Secondary school pupils' food choices around schools in a London borough: Fast food and walls of crisps.
The objective was to observe and document food behaviours of secondary school pupils from schools in a London borough. The research design combined a number of methods which included geographic information system (GIS) mapping of food outlets around three schools, systemised observations of food purchasing in those outlets before, during and after school, and focus groups conducted with pupils of those schools to gather their views in respect to those food choices. Results are summarised under the five 'A's of Access, Availability, Affordability and Acceptability & Attitudes: Access in that there were concentrations of food outlets around the schools. The majority of pupil food purchases were from newsagents, small local shops and supermarkets of chocolate, crisps (potato chips), fizzy drinks and energy drinks. Availability of fast food and unhealthy options were a feature of the streets surrounding the schools, with 200 m the optimal distance pupils were prepared to walk from and back to school at lunchtime. Affordability was ensured by the use of a consumer mentality and pupils sought out value for money offers; group purchasing of 'two for one' type offers encouraged this trend. Pupils reported healthy items on sale in school as expensive, and also that food was often sold in smaller portion sizes than that available from external food outlets. Acceptability and Attitudes, in that school food was not seen as 'cool', queuing for school food was not acceptable but queuing for food from takeaways was not viewed negatively; for younger pupils energy drinks were 'cool'. In conclusion, pupils recognised that school food was healthier but provided several reasons for not eating in school related to the five 'A's above.


T cell receptor sequences are the dominant factor contributing to the phenotype of CD8+ T cells with specificities against immunogenic viral antigens.
Antigen-specific CD8+ T cells mediate pathogen clearance. T cell phenotype is influenced by T cell receptor (TCR) sequences and environmental signals. Quantitative comparisons of these factors in human disease, while challenging to obtain, can provide foundational insights into basic T cell biology. Here, we investigate the phenotype kinetics of 679 CD8+ T cell clonotypes, each with specificity against one of three immunogenic viral antigens. Data were collected from a longitudinal study of 68 COVID-19 patients with antigens from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus (CMV), and influenza. Each antigen is associated with a different type of immune activation during COVID-19. We find TCR sequence to be by far the most important factor in shaping T cell phenotype and persistence for populations specific to any of these antigens. Our work demonstrates the important relationship between TCR sequence and T cell phenotype and persistence and helps explain why T cell phenotype often appears to be determined early in an infection.


Inflammatory pathways are upregulated in the nasal epithelium in patients with idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring of the lung parenchyma, leading to respiratory failure and death. High resolution computed tomography of the chest is often diagnostic for IPF, but its cost and the risk of radiation exposure limit its use as a screening tool even in patients at high risk for the disease. In patients with lung cancer, investigators have detected transcriptional signatures of disease in airway and nasal epithelial cells distal to the site of disease that are clinically useful as screening tools. Here we assessed the feasibility of distinguishing patients with IPF from age-matched controls through transcriptomic profiling of nasal epithelial curettage samples, which can be safely and repeatedly sampled over the course of a patient's illness. We recruited 10 patients with IPF and 23 age-matched healthy control subjects. Using 3' messenger RNA sequencing (mRNA-seq), we identified 224 differentially expressed genes, most of which were upregulated in patients with IPF compared with controls. Pathway enrichment analysis revealed upregulation of pathways related to immune response and inflammatory signaling in IPF patients compared with controls. These findings support the concept that fibrosis is associated with upregulation of inflammatory pathways across the respiratory epithelium with possible implications for disease detection and pathobiology.


Adaptation and psychometric properties of the PACIC short form.
The Patient Assessment of Chronic Illness Care (PACIC) is a widely used instrument to evaluate the quality and patient-centeredness of chronic illness care based on the Chronic Care Model (CCM). It is a validated and reliable instrument which consists of 20 items. Additionally, a short form with 11 items was developed. The aim of this study was to translate this short form into German and examine the psychometric properties among patients with a chronic illness in Germany. Observational study design. We performed a translation and cultural adaptation of the PACIC short form into German. The German version was externally validated with the 20-item PACIC. Cronbach a, descriptive statistics, and principal component analysis were used to assess psychometric properties. In total, 264 primary care patients completed the PACIC short form. The PACIC short form showed good convergent construct validity to the 20-item PACIC (Spearman rank correlation 0.82, P < .001) and high internal consistency (Cronbach a 0.87). Principal component analysis underlined the 1-dimensional structure of the instrument. No correlation between the mean overall score of the PACIC short form and the number of chronic conditions (r = 0.068; P = .273) was found. The PACIC short form showed good to very good psychometric properties and reliable measures regarding patient assessment of receiving care congruent with the CCM. It is a less burdensome instrument which can be used for further research of patients with more than 1 chronic condition.


Tachyarrhythmia Cycle Length in Appropriate versus Inappropriate Defibrillator Shocks in Brugada Syndrome, Early Repolarization Syndrome, or Idiopathic Ventricular Fibrillation.
Implantable cardioverter-defibrillators (ICDs) are indicated in patients with Brugada syndrome (BS), early repolarization syndrome (ERS), or idiopathic ventricular fibrillation (IVF) who are at high risk for sudden cardiac death. The optimal ICD programming for reducing inappropriate shocks in these patients remains to be determined. We investigated the difference in the mean cycle length of tachyarrhythmias that activated either appropriate or inappropriate ICD shocks in these three patient groups to determine the optimal ventricular fibrillation (VF) zone for minimizing inappropriate ICD shocks. We selected 41 patients (35 men) (mean age±standard deviation=42.6±13.0 year) who received ICD shocks between April 1996 and April 2014 to treat BS (n=24), ERS (n=9), or IVF (n=8). Clinical and ICD interrogation data were retrospectively collected and analyzed for all events with ICD shocks. Of the 244 episodes, 180 (73.8%) shocks were appropriate and 64 (26.2%) were inappropriate. The mean cycle lengths of the tachyarrhythmias that activated appropriate and inappropriate shocks were 178.9±28.7 ms and 284.8±24.4 ms, respectively (p<0.001). The cutoff value with the highest sensitivity and specificity for discriminating between appropriate and inappropriate shocks was 235 ms (sensitivity, 98.4%; specificity, 95.6%). When we programmed a single VF zone of ≤270 ms, inappropriate ICD shocks were reduced by 70.5% and appropriate shocks were missed in 1.7% of these patients. Programming of a single VF zone of ≤270 ms in patients with BS, ERS, or IVF could reduce inappropriate ICD shocks, with a low risk of missing appropriate shocks.


In Silico and In Vitro Comparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors.
Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) inhibitors of HIV-1 subtype CRF02_AG IN respectively to HIV-1 B. Structural models of B and CRF02_AG HIV-1 INs as unbound enzymes and in complex with the DNA substrate were built by homology modeling. IN inhibitors-raltegravir (RAL), elvitegravir (ELV) and L731,988-were docked onto the models, and their binding affinity for both HIV-1 B and CRF02_AG INs was compared. CRF02_AG INs were cloned and expressed from plasma of integrase strand transfer inhibitor (INSTI)-naïve infected patients. Our in silico and in vitro studies showed that the sequence variations between the INs of CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. The binding modes and affinities of INSTI inhibitors to B and CRF02_AG INs were found to be similar. Although previous studies suggested that several naturally occurring variations of CRF02_AG IN might alter either IN/vDNA interactions or INSTIs binding, our study demonstrate that these variations do affect neither IN activity nor its susceptibility to INSTIs.


Lutein-fortified infant formula fed to healthy term infants: evaluation of growth effects and safety.
Breast milk contains lutein derived from the mother's diet. This carotenoid is currently not added to infant formula, which has a small and variable lutein content from innate ingredients. This study was conducted to compare the growth of infants fed lutein-fortified infant formula with that of infants fed infant formula without lutein fortification. This 16-week study was prospective, randomized, controlled, and double-blind with parallel groups of healthy term infants fed either control formula (Wyeth S-26 Gold, designated as Gold) or experimental formula (Wyeth S-26 Gold fortified with lutein at 200 mcg/l, designated as Gold+Lutein). Two hundred thirty-two (232) infants<or=14 days postnatal age were randomized and 220 (94.8%) completed the study. Weight (g), head circumference (cm), and length (cm) were measured at Weeks 4, 8, 12, and 16. The primary endpoint was weight gain (g/day) from baseline to Week 16. Safety was assessed through monitoring of study events (SEs) throughout the study and evaluation of selected blood chemistry tests performed at Week 16. Infants in both treatment groups demonstrated appropriate growth. No differences between treatment groups were found in any of the measures of growth at any of the measurement time points. Both study formulas were well tolerated. The mean values of all measured blood chemistry parameters fell within the modified normal ranges for infants, and the values for both groups for any measured parameter were similar. Infants fed lutein-fortified S-26 Gold demonstrated growth equivalent to that of infants fed unfortified lutein formula.


Protective effect of rutin on cognitive impairment caused by phenytoin.
To study the effect of the co-administration of phenytoin (PHT) and rutin in comparison with PHT and piracetam (PIM) on seizure control, cognitive, and motor functions in mice. Increasing current electroshock seizure (ICES) test was used to evaluate the effect of the co-administration of PHT and PIM on convulsions. Cognitive functions in mice were assessed by a spontaneous alternation in behavior on a plus maze while motor functions were screened using rolling roller apparatus and by counting the number of arms entries on a plus maze. Brain acetyl-cholinesterase (AChE) activity was also estimated. The expression of data was done as mean ± standard error of the mean. The normally distributed data were subjected to one-way ANOVA followed by Dunnett's test. P < 0.05 was considered significant. The study showed that rutin when co-administered with PHT, significantly reversed PHT-induced reduction in spontaneous alternation without altering the efficacy of PHT against ICES, in both acute and chronic studies. Further, it also reversed PHT-induced increase in AChE activity. Rutin alleviated the PHT-induced cognitive impairment without compromising its antiepileptic efficacy.


