Isolation of amplified and overexpressed DNA sequences from adriamycin-resistant human breast cancer cells.
An MCF-7 human breast cancer cell line was selected which was 200-fold more resistant to Adriamycin than the wild type cell line. This Adriamycin-resistant (AdrR) cell line exhibited a multidrug-resistant phenotype and was cross-resistant to a wide range of antineoplastic agents including Vinca alkaloids, anthracyclines, and epipodophyllotoxins. Cytogenetic analysis of the AdrR cell line showed the presence of homogeneously staining regions on several chromosomes which were not present in the parental cell line. Using the technique of in-gel renaturation, DNA sequences which were amplified 50- to 100-fold in the AdrR cell line and which covered a total of over 140 kilobases were isolated. In addition, AdrR cells were found to contain amplified and overexpressed sequences which were homologous to hamster P-glycoprotein gene sequences. A hamster cDNA P-glycoprotein gene probe was used to screen a lambda gt10 cDNA library made from human AdrR cell line mRNA and human cDNA sequences homologous to the P-glycoprotein gene were isolated. Hybridization studies with the cloned human cDNA (pADR1) showed that the AdrR MCF-7 cell line contained a 60-fold amplification of this DNA sequence and that polyadenylated mRNA from the AdrR cell line contained a 4.8-kilobase transcript which was overexpressed 45-fold. There was a direct correlation between DNA and RNA copy number of this sequence and level of resistance among several MCF-7 Adriamycin-resistant cell lines. In situ hybridization studies demonstrated that the human P-glycoprotein gene sequence was found on chromosome 7q21.1 in normal human lymphocytes and that amplified DNA sequences isolated from the AdrR MCF-7 cells by the in-gel hybridization technique were linked to the human P-glycoprotein sequences in the homogeneously staining regions in the AdrR cells.


Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction.
The prognostic value of pretreatment pulse pressure as a predictor of myocardial infarction and the relation of pulse pressure and in-treatment diastolic blood pressure reduction to myocardial infarction were investigated in a union-sponsored systematic hypertension control program. In a prospective study, 2207 hypertensive patients with a pretreatment systolic blood pressure greater than or equal to 160 mm Hg and/or diastolic pressure greater than or equal to 95 mm Hg grouped according to tertile of pulse pressure (PP1, < or = 46; PP2, 47 to 62; PP3, > or = 63 mm Hg) were further stratified by the degree of diastolic fall: large (L), > or = 18; moderate (M), 7 to 17; small (S), < or = 6 mm Hg. During an average follow-up of 5 years, 132 cardiovascular events (50 myocardial infarctions, 23 strokes) were observed. Myocardial infarction rates per 1000 person-years were positively related to pulse pressure (PP1, 3.5; PP2, 2.9; PP3, 7.5; PP3 versus PP1, P = .02). Wide pulse pressure was identified as a predictor of myocardial infarction (PP3 versus [PP1 + PP2]: relative risk [RR] = 2.2, 95% confidence interval [CI] = 1.2-4.1), controlling for other known risk factors by Cox regression. A curvilinear relation (resembling a J shape) between diastolic fall and myocardial infarction was observed in patients with the widest pulse pressure, PP3 (L, 9.5; M, 3.9; S, 11.2; L versus M: RR = 2.5, 95% CI = 1.0-6.2; S versus M: RR = 2.9, 95% CI = 1.1-8.0).(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation.
To investigate long-term cardiac sequelae associated with anthracycline use in adjuvant chemotherapy of patients with early breast cancer. All 1,000 patients from three prospective trials of adjuvant chemotherapy containing doxorubicin (n = 637, median total dose of 294 mg/m(2)) or not containing the anthracycline (cyclophosphamide, methotrexate, and fluorouracil [CMF] regimen alone, n = 363) were analyzed for the relative incidence of congestive heart failure (CHF) and myocardial infarction (MI) during 14 years of follow-up. The 462 women continuously free of disease as of February 1996 were recalled, and 355 consented to undergo evaluation including 12-lead ECG and cardiac ultrasound with determination of left ventricular ejection fraction (LVEF) to assess the relative incidence of abnormalities in long-term survivors. Among the 1,000 patients, there were six cases of CHF and three cases of MI. Cumulative cardiac mortality accounted for 0.4% (doxorubicin-treated = 0.6%; CMF-treated = 0). Eighteen (5%) of the 355 patients undergoing cardiac evaluation after median 11 years of follow-up presented systolic dysfunction as defined by pathologic (< 50%, n = 8) or borderline (50% to 55%, n = 10) LVEF. Systolic dysfunction was higher in doxorubicin-treated (15 of 192; 8%) than in CMF-treated patients (three of 150; 2%). Breast irradiation had a significant impact on the occurrence of early CHF (four of 116; 3%), but not on systolic dysfunctions. At longer than 10 years of follow-up, the use of doxorubicin at a total dose commonly applied in regimens of adjuvant chemotherapy does not lead to cardiac clinical sequelae that counter-balance the benefit of treatment in patients with operable breast cancer who may be cured of their disease.


