was unpasteurized dairy products. Women scored significantly better than men on food safety knowledge and practice test parameters. Participants over age 50 had significantly higher food safety practice scores than the youngest age group. The food safety knowledge score of whites was significantly higher than that of Hispanics. It was determined for all participants that the food safety knowledge score had a small, positive effect on food safety practice score.


Extracellular vesicle long noncoding RNA as potential biomarkers of liver cancer.
Analysis of extracellular vesicles (EV) and their contents may be useful as disease biomarkers if they reflect the contents of cells of origin, differ between normal and diseased tissue and can be reliably detected. An increasing number of long noncoding RNA (lncRNA) are being reported to be aberrantly expressed in human cancers. These tumor-associated lncRNA may have potential as new biomarkers of disease. In this review, we highlight lncRNAs that are commonly associated with hepatocellular cancer, and summarize their potential biological roles and underlying molecular mechanisms. While lncRNA can be detected in the circulation, their low expression within circulating vesicles will require the use of highly sensitive detection technologies such as digital polymerase chain reaction or next-generation sequencing. While the integrity and functional role of tumor-specific lncRNAs within EV have yet to be established, their presence or enrichment within tumor cell-derived EV offers promise for their potential as disease biomarkers.


Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.
Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo.


Increased 24-hour ad libitum food intake is associated with lower plasma irisin concentrations the following morning in adult humans.
The relationship between food intake and irisin concentrations in humans is unclear. To determine whether the previous day's intake impacts fasting plasma irisin concentrations, or whether fasting irisin concentrations associate with subsequent ad libitum food intake. Sixty-six nondiabetic adults (42 men) were admitted for a study of the determinants of energy intake. After 6 days of a weight maintaining diet, ad libitum energy intake over 3 days was assessed using a vending machine paradigm. Fasting plasma irisin concentrations were measured on the morning of the second day of the vending period. There were no correlations between irisin and demographic or anthropometric parameters. On day 1, subjects consumed 144 ± 52% of weight maintaining energy needs. Every additional 500 kcal consumed on day 1 associated with a 3.4% lower irisin concentration the following morning (95% CI -6.2, -0.4%, p = 0.01; adjusted for age, sex and race). If energy intake was expressed as a percentage of weight maintaining energy needs, every 10% increase associated with a 1.9% lower irisin concentration (95% CI -3.7, -0.1%; adjusted p = 0.02). A 100 kcal increase in carbohydrate or fat consumption associated with a 1.3% (95% CI -2.5, -0.1%, p = 0.01) and a 0.6% (95% CI -1.1, -0.0%, p = 0.02) lower irisin concentration, respectively. There was no association between fasting irisin concentrations and subsequent energy intake on day 2 (r = 0.19, p = 0.1). Higher ad libitum 24 h energy intake was associated with lower fasting irisin concentrations the following morning, but fasting irisin concentrations did not predict subsequent energy intake. The decrease in irisin concentrations with increased energy intake is consistent with the detrimental metabolic effects of overeating.