Rapid dissolution microneedle based on polyvinyl alcohol/chitosan for local oral anesthesia.
At present, the main clinical methods of oral local anesthesia are direct injection of anesthetic and surface ointment. However, the pain and fear caused by the injection, the discomfort of topical anesthetic creams, and the scour and moist oral environment during the procedure pose great challenges to oral anesthesia. Herein, we designed a Lido-PVP/PVA DMNP microneedle (MN) for oral local anesthesia. The microneedle tip was consisted of Polyvinylpyrrolidone/Polyvinyl alcohol (PVP/PVA), which can quickly dissolve and release the lidocaine hydrochloride (Lido) drug within 5 min to achieve rapid anesthesia. The backing was composed of polyvinyl alcohol/chitosan (PVA/CS), and its excellent adhesion can overcome saliva erosion and anchor firmly to the oral mucosa, significantly improving the utilization rate of drugs, as well as the patient compliance. MNs have good mechanical properties for tissue insertion while possessing high drug loading (3 mg/MNs). Von Frey tests proved that MNs showed a faster and more effective local anesthetic effect (anesthesia takes effect at 5 min) compared to cream (anesthesia takes effect at 30 min). In addition, the excellent biocompatibility and no skin irritation endowed Lido-PVP/PVA DMNP MNs a great potential for oral local anesthesia in the oral cavity.


Thiazolidinediones and fractures: evidence from translating research into action for diabetes.
Thiazolidinedione (TZD) treatment has been associated with fractures. The purpose of this study was to examine the association between TZD treatment and fractures in type 2 diabetic patients. Using data from Translating Research into Action for Diabetes, a multicenter prospective observational study of diabetes care in managed care, we conducted a matched case-control study to assess the odds of TZD exposure in patients with type 2 diabetes with and without fractures. We identified 786 cases based on fractures detected in health plan administrative data. Up to four controls without any fracture diagnoses were matched to each case. Controls were matched on health plan, date of birth within 5 yr, sex, race/ethnicity, and body mass index within 5 kg/m(2). We performed conditional logistic regression for premenopausal and postmenopausal women and men to assess the odds of exposure to potential risk factors for fracture, including medications, self-reported limited mobility, and lower-extremity amputations. We found statistically significant increased odds of exposure to TZDs, glucocorticoids, loop diuretics, and self-reported limited mobility for women 50 yr of age and older with fractures. Exposure to both loop diuretics and TZDs, glucocorticoids, and insulin and limited mobility and lower-extremity amputation were associated with fractures in men. Postmenopausal women taking TZDs and the subset of men taking both loop diuretics and TZDs were at increased risk for fractures. In postmenopausal women, risk was associated with higher TZD dose. No difference between rosiglitazone and pioglitazone was apparent.


CXCR4 is a prognostic marker in acute myelogenous leukemia.
CXCR4 chemokine receptors retain hematopoietic progenitors and leukemia cells within the marrow microenvironment. We prospectively evaluated the prognostic implication of CXCR4 in 90 consecutive patients with acute myelogenous leukemia (AML) by flow cytometry. Patients were divided into groups with low (n=32), intermediate (n=26), or high (n=32) CXCR4 expression, as defined by CXCR4 mean fluorescence intensity ratio thresholds of less than 5, 5 to 10, or more than 10, respectively. We found that low CXCR4 expression on AML cells correlated with a better prognosis, resulting in a longer relapse-free and overall survival of 24.3+/-2.9 months for low CXCR4-expressing patients, compared with 17.4+/-3.4 months for intermediate and 12.8+/-2 months (mean+/-SEM) for patients with high expression. In univariate analyses, CXCR4 expression, cytogenetics, white blood cell count, and serum lactate dehydrogenase (LDH) predicted for shorter survival. Multivariate analysis revealed CXCR4 expression and unfavorable cytogenetics as independent prognostic factors. We conclude that CXCR4 expression in AML is an independent prognostic predictor for disease relapse and survival that can rapidly and easily be determined at disease presentation. These findings warrant further investigation into the role of CXCR4 in AML and suggest that CXCR4 should be incorporated into the risk assessment of AML patients.


Synthesis of large-pore zeolites from chiral structure-directing agents with two l-prolinol units.
In this work, we perform an in-depth experimental and computational study about the structure-directing effect of two new chiral organic quaternary ammonium dications bearing two N-methyl-prolinol units linked by a xylene spacer in para or meta relative orientation, displaying four enantiopure stereogenic centers in (S) configuration. Synthesis results show that the para-xylene derivative is an efficient structure-directing agent, promoting the crystallization of ZSM-12 (in pure-silica composition), beta zeolite (as pure-silica, or in the presence of Al or Ge), and a mixture of polymorphs C, A and B of zeolite beta (in the presence of Ge). In contrast, the meta-xylene derivative showed a much poorer structure-directing activity, yielding only amorphous materials unless Ge is present in the gel, where beta and polymorph C (together with A and B) zeolites crystallized. Molecular simulations showed that the para-xylene dication displays a cylindrical shape suitable for confining in zeolite pores, while the meta-xylene derivative has an angular shape that shifts from the typical dimensions required for 12MR zeolite channels. Despite enantio-purity of the para-xylene dication with (S,S,S,S) configuration, no enrichment in polymorph A of the zeolite beta samples obtained was observed by Transmission Electron Microscopy. With the aid of molecular simulations, the failure in transferring chirality to the zeolite is explained by the loose fit of this SDA in the large-pores of zeolite beta, and a lack of close geometrical fit with the chiral element of polymorph A, as evidenced by the very similar interaction of the cation with the two enantiomorphic space groups of polymorph A. Nevertheless, the molecular-level knowledge gained in this work can provide insights for the future design of more efficient SDAs towards the synthesis of chiral zeolites.


Veterans' Pharmacy and Health Care Utilization Following Implementation of the Medicare Part D Pharmacy Benefit.
We examined associations between enrollment in Medicare Part D pharmacy benefits and changes in medication acquisition from Department of Veterans Affairs (VA) pharmacies. We included all women and a random 10% sample of men who were VA enrollees, ≥65 years old as of January 1, 2004, and alive through December 2007. We used difference-in-differences models with propensity score weighting to examine changes in medication acquisition between 2005 (before Part D was implemented) and 2007 (after Part D implementation) for veterans who were or were not Part D enrolled. Of 231,716 veterans meeting inclusion criteria, 49,881 (21.5%) were enrolled. While 30-day medication supplies decreased from 26.2 to 23.4 for enrolled veterans, they increased from 36.6 to 37.4 for nonenrolled veterans (difference-in-differences: -4.0, p < .001). Reductions in 30-day supplies were greater among veterans who were required to pay VA copayments for some or all medications and who used VA and Medicare outpatient services.


Long-lived nuclear spin states far from magnetic equivalence.
Clusters of coupled nuclear spins may form long-lived nuclear spin states, which interact weakly with the environment, compared to ordinary nuclear magnetization. All experimental demonstrations of long-lived states have so far involved spin systems which are close to the condition of magnetic equivalence, in which the network of spin-spin couplings is conserved under all pair exchanges of symmetry-related nuclei. We show that the four-spin system of trans-[2,3-(13)C2]-but-2-enedioate exhibits a long-lived nuclear spin state, even though this spin system is very far from magnetic equivalence. The 4-spin long-lived state is accessed by slightly asymmetric chemical substitutions of the centrosymmetric molecular core. The long-lived state is a consequence of the locally centrosymmetric molecular geometry for the trans isomer, and is absent for the cis isomer. A general group theoretical description of long-lived states is presented. It is shown that the symmetries of coherent and incoherent interactions are both important for the existence of long-lived states.


Neglected gaps in improving the health, wellbeing, and care for sexual and gender minority young people living in low- and lower-middle- income countries: a scoping review.
There is a lack of reliable data on the size, characteristics, and experiences of sexual and gender minority (SGM) young people (ages 10-24) in low- and lower-middle- income countries (LMICs). This review examines the research conducted in the last thirteen years with and about SGM young people living in low-income settings and seeks to answer the question: What is known about the mental and physical health needs, safety, and wellbeing of SGM young people living in LMICs? We conducted a scoping review informed by the methodological frameworks put forth by Arksey and O'Malley and the Joanna Briggs Institute. We systematically searched two general social science databases and one topic-specific database for peer-reviewed papers, of any research design, that included SGM young people or explored attitudes toward SGM young people in LMICs. We included papers that reported on factors influencing the health and wellbeing of SGM populations, including physical and mental health, healthcare-seeking behaviors, substance use, experiences of discrimination and/or stigma, experiences of violence and abuse (emotional, physical, and/or sexual), economically motivated paid sex practices, housing or economic security, and attitudes of others toward SGM populations. Of the 5,409 unique records identified, 79 papers drawing from data collected from 74 unique studies met the inclusion criteria. Only 50 of the 79 papers included SGM young people as participants, with just 13 focusing exclusively on SGM young people ages 10-24. The included papers were classified into three thematic groupings: attitudes toward SGM populations (n = 26), risks to health (n = 40), and experiences of stigma and discrimination (n = 13). The findings indicate that the health and wellbeing of SGM young people in LMICs has been historically under-researched. While SGM young people have received more attention from researchers in recent years, the body of literature as a whole is disjointed and sparse, and often studies are about SGM young people, rather than with and for them. Our review highlights the need for more and better research, more accurate and disaggregated demographic data, and leadership and participation of SGM-led community-based organizations in the co-design of studies that focus on SGM young people.


Field Evaluation of Xpert HPV Point-of-Care Test for Detection of Human Papillomavirus Infection by Use of Self-Collected Vaginal and Clinician-Collected Cervical Specimens.
The World Health Organization has recommended that testing for high-risk human papillomavirus (HPV) (hrHPV) infection be incorporated into cervical screening programs in all settings worldwide. In many high-burden, low-income countries, it will not be feasible to achieve high cervical screening coverage using hrHPV assays that require clinician-collected samples. We conducted the first evaluation of self-collected vaginal specimens compared with clinician-collected cervical specimens for the detection of hrHPV infection using the Xpert HPV test. Women aged 30 to 54 years attending two well-woman clinics in Papua New Guinea were invited to participate and provided self-collected vaginal and clinician-collected cervical cytobrush specimens. Both specimen types were tested at the point of care by using the Xpert HPV test. Women were given their cervical test result the same day. Those with a positive hrHPV test and positive examination upon visual inspection of the cervix with acetic acid were offered same-day cervical cryotherapy. A total of 1,005 women were enrolled, with 124 (12.3%; 95% confidence interval [CI], 10.3%, 14.4%) being positive for any hrHPV infection. There was a 99.4% overall percent agreement (OPA) between vaginal and cervical tests for HPV-16 (95% CI, 98.9%, 99.9%), a 98.5% OPA for HPV-18/45 (95% CI, 97.7%, 99.3%), a 94.4% OPA for other hrHPV infections (95% CI, 92.9%, 95.9%), and a 93.4% OPA for all hrHPV types combined (95% CI, 91.8%, 95.0%). Self-collected vaginal specimens had excellent agreement with clinician-collected cervical specimens for the detection of hrHPV infection using the Xpert HPV test. This approach provides for the first time an opportunity to incorporate point-of-care hrHPV testing into clinical cervical screening algorithms in high-burden, low-income settings.


RHEB1 expression in embryonic and postnatal mouse.
Ras homolog enriched in brain (RHEB1) is a member within the superfamily of GTP-binding proteins encoded by the RAS oncogenes. RHEB1 is located at the crossroad of several important pathways including the insulin-signaling pathways and thus plays an important role in different physiological processes. To understand better the physiological relevance of RHEB1 protein, the expression pattern of RHEB1 was analyzed in both embryonic (at E3.5-E16.5) and adult (1-month old) mice. RHEB1 immunostaining and X-gal staining were used for wild-type and Rheb1 gene trap mutant mice, respectively. These independent methods revealed similar RHEB1 expression patterns during both embryonic and postnatal developments. Ubiquitous uniform RHEB1/β-gal and/or RHEB1 expression was seen in preimplantation embryos at E3.5 and postimplantation embryos up to E12.5. Between stages E13.5 and E16.5, RHEB1 expression levels became complex: In particular, strong expression was identified in neural tissues, including the neuroepithelial layer of the mesencephalon, telencephalon, and neural tube of CNS and dorsal root ganglia. In addition, strong expression was seen in certain peripheral tissues including heart, intestine, muscle, and urinary bladder. Postnatal mice have broad spatial RHEB1 expression in different regions of the cerebral cortex, subcortical regions (including hippocampus), olfactory bulb, medulla oblongata, and cerebellum (particularly in Purkinje cells). Significant RHEB1 expression was also viewed in internal organs including the heart, intestine, urinary bladder, and muscle. Moreover, adult animals have complex tissue- and organ-specific RHEB1 expression patterns with different intensities observed throughout postnatal development. Its expression level is in general comparable in CNS and other organs of mouse. Thus, the expression pattern of RHEB1 suggests that it likely plays a ubiquitous role in the development of the early embryo with more tissue-specific roles in later development.


Hypothermia in multisystem trauma.
Exsanguinating hemorrhage is a common clinical feature of multisystem trauma that results in death or severe disability. Cardiovascular collapse resulting from hemorrhage is unresponsive to conventional methods of cardiopulmonary resuscitation. Even when bleeding is controlled rapidly, adequate circulation cannot be restored in time to avoid neurologic consequences that appear after only 5 mins of cerebral ischemia and hypoperfusion. Reperfusion adds further insult to injury. A novel solution to this problem would be to institute a therapy that makes cells and organs more resistant to ischemic injury, thereby extending the time they can tolerate such an insult. Hypothermia can attenuate some effects of ischemia and reperfusion. Accumulating preclinical data demonstrate that hypothermia can be induced safely and rapidly to achieve emergency preservation for resuscitation during lethal hemorrhage. Hypothermia may be an effective therapeutic approach for otherwise lethal traumatic hemorrhage, and a clinical trial to determine its utility is warranted.


[A search for the focus in patients with fever of unknown origin: is positron-emission tomography with F-18-fluorodeoxyglucose helpful?].
Search for focus in patients with fever of unknown origin (FUO). In four patients with the above mentioned problem, F-18-FDG-PET was performed, following the common imaging methods, which were without evidence for a focus. The origin of FUO was verified in all patients by PET: Tuberculosis, pneumocystis-carinii pneumonia, chronic inflammatory hematoma, aortitis. Successful implementation of F-18-FDG-PET as additional imaging method in patients with FUO seems reasonable. This has to be verified by further prospective studies.


Pharmaceutical consumption and cost in patients with dementia: A longitudinal study by the Registry of Dementias of Girona (ReDeGi) in Catalonia (Spain).
Drug spending increases exponentially from the age of 65-70 years, and dementia is one of the diseases significantly contributing to this increase. Our aim was to describe pharmaceutical consumption and cost in patients with dementia, using the Anatomical Therapeutic Chemical (ATC) classification system. We also assessed the evolution of costs and consumption, and the variables associated to this evolution during three years. Three years prospective cohort study using data from the ReDeGi and the Health Region of Girona (HRG) Pharmacy Unit database from the Public Catalan Healthcare Service (PCHS). Frequency of consumption and costs of ATC categories of drugs were calculated. Sample of 869 patients with dementia, most of them with a diagnosis of degenerative dementia (72.6%), and in a mild stage of the disease (68.2%). Central nervous system (CNS) drugs had the highest consumption rate (97.2%), followed by metabolic system drugs (80.1%), and cardiovascular system drugs (75.4%). Total pharmaceutical cost was of 2124.8 € per patient/year (standard deviation (SD)=1018.5 €), and spending on CNS drugs was 55.5% of the total cost. After 36 months, pharmaceutical cost increased in 694.9 € (SD=1741.9), which was associated with dementia severity and institutionalization at baseline. Pharmaceutical consumption and costs are high in patients with dementia, and they increase with time, showing an association with baseline dementia severity and institutionalization. CNS drugs are the pharmaceuticals with highest prescription rates and associated costs.


Cold denaturation of α-synuclein amyloid fibrils.
Although amyloid fibrils are associated with numerous pathologies, their conformational stability remains largely unclear. Herein, we probe the thermal stability of various amyloid fibrils. α-Synuclein fibrils cold-denatured to monomers at 0-20 °C and heat-denatured at 60-110 °C. Meanwhile, the fibrils of β2-microglobulin, Alzheimer's Aβ1-40/Aβ1-42 peptides, and insulin exhibited only heat denaturation, although they showed a decrease in stability at low temperature. A comparison of structural parameters with positive enthalpy and heat capacity changes which showed opposite signs to protein folding suggested that the burial of charged residues in fibril cores contributed to the cold denaturation of α-synuclein fibrils. We propose that although cold-denaturation is common to both native proteins and misfolded fibrillar states, the main-chain dominated amyloid structures may explain amyloid-specific cold denaturation arising from the unfavorable burial of charged side-chains in fibril cores.


Leisure-time physical activity alone may not be a sufficient public health approach to prevent obesity--a focus on China.
Much small-scale research has identified the role of physical activity in obesity prevention. This is the 'energy expenditure' side of the energy balance equation. Although around half an hour of daily moderate-intensity physical activity is required for cardiovascular health and disease prevention, the quantum of physical activity required for obesity prevention and weight loss is around 60-90 minutes per day. This amount of physical activity is difficult to achieve through leisure time physical activity (LTPA) alone, and additional energy expenditure is needed in the domains of active transport, occupation activity and in domestic settings. Modeling of 24-hour energy expenditures demonstrate the need for 'active living', namely energy expenditure over and above that due to LTPA, for weight loss and obesity prevention. The consequences of this for developing countries such as China are the need to focus on preventing the declines in energy expenditure attributable to urbanization, industrialization, and motor vehicle dependence. These will pose policy challenges in the developing world, if they are to be taken seriously as obesity prevention strategies.


Modification of the Superomedial Pedicle in Wise-Pattern Breast Reduction: New Sling Suspension Technique to Prevent (Pseudo) Ptosis.
The combination of the superomedial pedicle with the traditional Wise-pattern skin resection has gained increasing popularity for its versatility and ability to achieve significant reduction of breast parenchyma and skin envelope. The author describes a reproducible new dermal suspension technique for cranial stabilization and fixation of the superomedial pedicle in Wise inverted T breast reductions to prevent pseudoptosis. One patient had a small dermal skin abscess caudal from the right areola as a tissue reaction on the remaining suture. The other peri- and post-operative cases were uncomplicated. Two patients experienced a two-week postoperative pain in the areas treated by liposuction. There was no reduced or increased sensibility of the nipple-areola complex. No signs of (pseudo) ptosis were seen. There was a 100% patient satisfaction rate. Our technique denoted to a direct support of the pedicle using a non-interrupted dermal suspension flap continued with the pedicle to be a medial, caudal and lateral support for the pedicle. The dermal sling reduced the anterior force generated by the pedicle. The pedicle enfolded by the dermal flap formed a vital basis for ingrowth in the surrounding tissue.


Interaction between methylxanthines and the benzodiazepine receptor.
3H-Flunitrazepam (500 pM) was used to estimate the inhibitory effects of caffeine, theophylline, theobromine and 3-methylxanthine on binding to rat brain homogenates. Caffeine and theophylline showed a low affinity competitive type of inhibition in vitro, but no inhibition in vivo. Low concentrations of caffeine failed to show clear inhibitory capabilities against low concentrations of 3H-flunitrazepam. The results suggest that only the toxic central nervous system effects of methylxanthines are mediated via the benzodiazepine receptor.


Demystification of AI-driven medical image interpretation: past, present and future.
The recent explosion of 'big data' has ushered in a new era of artificial intelligence (AI) algorithms in every sphere of technological activity, including medicine, and in particular radiology. However, the recent success of AI in certain flagship applications has, to some extent, masked decades-long advances in computational technology development for medical image analysis. In this article, we provide an overview of the history of AI methods for radiological image analysis in order to provide a context for the latest developments. We review the functioning, strengths and limitations of more classical methods as well as of the more recent deep learning techniques. We discuss the unique characteristics of medical data and medical science that set medicine apart from other technological domains in order to highlight not only the potential of AI in radiology but also the very real and often overlooked constraints that may limit the applicability of certain AI methods. Finally, we provide a comprehensive perspective on the potential impact of AI on radiology and on how to evaluate it not only from a technical point of view but also from a clinical one, so that patients can ultimately benefit from it. KEY POINTS: • Artificial intelligence (AI) research in medical imaging has a long history • The functioning, strengths and limitations of more classical AI methods is reviewed, together with that of more recent deep learning methods. • A perspective is provided on the potential impact of AI on radiology and on its evaluation from both technical and clinical points of view.


Temperature and blood flow measurements in and around 7,12-dimethylbenz(a)anthracene-induced tumor and Walker 256 carcinosarcomas in rats.
By means of an implanted transmitter, a circadian rhythm of temperature was found both in 7,12-dimethylbenz(a)anthracene-induced tumors and in Walker 256 carcinosarcomas. There was no significant difference in the temperatures of the two tumors. The temperature was lowest in periods of rest, and the temperature difference between light and dark periods was about 1 degree. Both tumors were found to have a higher temperature than that of s.c. tissue. External temperature measurements of the skin covering the 7,12-dimethylbenz(a)anthracene-induced tumor by thermistor probe and by thermography showed a temperature 1-2 degrees below the temperature of surrounding skin areas. In the 7,12-dimethylbenz(a)anthracene-induced tumors the blood flow was low, which should correspond to a relatively small heat production, although the temperature was relatively high. Blood flow in skin overlying tumor was high, presumably a perifocal hyperemic reaction, although the temperature was relatively low in this area. Thus tissue temperatures was not indicative of blood flow.


Five-year intra-individual variability in C-reactive protein levels in a Japanese population-based study: the Jichi Medical School Cohort Study at Yamato, 1993-1998.
C-reactive protein (CRP) is an acute-phase reactant that is related to future cardiovascular events. However, little is known about the long-term intra-individual stability of CRP in community residents. The 5-year intra-individual correlation of CRP levels was examined in the Jichi Medical School Cohort Study in Japan. CRP measurements were obtained in 1993 and in 1998 from 388 presumptively healthy individuals aged 30-69 years at baseline. The Pearson's correlation coefficient of CRP between baseline and follow-up measurements was 0.43 (95% confidence interval (CI): 0.34-0.51). Additional analyses by sex and smoking status at baseline revealed similar coefficients. The correlation coefficient of CRP was lower than that of other classical risk factors, such as body-mass index (BMI), blood pressure, and total and high-density lipoprotein (HDL) cholesterol. A subgroup of individuals with higher levels of CRP at both baseline and follow-up measurements had higher BMI, hemoglobin Alc, and plasma fibrinogen, and lower levels of HDL-cholesterol than others, even after adjusting for age, sex, and smoking status in a multiple logistic model. In conclusion, the stability of CRP levels was statistically significant in a long-term population-based study. A subgroup with higher levels of CRP who had an aggregation of cardiovascular risk factors was identified by the 2 measurements.


Martini 3 Force Field Parameters for Protein Lipidation Post-Translational Modifications.
Protein lipidations are vital co/post-translational modifications that tether lipid tails to specific protein amino acids, allowing them to anchor to biological membranes, switch their subcellular localization, and modulate association with other proteins. Such lipidations are thus crucial for multiple biological processes including signal transduction, protein trafficking, and membrane localization and are implicated in various diseases as well. Examples of lipid-anchored proteins include the Ras family of proteins that undergo farnesylation; actin and gelsolin that are myristoylated; phospholipase D that is palmitoylated; glycosylphosphatidylinositol-anchored proteins; and others. Here, we develop parameters for cysteine-targeting farnesylation, geranylgeranylation, and palmitoylation, as well as glycine-targeting myristoylation for the latest version of the Martini 3 coarse-grained force field. The parameters are developed using the CHARMM36m all-atom force field parameters as reference. The behavior of the coarse-grained models is consistent with that of the all-atom force field for all lipidations and reproduces key dynamical and structural features of lipid-anchored peptides, such as the solvent-accessible surface area, bilayer penetration depth, and representative conformations of the anchors. The parameters are also validated in simulations of the lipid-anchored peripheral membrane proteins Rheb and Arf1, after comparison with independent all-atom simulations. The parameters, along with mapping schemes for the popular martinize2 tool, are available for download at 10.5281/zenodo.7849262 and also as supporting information.


Veterans Health Administration mental health treatment settings of patients who report military sexual trauma.
The comprehensive Veterans Health Administration (VHA) policies on military sexual trauma (MST) include provider education and training at each VHA facility. No published data exist that indicate the settings in which VHA mental health patients with MST are treated. Such information could help set priorities for targeted MST-related education and training. The major aim of this article was to describe the VHA mental health outpatient settings in which patients with MST are most likely to be treated. National data from 79,903 female and 889,998 male veteran patients with at least one face-to-face outpatient mental health encounter at any VHA facility in fiscal year 2008 were analyzed. Among all veterans in VHA outpatient mental health care, 35.8% of women and 2.4% of men reported MST. The proportion of MST-positive patients ranged from 25.9% to 81.0% of women and from 1.5% to 56.1% of men across 9 major clinic setting categories. Proportions of women with MST were substantial across specialty MST clinics, specialty posttraumatic stress disorder clinics, psychosocial rehabilitation, and substance use disorder clinics, reflecting a wide range of settings. These settings should be prioritized for MST-related provider education and training. By contrast, male MST patients represented only a small proportion of patients in all clinics, with the exception of MST specialty clinics. Tailored conceptualizations of trauma-informed care are proposed for settings that encounter MST patients, even if these settings do not directly focus on the treatment of traumatic stress.


Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial.
Garlic powder tablets have been reported to lower serum cholesterol levels. There is widespread belief among the general public that garlic powder tablets aid in controlling cholesterol levels. However, much of the prior data demonstrating the cholesterol-lowering effect of garlic tablets involved studies that were inadequately controlled. To determine the lipid-lowering effect of garlic powder tablets in patients with hypercholesterolemia. This was a randomized, double-blind, placebo-controlled, 12-week, parallel treatment study carried out in 2 outpatient lipid clinics. Entry into the study after 8 weeks of diet stabilization required a mean low-density lipoprotein cholesterol level on 2 visits of 4.1 mmol/L (160 mg/dL) or lower and a triglyceride level of 4.0 mmol/L (350 mg/dL) or lower. The active treatment arm received tablets containing 300 mg of garlic powder (Kwai) 3 times per day, given with meals (total, 900 mg/d). This is equivalent to approximately 2.7 g or approximately 1 clove of fresh garlic per day. The placebo arm received an identical-looking tablet, also given 3 times per day with meals. The main outcome measures included levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol after 12 weeks of treatment. Twenty-eight patients (43% male; mean +/- SD age, 58 +/- 14 years) received garlic powder treatment and 22 (68% male; mean +/- SD age, 57 +/- 13 years) received placebo treatment. There were no significant lipid or lipoprotein changes in either the placebo- or garlic-treated groups and no significant difference between changes in the placebo-treated group compared with changes in the garlic-treated patients. Garlic powder (900 mg/d) treatment for 12 weeks was ineffective in lowering cholesterol levels in patients with hypercholesterolemia.


Transmembrane macromolecule rotation model--molecular hypothesis of membrane excitation.
A hypothesis concerning the molecular changes in the nerve cell membrane during excitation is presented. Based upon established principles about the interaction of hydrophobic and hydrophilic ligands and upon recent facts concerning the contraction of neurofilaments, the hypothesis accounts for both the initiation of the action potential and its conduction along the nerve axon without attenuation. The hypothesis can be summarized as follows: When acetylcholine combines with the acetylcholine receptor (AchR) alpha subunit, hydrophobic subsites are exposed at the bound surface of AchR. Since hydrophobic portions are quite unstable, the subsites move to the center of the membrane, which is hydrophobic. It is postulated that the rotation of receptor subunits makes the center an ion channel. Ca++ flowing in through the ion channel causes the undercoating filaments to contract and this contraction results in the conduction of an action potential along the axon. The contraction of the undercoating filaments induces transmembrane rotation of globular protein connected to the filaments. At right angles to the axon the force of the hydrophobic bond between membrane macromolecules is so strong that many cylindrical lipid structures are formed. The gaps between the rotatory cylinders serve as ion channels. Ca++ passing through the ion channels allows for the conduction of an action potential without attenuation.


A fatal case of meningoencephalitis due to a free-living amoeba of uncertain identity--probably acanthamoeba sp.
There are 2 main types of meningoencephalitis caused by free-living amoebae. The first is a well-defined acutely fatal disease resembling fulminating bacterial meningitis. It is caused by the single species Naegleria fowleri. The second is a more poorly defined disease that runs a subacute or chronic course and is characterized by focal granulomatous lesions in the brain. The causative organisms are probably Acanthamoeba sp. in most cases, but it is possible that other genera may be involved. The first case of the subacute form of the disease to be recognized in Australia is described. A 2 1/2-yr-old, previously well girl presented with ataxia and lower motor neurone paralyses. The cerebrospinal fluid was pleocytic and she was thought to be suffering from a relatively minor viral brain-stem encephalitis. Her symptoms persisted in a peculiarly fluctuating way for 30 d when she suddenly collapsed and died from an intracranial haemorrhage. Necropsy showed focal granulomatous lesions associated with necrotizing vasculitis in the basal regions of the brain. The lesions contained well preserved free-living amoebae which were morphologically different from N. fowleri and most closely resembled Acanthamoeba sp. The ultrastructure of the organisms was particularly well preserved and is described in some detail. Immunohistological studies also excluded N. fowleri but were inconclusive for Acanthamoeba or other genera of free-living amoebae. Difficulties with the diagnosis and treatment of this disease are discussed and some practical suggestions are made.


Different ovarian responses to potential mates underlie species-specific breeding strategies in common marmoset and Goeldi's monkey.
Callitrichids are cooperative breeders, characterized by obligate twinning, extensive paternal care, and monopolization of reproduction by the dominant female. This is the case in the common marmoset, and in common marmoset groups of more than one adult female, subordinate females are typically acyclic consistent with infertility. However, one callitrichid, Goeldi's monkey, gives birth to singletons and exhibits low paternal care. Given these reproductive traits of Goeldi's monkey, we hypothesized that there would not be suppression of ovarian activity. To test this hypothesis, we applied non-invasive endocrine methods in a step-wise experiment with laboratory groups of both species. In each species, six pairs of sisters were studied alone, in visual contact with an unrelated male and in a polygynous trio with the male, and urine samples were collected for determination of oestrogen titres reflecting ovarian activity. Common marmoset sister pairs exhibited a marked difference in social status: during the study 5 of 6 dominant females conceived but only 1 of 6 subordinate females; the remaining 5 subordinates were acyclic at the end of the study, and instances of ovulation typically resulted in aggression. Goeldi's monkey sister pairs showed no status differences: in all pairs, however, both sisters exhibited a temporary cessation of ovarian cyclicity on trio formation, followed by ovulation and conception. We conclude that these marked differences in ovarian responses reflect the differences in inter-female competition for paternal caregiving resources. In common marmosets with high inter-female competition, suppression of ovulation functions to reduce aggression received by subordinate females; in Goeldi's monkey with low competition, temporary cessation of ovulation could facilitate female choice.


Dynamic arc radiosurgery field shaping: a comparison with static field conformal and noncoplanar circular arcs.
Recent advances in field-shaping technology and linac multileaf collimator (MLC) integration have resulted in new approaches to performing stereotactic radiosurgery. We present a modeling study comparing the absolute dose distributions from three radiosurgery delivery techniques: a conventional approach utilizing noncoplanar circular arcs, a static field conformal approach, and a dynamic arc field-shaping approach. In the latter, the MLC leaves more in a continuous fashion, conforming to the beam's-eye-view projection of the target at every increment along the path of an arc. For the analysis, we devised a simulated target consisting of three overlapping spheres. This was chosen because it offered a straightforward planning approach for all three techniques, primarily the multiple isocenter approach. In addition, three representative cases were selected from the prior radiosurgery experience. These range in increasing size, from 0.50 to 9.79 cm(3), and in complexity, requiring from 3 isocenters to 16 in the case of circular arcs. In each situation, the goals were twofold: (1) to cover the entire volume with as high an appropriate isodose level (90% in the case of the conformal and dynamic arc techniques, 50% in the case of circular collimators) while (2) minimizing the dose to normal brain and where applicable, any adjacent radiation-sensitive structures. Because of the latter requirement, a single isocenter circular arc approach was ruled out for the analysis. In the case of large or irregularly shaped lesions, the circular arc technique requires multiple isocenters, producing a high level of dose heterogeneity within the target volume. Both the static field and dynamic arc conformal techniques, as with all single isocenter approaches, produce a highly homogeneous dose throughout the target region. For a given large dose, peripheral dose is decreased as additional beams or arc degrees are added with either of the conformal approaches. Dose--volume histogram analysis evaluating the peripheral dose shows that, in many cases, dose to surrounding structures can be reduced through the use of a conformal static or dynamic arc approach over the conventional multiple isocenter, circular arc techniques. Dynamic arc shaping is an efficient and effective method for accurately delivering a homogeneous target dose while simultaneously minimizing peripheral dose in radiosurgery applications.


Appointment Template Redesign in a Women's Health Clinic Using Clinical Constraints to Improve Service Quality and Efficiency.
Patient wait time is a critical element of access to care that has long been recognized as a major problem in modern outpatient health care delivery systems. It impacts patient and medical staff productivity, stress, quality and efficiency of medical care, as well as health-care cost and availability. This study was conducted in a Women's Health Clinic. The objective was to improve clinic service quality by redesigning patient appointment template using the clinical constraints. The proposed scheduling template consisted of two key elements: the redesign of appointment types and the determination of the length of time slots using defined constraints. The re-classification technique was used for the redesign of appointment visit types to capture service variation for scheduling purposes. Then, the appointment length was determined by incorporating clinic constraints or goals, such as patient wait time, physician idle time, overtime, finish time, lunch hours, when the last appointment was scheduled, and the desired number of appointment slots, to converge the optimal length of appointment slots for each visit type. The redesigned template was implemented and the results indicated a 73% reduction in average patient waiting from the reported 40 to 11 minutes. The patient no-show rate was reduced by 4% from 24% to 20%. The morning section on average finished about 11:50 am. The clinic day was finished around 4:45 pm. Provider average idle time was estimated to be about 5 minutes, which can be used for charting/documenting patients. This study provided an alternative method of redesigning appointment scheduling templates using only the clinical constraints rather than the traditional way that required an objective function. This paper also documented the employed methods step by step in a real clinic setting. The implementation results concluded a significant improvement on patient wait time and no-show rate.


Extracranial Cervical Artery Dissections.
Cervical artery dissections (CeAD) include both internal carotid and vertebral artery dissections. They are rare but important causes of stroke, especially in younger patients. CeAD should be considered in patients with strokelike symptoms, a new-onset headache and/or neck pain, and/or other risk factors. Early imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is key to making the diagnosis. Treatment may vary depending on the extent of the dissection, timing of the dissection, and other comorbidities. The overall prognosis is good, but does depend on the initial severity of symptoms.


RGS3 interacts with 14-3-3 via the N-terminal region distinct from the RGS (regulator of G-protein signalling) domain.
RGS3 belongs to a family of the regulators of G-protein signalling (RGS), which bind and inhibit the G alpha subunits of heterotrimeric G-proteins via a homologous RGS domain. Increasing evidence suggests that RGS proteins can also interact with targets other than G-proteins. Employing yeast two-hybrid screening of a cDNA library, we identified an interaction between RGS3 and the phosphoserine-binding protein 14-3-3. This interaction was confirmed by in vitro binding and co-immunoprecipitation experiments. RGS3-deletion analysis revealed the presence of a single 14-3-3-binding site located outside of the RGS domain. Ser(264) was then identified as the 14-3-3-binding site of RGS3. The S(264)A mutation resulted in the loss of RGS3 binding to 14-3-3, without affecting its ability to bind G alpha(q). Signalling studies showed that the S(264)A mutant was more potent than the wild-type RGS3 in inhibition of G-protein-mediated signalling. Binding experiments revealed that RGS3 exists in two separate pools, either 14-3-3-bound or G-protein-bound, and that the 14-3-3-bound RGS3 is unable to interact with G-proteins. These data are consistent with the model wherein 14-3-3 serves as a scavenger of RGS3, regulating the amounts of RGS3 available for binding G-proteins. This study describes a new level in the regulation of G-protein signalling, in which the inhibitors of G-proteins, RGS proteins, can themselves be regulated by phosphorylation and binding 14-3-3.


Developmental and genetic regulation of human surfactant protein B in vivo.
Genetic and developmental disruption of surfactant protein B (SP-B) expression causes neonatal respiratory distress syndrome (RDS). To assess developmental and genetic regulation of SP-B expression in vivo. To evaluate in vivo developmental regulation of SP-B, we used immunoblotting to compare frequency of detection of mature and pro-SP-B peptides in developmentally distinct cohorts: 24 amniotic fluid samples, unfractionated tracheal aspirates from 101 infants >or=34 weeks' gestation with (75) and without (26) neonatal RDS, and 6 nonsmoking adults. To examine genetic regulation, we used univariate and logistic regression analyses to detect associations between common SP-B (SFTPB) genotypes and SP-B peptides in the neonatal RDS cohort. We found pro-SP-B peptides in 24/24 amniotic fluid samples and in 100/101 tracheal aspirates from newborn infants but none in bronchoalveolar lavage from normal adults (0/6) (p < 0.001). We detected an association (p = 0.0011) between pro-SP-B peptides (M(r) 40 and 42 kDa) and genotype of a nonsynonymous single nucleotide polymorphism at genomic position 1580 that regulates amino-terminus glycosylation. Pro-SP-B peptides are more common in developmentally less mature humans. Association of genotype at genomic position 1580 with pro-SP-B peptides (M(r) 40 and 42 kDa) suggests genetic regulation of amino terminus glycosylation in vivo.


All-cause and cause-specific mortality of immigrants and native born in the United States.
This study examined whether US-born people and immigrants 25 years or older differ in their risks of all-cause and cause-specific mortality and whether these differentials, if they exist, vary according to age, sex, and race/ethnicity. Using data from the National Longitudinal Mortality Study (1979-1989), we derived mortality risks of immigrants relative to those of US-born people by using a Cox regression model after adjusting for age, race/ethnicity, marital status, urban/rural residence, education, occupation, and family income. Immigrant men and women had, respectively, an 18% and 13% lower risk of overall mortality than their US-born counterparts. Reduced mortality risks were especially pronounced for younger and for Black and Hispanic immigrants. Immigrants showed significantly lower risks of mortality from cardiovascular diseases, lung and prostate cancer, chronic obstructive pulmonary diseases, cirrhosis, pneumonia and influenza, unintentional injuries, and suicide but higher risks of mortality from stomach and brain cancer and infectious diseases. Mortality patterns for immigrants and for US-born people vary considerably, with immigrants experiencing lower mortality from several major causes of death. Future research needs to examine the role of sociocultural and behavioral factors in explaining the mortality advantage of immigrants.


Training oncology physicians to advise their patients on complementary and integrative medicine: An implementation study for a manual-guided consultation.
The unmonitored use of complementary medicine in patients with cancer can be associated with an increased risk of safety-related issues, such as lower adherence to conventional cancer therapies. Training oncology physicians to advise their patients about the effectiveness and safety of these therapies could improve this situation. The objective of this study was to develop and pretest a consultation framework that has high potential to be widely implemented. The framework comprises: 1) a systematically developed and tested, manualized, guided consultation; and 2) blended learning training (e-learning and communication skills training workshop) to upskill oncology physicians in advising their patients on complementary and integrative medicine (CIM). For this implementation study, mixed methods were used to develop the manual (literature review, consensus procedure, pilot testing) and the training (questionnaires and interviews with oncology physicians and patients with cancer and an examination of the skills in a setting with standardized patients). The training was tested with 47 oncology physicians from across Germany. The manual-guided consultation (context: general information on the setting and communication techniques; inform: consultation duration and content; capture: previous CIM use; prioritize: focus on consultation; advise: evidence-based CIM recommendations; discuss, advise, accept, or advise against other CIM; concretize advice: summary and implementation; and monitor: documentation) was considered suitable. The structure and time frame (maximum, 20 minutes) of the consultation as well as the training were feasible and well accepted. The current study demonstrates that the KOKON-KTO framework (a German acronym for Competence Network for Complementary Medicine - Consultation Training for Oncology Physicians) is suitable for training oncology physicians. Its implementation can lead to better physician-patient communication about CIM in cancer.


[Ecological service assessment of human-dominated freshwater ecosystem with a case study in Yangzhou Prefecture, China.
Freshwater ecosystems provide a host of services to humanity. These services are now rapidly being lost, not least because of the inability of making the impacts measurable. To overcome this obstacle, assessment frameworks for freshwater ecosystem services are needed. A simple water equivalent framework to assess the ecological services provided by freshwater ecosystems was developed in this study. It translated the occupation of freshwater ecosystem services into biologically freshwater volumes and then compares this consumption to the freshwater throughput, that is, the ecological capacity available in this region. In this way, we use the example of Yangzhou Prefecture, to account the main categories of human occupation of water ecosystem services. The result showed that there is a huge gap between the consumption and the supply of freshwater ecosystem services. This must encourage local government to make land-use and water management decisions both economically rational and environmentally sound.


Hepatitis B virus infection and coronary atherosclerosis: results from a population with relatively high prevalence of hepatitis B virus.
To investigate the possible association between hepatitis B virus (HBV) infection and angiographically proven coronary artery disease (CAD) in a population with relatively high prevalence of HBV. Sera from 434 patients who underwent coronary angiography were tested for HBV antigens (HBsAg, HBeAg) and antibodies (Anti-HBs, Anti-HBc and Anti-HBe) by ELISA. Seventy-seven percent (224/291) of the patients with CAD and 73.4% (105/143) of the patients without angiographic evidence of atherosclerosis were seropositive for HBV (P > 0.05). However, C-reactive protein (CRP) levels were significantly higher in patients with CAD (P = 0.008), while lower in HBV seropositive population (P = 0.043 and P = 0.021 after adjustment for conventional risk factors). Our results suggested HBV infection negatively correlates with CRP levels, but seems not to be associated with coronary atherosclerosis.


Methacholine-induced cutaneous flare response: bivariate analysis of responsiveness and sensitivity.
Cutaneous reactions to allergens exhibit a sigmoid dose-response relationship. Available methods for evaluating the allergen skin-test response do not adequately account for the sigmoid curve. Methodologic factors handicap quantitative studies of allergens based on skin-test reactivity. This problem was evaluated with a pharmacologic agonist that mimics cutaneous reactivity. Epicutaneous tests with appropriate concentrations of methacholine were used to provoke flare responses in 84 healthy subjects. A novel hyperbolic tangent model of the sigmoid dose-response curve was used to estimate responsiveness (R) as the midpoint of the sigmoid curve. Sensitivity (C) was estimated as the agonist concentration yielding a flare response equivalent to R. Estimates of sensitivity were independent of estimates of responsiveness (r=-0.0565, p=0.6642). The geometric mean methacholine sensitivity among health subjects was 287 mM/L, and average methacholine responsiveness was 4.9 mm. The mathematic model used in these studies fitted observations surprisingly well (X2(84)=37.044, p greater than 0.95). Differences in methacholine sensitivity and responsiveness related to race, sex, and allergic and/or vasomotor tendencies were detected but were subtle and did not account for a significant portion of the variation among healthy subjects. This model may provide a useful method for quantifying cutaneous immediate hypersensitivity reactions in patients.


[The effect of EDTA with different density on adhesive power of casting post and its scanning electromicroscopy (SEM) observation]
OBJECTIVE:To evaluate the effect of EDTA with different density on adhesive power of casting post.METHODS:Four different density of EDTA(5%,10%,15%,17%)were used to rinse the smear layer of root canal for 60 extracted teeth before they were cemented with ZP;on the other,a SEM observation was made on the rinse of root canal and the combination of adhesive and root canal.Meanwhile,a comparison was also made, after the rinse of EDTA,of tensile strength of casting post after their cement.RESULTS:EDTA with different density have different effect in the rinse of smear layer of root canal,it was proved by both SEM observation and the records of tensile strength of casting post. CONCLUSION:EDTA with density 10% is more effective in both the rinse of smear layer of root canal and the enhancement of adhesive power of casting post.


Selective Immunosuppression Targeting the NLRP3 Inflammasome Mitigates the Foreign Body Response to Implanted Biomaterials While Preserving Angiogenesis.
Medical devices are a mainstay of the healthcare industry, providing clinicians with innovative tools to diagnose, monitor, and treat a range of medical conditions. For implantable devices, it is widely regarded that chronic inflammation during the foreign body response (FBR) is detrimental to device performance, but also required for tissue regeneration and host integration. Current strategies to mitigate the FBR rely on broad acting anti-inflammatory drugs, most commonly, dexamethasone (DEX), which can inhibit angiogenesis and compromise long-term device function. This study challenges prevailing assumptions by suggesting that FBR inflammation is multifaceted, and selectively targeting its individual pathways can stop implant fibrosis while preserving beneficial repair pathways linked to improved device performance. MCC950, an anti-inflammatory drug that selectively inhibits the NLRP3 inflammasome, targets pathological inflammation without compromising global immune function. The effects of MCC950 and DEX on the FBR are compared using implanted polycaprolactone (PCL) scaffolds. The results demonstrate that both DEX and MCC950 halt immune cell recruitment and cytokine release, leading to reduced FBR. However, MCC950 achieves this while supporting capillary growth and enhancing tissue angiogenesis. These findings support selective immunosuppression approaches as a potential future direction for treating the FBR and enhancing the longevity and safety of implantable devices.


Rubiscolin-6, a delta opioid peptide derived from spinach Rubisco, has anxiolytic effect via activating sigma1 and dopamine D1 receptors.
Rubiscolin-6 (Tyr-Pro-Leu-Asp-Leu-Phe) is a delta opioid peptide derived from the large subunit of spinach d-ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). We previously reported that rubiscolin-6 had an analgesic effect and stimulated memory consolidation. Here we show that intraperitoneally (i.p.) or orally administered rubiscolin-6 has an anxiolytic effect at a dose of 10 mg/kg or 100 mg/kg, respectively, in the elevated plus-maze test in mice. The anxiolytic effects of rubscolin-6 after i.p. (10 mg/kg) and oral (100 mg/kg) administration were blocked by a delta opioid receptor antagonist, naltrindole (1 mg/kg, s.c.), suggesting that the anxiolytic activity of rubiscolin-6 is mediated by delta opioid receptor. The anxiolytic effect of rubiscolin-6 (10 mg/kg, i.p.) was also blocked by a dopamine D(1) antagonist, SCH23390 (30 microg/kg, i.p.), but not by a dopamine D(2) antagonist, raclopride (15 microg/kg, i.p.). The anxiolytic effect of rubiscolin-6 (10 mg/kg, i.p.) was blocked by sigma(1) receptor antagonist, BMY14802 (0.5 mg/kg, i.p.) or BD1047 (10 mg/kg, i.p.). Taken together, the anxiolytic effect of rubiscolin-6 is mediated by sigma(1) and dopamine D(1) receptors downstream of delta opioid receptor.


Proposal for a Novel Severity Grading System for Pterygia Based on Corneal Topographic Data.
To propose a grading system of pterygium severity based on corneal higher-order irregularity (HOI) and to evaluate postoperative changes in corneal irregularity of the graded pterygia. In 268 eyes of 226 patients undergoing excision surgery of primary nasal pterygium, Placido corneal topography images were taken before and until 6 months after surgery. The best-corrected visual acuity (BCVA) and pterygium size with respect to the corneal diameter were also measured. HOI components within 1.0-, 3.0-, and 5.0-mm diameters were obtained using Fourier harmonic analysis of corneal topography data. With threshold levels when the HOIs for 3 diameters steeply increased, 4 levels of grading from 0 (mild) to 3 (severe) were determined. Associations of the grades with the preoperative surface regularity index (SRI), irregular components (IRRs) obtained from the 3.0-mm diameter Fourier analysis, and BCVA were examined. Time-course changes in the indexes after surgery were evaluated for each grade. There were 62, 65, 41, and 100 eyes in grades 0 to 3, respectively. Preoperatively, the SRI in grade 3 was significantly higher than in the other grades (P < 0.001), and the IRR and BCVA varied with the grade (P < 0.001). Between 1 and 6 months postoperatively, grade 3 pterygia showed significant changes in the SRI and IRR (P = 0.013 and 0.017, respectively), whereas there was no change after 3 months postoperatively in the SRI, IRR, and BCVA for all other grades. The proposed grading effectively classified the severity of pterygia and evaluated postoperative restoration of corneal irregularity. Using corneal topographic data allowed for objective evaluation of pterygium severity.


[Study on no-fusion expression and purification of Glycine max dehydration-responsive element-binding protein (GmDREB1) expressed in E. coli].
To obtain enough GmDREB1 protein comparable with native protein for further safety assessment of the protein. The GmDREB1 gene was cloned into no-fusion expression vector pBV220 and the recombinant vector pBV220-GmDREB1 was obtained. The constructed vector was transformed into expression host E. coli DH5a. The protein expression was optimized by improving the codon, induced expression conditions and selecting the appropriate vector. The protein was obtained by cation exchange chromatography and gel filtration chromatography and identified by N-terminal amino acid sequencing, western blotting and activity determination. The soluble protein was expressed efficiently in E. coli DH5a containing the optimized target gene by 42 degrees C induction for 3 hours and the purified protein consistent with the native protein was obtained through the chromatography. The results of this study illustrated that the GmDREB1 protein could be acquired through prokaryotic host expression which had comparable N-terminal amino acid sequences, immunogenicity and biological activities with those of native GmDREB1 protein.


PhysNet: A Neural Network for Predicting Energies, Forces, Dipole Moments, and Partial Charges.
In recent years, machine learning (ML) methods have become increasingly popular in computational chemistry. After being trained on appropriate ab initio reference data, these methods allow for accurately predicting the properties of chemical systems, circumventing the need for explicitly solving the electronic Schrödinger equation. Because of their computational efficiency and scalability to large data sets, deep neural networks (DNNs) are a particularly promising ML algorithm for chemical applications. This work introduces PhysNet, a DNN architecture designed for predicting energies, forces, and dipole moments of chemical systems. PhysNet achieves state-of-the-art performance on the QM9, MD17, and ISO17 benchmarks. Further, two new data sets are generated in order to probe the performance of ML models for describing chemical reactions, long-range interactions, and condensed phase systems. It is shown that explicitly including electrostatics in energy predictions is crucial for a qualitatively correct description of the asymptotic regions of a potential energy surface (PES). PhysNet models trained on a systematically constructed set of small peptide fragments (at most eight heavy atoms) are able to generalize to considerably larger proteins like deca-alanine (Ala10): The optimized geometry of helical Ala10 predicted by PhysNet is virtually identical to ab initio results (RMSD = 0.21 Å). By running unbiased molecular dynamics (MD) simulations of Ala10 on the PhysNet-PES in gas phase, it is found that instead of a helical structure, Ala10 folds into a "wreath-shaped" configuration, which is more stable than the helical form by 0.46 kcal mol-1 according to the reference ab initio calculations.


Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse.
Acetaldehyde, the end product of oxidative ethanol metabolism, contributes to alcohol-induced disease in the liver, but cannot account for damage in organs such as the pancreas, heart, or brain, where oxidative metabolism is minimal or absent; nor can it account for the varied patterns of organ damage found in chronic alcoholics. Thus other biochemical mediators may be important in the pathogenesis of alcohol-induced organ damage. Many human organs were found to metabolize ethanol through a recently described nonoxidative pathway to form fatty acid ethyl esters. Organs lacking oxidative alcohol metabolism yet frequently damaged by ethanol abuse have high fatty acid ethyl ester synthetic activities and show substantial transient accumulations of fatty acid ethyl esters. Thus nonoxidative ethanol metabolism in addition to the oxidative pathway may be important in the pathophysiology of ethanol-induced disease in humans.


Potential Antitumor Effects of Pomegranates and Its Ingredients.
The treatment based on plant or plant derivatives is a promising strategy in the killing of cancers cells. Moreover, wide-ranging finding has established that medicinal plant and its ingredient modulate several cells signaling pathways or inhibiting the carcinogenesis process. In this vista, pomegranates fruits, seeds and peels illustrate cancer preventive role seems to be due to rich source of antioxidant and other valuable ingredients. Furthermore, anti-tumour activities of pomegranates have been evidences through the modulation of cell signaling pathways including transcription factor, apoptosis and angiogenesis. In this review article, anti-tumor activity of pomegranates and its components or its different type of extracts are described to understand the mechanism of action of pomegranates in cancer therapy.


Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship.
To describe the clinical and biochemical features, and perform molecular analysis for candidate abnormalities in a novel familial syndrome of intrauterine growth retardation (IUGR), failure of an adolescent growth spurt with proportional adult short stature, minimal subluxation of the 5th metacarpal-phalangeal joint, and adult-onset insulin-resistant diabetes unrelated to obesity or other manifestations of metabolic syndrome (MS). Detailed clinical history, auxological, biochemical, radiological, and molecular studies, including DNA analysis and in vitro study of the GH/IGF1 pathway. Ten affected adults from two generations of five related families were studied in detail, and information obtained about nine other likely affected individuals. Height Z-scores ranged from -7.3 to -3.8. Unaffected parents of the older generation and frequency of confirmed and suspected instances of the syndrome in the two generations studied is consistent with autosomal recessive inheritance. Insulin resistance was uniformly present in seven subjects tested who were not taking insulin. Diabetes severity did not correlate with overweight. Subjects did not have other typical manifestations of MS such as substantial hyperlipidemia, osteoporosis, or hypertension. No biochemical abnormality in the GH/IGF1 axis or molecular defect was found. While the association of IUGR and adult MS, including diabetes, has been well documented, these subjects did not have typical manifestations of MS. Abnormalities in common components that could result in a combination of IUGR, severe postnatal growth, and insulin resistance have been ruled out. A mutation in an unidentified gene may affect intrauterine and postnatal growth, with insulin resistance directly affected or as a result of this growth phenomenon.


Reversal of intracellular toxicity of the trichothecene mycotoxin T-2 with monoclonal antibody.
The trichothecene mycotoxin T-2 is a potent inhibitor of intracellular protein synthesis. We have previously shown that a mouse immunoglobulin G1 monoclonal antibody (15H6) specific for T-2 toxin can neutralize the in vitro protein synthesis inhibitory effect of the toxin in human B-lymphoblastoid cultures, and protect rats from lethal toxemia. We now report that these monoclonal antibodies can induce the net efflux of [3H]-T-2 toxin from poisoned human B-lymphoblastoid cells in vitro, and restore protein synthesis. Administration of the monoclonal antibodies (250 mg/kg) 30 min before infusion of a lethal dose (1 mg/kg) of T-2 toxin causes the sequestration of the toxin in the plasma compartment. When administered 35 min after T-2 toxin, a time when the bulk of toxin is in the tissues, the monoclonal antibodies facilitate the migration of toxin back into the plasma compartment. These data demonstrate that monoclonal antibodies can be of therapeutic value against an intracellular toxin.


Reimbursement policies, incentives and disincentives to perform laparoscopic surgery in Israel.
The introduction of laparoscopic surgery was believed to bestow great advantages to patients and health services. Health services and societal costs may also be affected by changes in length of hospital stay, operating room costs and return to normal activity. The aim of this paper is to examine the influence of two different reimbursement methods (per diem and DRG) on the incentives and disincentives given to different role players in the Israeli health-care system regarding two common surgical procedures: appendectomy and inguinal hernia repair. Three different perspectives are discussed: society, the hospitals and the sick funds. From the hospital's perspective, laparoscopic surgery is usually more expensive compared to open procedures, mainly due to higher operating room costs. We suggest that as far as current reimbursement methods are preserved, hospitals have no economic incentive to adopt the laparoscopic technology as benefits occur only to society. In general, sick funds would encourage hospitals to perform laparoscopic appendectomy, where the payment is per diem and would be economically indifferent regarding laparoscopic inguinal hernia repair, where hospitals are compensated on a DRG basis. It has been suggested that economic advantages to society may arise from a faster return to work after laparoscopic appendectomy and laparoscopic inguinal hernia repair. In this case, new payment arrangements should be set to give proper incentives for the adoption of laparoscopic procedures.


Partitioning of diet between species and life history stages of sympatric and cryptic snappers (Lutjanidae) based on DNA metabarcoding.
Lutjanus erythropterus and L. malabaricus are sympatric, sister taxa that are important to fisheries throughout the Indo-Pacific. Their juveniles are morphologically indistinguishable (i.e. cryptic). A DNA metabarcoding dietary study was undertaken to assess the diet composition and partitioning between the juvenile and adult life history stages of these two lutjanids. Major prey taxa were comprised of teleosts and crustaceans for all groups except adult L. erythropterus, which instead consumed soft bodied invertebrates (e.g. tunicates, comb jellies and medusae) as well as teleosts, with crustaceans being notably absent. Diet composition was significantly different among life history stages and species, which may be associated with niche habitat partitioning or differences in mouth morphology within adult life stages. This study provides the first evidence of diet partitioning between cryptic juveniles of overlapping lutjanid species, thus providing new insights into the ecological interactions, habitat associations, and the specialised adaptations required for the coexistence of closely related species. This study has improved our understanding of the differential contributions of the juvenile and adult diets of these sympatric species within food webs. The diet partitioning reported in this study was only revealed by the taxonomic resolution provided by the DNA metabarcoding approach and highlights the potential utility of this method to refine the dietary components of reef fishes more generally.


Diagnosis of septic pelvic thrombophlebitis by measurement of fibrinopeptide A.
Septic pelvic thrombophlebitis is an uncommon but potentially life-threatening complication of puerperal endometritis. The lack of specific physical findings necessitates a diagnosis based by exclusion on the patient's response to anticoagulation. Fibrinopeptide A (FPA) is the first peptide cleaved from fibrinogen during thrombin-mediated fibrin generation. Because of its short half-life, FPA accurately reflects the level of ongoing fibrin generation. In a preliminary study of 40 puerperal patients, FPA successfully differentiated puerperal fever secondary to endometritis or abscess from fever responsive to a heparin trial. The mean FPA level in patients presumed to have septic pelvic thrombophlebitis was 23.8 ng/ml as opposed to 7 ng/ml in patients with endometritis. No patient with septic pelvic thrombophlebitis as diagnosed by her response to a heparin trial had a level of FPA less than 14 ng/ml. There was no overlap of FPA levels between patients with endometritis or abscess and septic pelvic thrombophlebitis. The data suggest further prospective evaluation of FPA for the diagnosis of septic pelvic thrombophlebitis is warranted.


Structure of the RWJ-51084-bovine pancreatic beta-trypsin complex at 1.8 A.
The three-dimensional structure of bovine pancreatic trypsin complexed with the inhibitor RWJ-51084 has been determined at 1.8 A resolution. These crystals belong to the trigonal space group P3(1)21, with unit-cell parameters a = b = 53.43, c = 107.76 A. The refined R and R(free) values are 0.175 and 0.237, respectively. The carbonyl group bonded to the benzothiazole group of the inhibitor is covalently linked to the hydroxyl O atom of Ser195, forming a tetrahedral intermediate hemiketal structure. The other carbonyl O atom of the inhibitor forms a hydrogen bond with the Gln192 side-chain amide group. The benzothiazole group is oriented with the aromatic N atom of RWJ-51084 accepting a hydrogen bond from His57 NE2. The arginine side chain of the inhibitor extends into the deep and narrow pocket of the S1 specificity site of trypsin, forming a network of hydrogen bonds.


Functional analysis of germline ETV6 W380R mutation causing inherited thrombocytopenia and secondary acute lymphoblastic leukemia or essential thrombocythemia.
Germline mutations in ETV6 gene cause inherited thrombocytopenia with leukemia predisposition. Here, we report on functional validation of ETV6 W380R mutation segregating with thrombocytopenia in a family where two family members also suffered from acute lymphoblastic leukemia (ALL) or essential thrombocythemia (ET). In-silico analysis predicted impaired DNA binding due to W380R mutation. Functional analysis showed that this mutation prevents the ETV6 protein from localizing into the cell nucleus and impairs the transcriptional repression activity of ETV6. Based on the germline ETV6 mutation, ET probably started with somatic JAK2 V617F mutation, whereas ALL could be caused by diverse mechanisms: high-hyperdiploidity; somatic deletion of exon 1 IKZF1 gene; or somatic mutations of other genes found by exome sequencing of the ALL sample taken at the diagnosis.


Effects of potential dietary inhibitors of endogenous DNA damage on mutagenesis and lipid peroxidation in lacZ mice.
The effects of a nine month administration of dietary: (1) 3H-1,2-dithiole-3-thione (D3T), (2) N-acetylcysteine (NAC), (3) antioxidant vitamin mix, (vitamin C+E), (4) free radical scavenger, amifostine, and (5) calorie restriction, (CR), on mutagenesis and lipid peroxidation in lung, kidney, spleen and liver of lacZ transgenic mice were examined. These agents/diets were chosen because they might inhibit certain proposed mechanisms of endogenous damage to DNA. The agents were added to a high fat, reduced antioxidant AIN-76 diet, to better approximate a Western style diet than the conventional AIN-76 diet. As the lacZ gene is not expressed, mutations in that gene are neutral, and simply accumulate over time. The mutant fractions in control mice increased about 50-100%. Most of the agents inhibited to various extents the age-related increase in mutagenesis in lung, kidney, and/or spleen, but no inhibition was observed in liver. There was no significant effect of age on lipid peroxidation levels in controls, possibly reflecting steady state turnover of lipid peroxidation products. Almost all of the treatments except D3T inhibited lipid peroxidation in most organs to different degrees. The vitamin C+E mix was the most effective at inhibiting lipid peroxidation, but a single most effective inhibitor of mutagenesis could not be discerned. Some associations were observed between the reduction in lipid peroxidation and the inhibition of mutagenesis. The results are consistent with a partial role for oxidative stress in the age-related increase in mutagenesis. These observations may have implications for chemoprevention of carcinogenesis.


Expression of glial filament protein (GFP) in nerve sheaths and non-neural cells re-examined using monoclonal antibodies, with special emphasis on the co-expression of GFP and cytokeratins in epithelial cells of human salivary gland and pleomorphic adenomas.
We describe two novel monoclonal antibodies specific for glial filament protein (GFP), i.e., GF12.23 and GF12.24 (both IgG2a]. These cross-react over a broad range of species with epitopes located in the alpha-helical rod domain typical of all intermediate filament (IF) proteins. These monoclonal antibodies were used, in conjunction with other monoclonal GFP antibodies, rabbit antiserum to GFP, and various antibodies to other cytoskeletal proteins, to examine the occurrence of GFP in cells outside of the central nervous system of rodents, cows, and humans. We detected some scattered GFP-containing cells in the neural sheaths in some species but not in others, and we obtained different results when comparing the rabbit antisera with the monoclonal GFP antibodies. In the enteric glia of rats, we observed GFP-positive cells with all of the antibodies used, whereas in human intestine, the various monoclonal antibodies showed no reaction with any intestinal cells. Similarly, no GFP was detected in surface cells of the lens of cows and rats using any of the GFP antibodies, whereas some reaction was seen in murine lens tissue. We were also unable to detect GFP-positive cells in human, bovine, or rat liver with any of the monoclonal antibodies, which is in contrast to the reactivity of the rabbit GFP antisera with some stellate perisinusoidal cells of rat but not bovine or human liver. The possible reasons for the discrepancies between the different species and the different antibody preparations used are discussed. In addition, using double-label immunofluorescence microscopy, we showed that normal human parotid glands contain a certain type of epithelial cell that co-expresses cytokeratins and desmosomal proteins with GFP. The histological distribution of these GFP-positive cells suggests that they represent a subset of the myoepithelial cells present in this tissue. Cells co-expressing cytokeratins and GFP - in some cases, apparently together with vimentin as the third IF protein present - were also identified in tumors derived from this salivary-gland epithelium, i.e., pleomorphic adenomas, in which GFP-positive cells were relatively frequent in the myxoid and chondroid components, thus confirming the work of other investigators. Possible implications for the concept of histogenesis of these tumor cells are discussed, as are possible mechanisms resulting in the co-expression of IF proteins.


A new ELISA for use in a 3-ELISA system to assess concentrations of VEGF splice variants and VEGF(110) in ovarian cancer tumors.
Vascular endothelial growth factor (VEGF), which affects tumor angiogenesis, is expressed as different splice variants, including the major isoforms VEGF(165) and VEGF(121), and can be cleaved by plasmin to generate VEGF(110). The amount of VEGF(121) and VEGF(110) in biological samples has not been well studied. We developed an ELISA that detects VEGF(165) and VEGF(121) equally, but does not detect VEGF(110). We used this ELISA together with 2 other ELISAs, one detecting VEGF(165) and the other detecting VEGF(165), VEGF(121), and VEGF(110) equally, to assess the concentrations of VEGF(121) and VEGF(110) in ovarian cancer tumors. The median concentrations in ovarian cancer tumor lysates were 0.61 (range <0.055-74) fmol/mg protein for VEGF(165), 1.4 (range <0.20-500) fmol/mg protein for VEGF(165) plus VEGF(121), and 2.3 (range <0.079-520) fmol/mg protein for total VEGF including VEGF(110) (n = 248). VEGF concentrations measured by the 3 ELISAs were highly correlated (r = 0.91-0.94). Median estimated VEGF(121) and VEGF(110) concentrations were 0.77 and 0.58 fmol/mg protein, respectively. In lysates with measurable VEGF(165) and total VEGF concentrations, mean VEGF(165) was approximately 31% (SD 23%) of the total VEGF (n = 217). In contrast, VEGF(165) constituted approximately half of the total circulating VEGF. VEGF(165), VEGF(121), and VEGF(110) may be present at significant amounts in ovarian cancer tumors.


Temporal Trends in Hospitalization for Acute Decompensated Heart Failure in the United States, 1998-2011.
Estimates of the numbers and rates of acute decompensated heart failure (ADHF) hospitalization are central to understanding health-care utilization and efforts to improve patient care. We comprehensively estimated the frequency, rate, and trends of ADHF hospitalization in the United States. Based on Atherosclerosis Risk in Communities (ARIC) Study surveillance adjudicating 12,450 eligible hospitalizations during 2005-2010, we developed prediction models for ADHF separately for 3 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 428 discharge diagnosis groups: 428 primary, 428 nonprimary, or 428 absent. We applied the models to data from the National Inpatient Sample (11.5 million hospitalizations of persons aged ≥55 years with eligible ICD-9-CM codes), an all-payer, 20% probability sample of US community hospitals. The average estimated number of ADHF hospitalizations per year was 1.76 million (428 primary, 0.80 million; 428 nonprimary, 0.83 million; 428 absent, 0.13 million). During 1998-2004, the rate of ADHF hospitalization increased by 2.0%/year (95% confidence interval (CI): 1.8, 2.5) versus a 1.4%/year (95% CI: 0.8, 2.1) increase in code 428 primary hospitalizations (P < 0.001). In contrast, during 2005-2011, numbers of ADHF hospitalizations were stable (-0.5%/year; 95% CI: -1.4, 0.3), while the numbers of 428-primary hospitalizations decreased by -1.5%/year (95% CI: -2.2, -0.8) (P for contrast = 0.03). In conclusion, the estimated number of hospitalizations with ADHF is approximately 2 times higher than the number of hospitalizations with ICD-9-CM code 428 in the primary position. The trend increased more steeply prior to 2005 and was relatively flat after 2005.


Primary study in experimental antiangiogenic therapy of nasopharyngeal carcinoma with AGM-1470 (TNP-470).
To evaluate the efficacy of the angiogenesis inhibitor AGM-1470 for the experimental treatment of nasopharyngeal carcinoma (NPC). A NPC human tumour model was built by tumour-bearing nude mice using the NPC cell line CNE-2. Twenty-one BALB/c nude mice bearing CNE-2 xenografts were randomized into a treatment group and a control group. In the treatment group, AGM-1470 was injected 30 mg/kg subcutaneously every other day; while the vehicle (three per cent ethanol solution in 0.9 per cent saline) was given to the mice in control group. Tumour volumes and animal weights were measured every third day. Autopsy was performed after 18 days of treatment. The tumour tissue as well as the murine tissues of heart, kidney, and liver in each mouse were removed for formalin fixation and routine HE staining. Pathological evaluation was performed in these tissues. There was a significant difference in tumour volume between the two groups at day 9 of treatment and this increased thereafter. At day 15 of treatment, the tumour volume was 4251 +/- 559 mm3 (n = 10) in the control group versus 3122 +/- 967 mm3 (n = 11) in the AGM-1470 treated group (p = 0.004); and T:C ratio (mean tumour volume of treated/mean tumour volume of control) was 0.73, resulting in a 27 per cent decrease in tumour growth. Central necrosis and consequential shrinkage of tumours occurred in both groups at the end of experiment. Physical toxicity and histological toxicity of heart, liver, and kidney did not result from AGM-1470 therapy. AGM-1470 suppresses the growth of the human NPC cell line CNE-2. Treatment by AGM-1470 has no physical nor histological toxicity. Angiogenesis inhibitors may be effective in the treatment of the local lesion of NPC.


Technical rationality and the decentring of patients and care delivery: A critique of 'unavoidable' in the context of patient harm.
In recent decades, debate on the quality and safety of healthcare has been dominated by a measure and manage administrative rationality. More recently, this rationality has been overlaid by ideas from human factors, ergonomics and systems engineering. Little critical attention has been given in the nursing literature to how risk of harm is understood and actioned, or how patients can be subjectified and marginalised through these discourses. The problem of assuring safety for particular patient groups, and the dominance of technical forms of rationality, has seen the word 'unavoidable' used in connection with intractable forms of patient harm. Employing pressure injury policy as an exemplar, and critically reviewing notions of risk and unavoidable harm, we problematise the concept of unavoidable patient harm, highlighting how this dominant safety rationality risks perverse and taken-for-granted assumptions about patients, care processes and the nature of risk and harm. In this orthodoxy, those who specify or measure risk are positioned as having more insight into the nature of risk, compared to those who simply experience risk. Driven almost exclusively as a technical and administrative pursuit, the patient safety agenda risks decentring the focus from patients and patient care.


[Evaluation of coronary bed function by positron emission tomography using 13N-ammonium during cold stimulation].
The present investigation was to study the time course of changes in myocardial blood flow (MBF) in response to cold stimulation. Thirty-eight patients having risk factors of cardiovascular complications were examined. The time course of MBF changes was estimated by positron emission tomography (PET) using 13N-ammonium at rest and during a cold test (CT). Endothelium-dependent vasodilation of the brachial artery was determined from the results of a reactive hyperemia test, by applying ultrasonic duplex scanning. No significant MBF increase in response to the cold test was an indicator of coronary arterial endothelial dysfunction at cardiac 13N-ammonium PET. Agreement of the results of brachial arterial ultrasonography during reactive hyperemia and cardiac 13N-ammonium PET in the presence of the cold test suggests that endothelial dysfunction is generalized. Cardiovascular risk factors, such as left ventricular hypertrophy, smoking, dyslipidemia, and diabetes mellitus, substantially affect coronary arterial function. Left ventricular hypertrophy is an independent factor that influences the size of the coronary reserve and, in combination with endothelial dysfunction, worsens coronary microcirculation.