Comparison of human regular and lispro insulins after interruption of continuous subcutaneous insulin infusion and in the treatment of acutely decompensated IDDM.
To compare the rapidity of metabolic decompensation after interruption of CSII between human regular and lispro insulin and to compare these two insulins in the correction of the hyperglycemia and ketosis of mildly decompensated IDDM. Lispro insulin may be especially useful for insulin pump therapy (continuous subcutaneous insulin infusion [CSII]). A total of 18 patients with well-controlled IDDM (HbA1c 7.7 +/- 1.1%, age 30 +/- 11 years) were studied. All were being treated with CSII (nine with human regular and nine with lispro insulin). The study consisted of two phases: 1) an insulin interruption phase, in which the basal insulin infusion was stopped (at 0300) and plasma insulin, glucose, and beta-O-hydroxybutyrate (beta-OHB) were measured every 15-60 min for 6 h after interruption of the insulin infusion and 2) an insulin replacement phase, which involved measuring plasma insulin, glucose, and beta-OHB for 2 h after a single injection of either human regular or lispro insulin to correct the hyperglycemia and ketosis that developed during the first phase of the study. After interruption of the basal insulin infusion during the insulin interruption phase, plasma insulin levels fell gradually in both groups to nadir values of 1.6 +/- 0.8 and 2.0 +/- 1.2 microU/ml in the regular insulin- and insulin lispro-treated groups, respectively. Plasma glucose concentrations rose to 13.8 +/- 1.9 and 16.0 +/- 1.7 mmol/l in the regular insulin- and insulin lispro-treated groups, respectively. No significant differences were seen between the therapy groups at any time in the insulin levels or in the concentrations of plasma glucose or beta-OHB. In the insulin replacement phase, insulin levels rose more rapidly in those treated with lispro insulin, reaching a greater peak value (e.g., at 60 min, plasma insulin 25 +/- 3.4 vs. 15.6 +/- 2.6 microU/ml, P < 0.05). In association with this, plasma glucose decreased to a lower nadir after lispro insulin (9.7 +/- 0.4 vs. 13.7 +/- 0.7 mmol/l, lispro- vs. regular-treated groups at 120 min after insulin administration, P < 0.01). beta-OHB levels decreased rapidly in both groups. In patients treated with CSII, interruption of the basal insulin infusion in the middle of the night does not result in more rapid metabolic decompensation in patients treated with lispro compared with those treated with regular human insulin. Lispro insulin is effective in treating mild ketosis and hyperglycemia, and its rapid action may be advantageous in the "sick day" management at home of patients with IDDM.


Alarming levels of drug-resistant tuberculosis in HIV-infected patients in metropolitan Mumbai, India.
Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India. A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases. Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%-40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models. The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV-infected patients by systematically offering access to first and second-line DST to all patients with 'presumptive TB' rather than 'presumptive DR-TB' and tailor the treatment regimen based on the resistance patterns.


Effect of curare on maximum static PV relationships of the respiratory system.
The effect of respiratory muscle weakness on the maximum static pressure-volume (PV) characteristics of the respiratory system was studied in four healthy males infused slowly with d-tubocurarine (dtc). Inspiratory capacity (IC), expiratory reserve volume (ERV), maximum static inspiratory and expiratory mouth pressures at four lung volumes, and handgrip were measured during induction of, and recovery from muscle weakness. The maximum effect of dtc varied among the muscle groups tested; peripheral muscles were most severely affected, expiratory muscles moderately, and inspiratory muscles least affected. At each level of weakness studied, decreases of IC and ERV were proportional to decreases of maximum static mouth pressures. Vital capacity, measured at each level of weakness was much less than values predicted from the static mechanical properties of the respiratory system. Our findings suggest that the marked change in the extremes of lung volume during submaximal neuromuscular blockade (SMNB) is due, in part, to unequal distribution of muscle weakness, reflected by decreased ability to change ribcage dimensions even at modest levels of SMNB.


Synthesis and solution conformation of homo-beta-peptides consisting of N-mannofuranosyl-3-ulosonic acids.
The synthesis and solution conformation of homo-oligomers of beta-aminoacids, beta-N-mannofuranosyl-3-ulosonic acids, have been studied by NMR, MD simulation, and circular dichroism. These oligomers feature a spirocyclic disubstitution and a N,O-acetal functionality at the beta-carbon of the backbone, an unprecedented situation in the realm of beta-peptides. Our study shows that tetramer 10 and hexamer 11 adopt a characteristic secondary structure. In the hexamer 11, NMR investigations coupled with MD simulations suggest the preference for a double C(8) turn forming conformation.


The reversal of the spontaneous exchange bias effect and zero-field-cooling magnetization in La1.5Sr0.5Co1-xFexMnO6: the effect of Fe doping.
The crystal structure, electronic structure and magnetic properties were systematically studied in a series of Fe-doped La1.5Sr0.5CoMnO6 double perovskites. The X-ray diffraction patterns of the samples are all refined with a rhombohedral (R3[combining macron]c) structure. The parameters a and c continuously increase with increasing Fe doping concentration x. X-ray photoelectron spectroscopy (XPS) spectra of the Mn, Co, and Fe 2p core levels, consistent with the soft X-ray absorption spectroscopy (XAS) spectra of Mn, Co, and Fe L2,3 edges, indicate that their valence states are Mn3+ and Mn4+, Co2+ and Co3+, and Fe3+, respectively. However, relative to samples with x ≤ 0.1, there is an abrupt change of photon energy in the Co- and Fe-2p XAS spectra for x ≥ 0.2, implying the spin state transition is from high to low. In addition, this is further confirmed by a comparison between the calculated effective spin moment from the paramagnetic data and the theoretical value. Interestingly, we demonstrate the reversal of both zero-field-cooling magnetization and the sign switching of the spontaneous exchange bias (SEB) with the doping concentration from magnetic measurements. The magnetization reverses from positive to negative with the temperature decreasing across the compensation temperature at the critical concentration x = 0.2. Meanwhile, the exchange bias field of the SEB reverses from large negative values to positive ones. Our findings allow us to propose that the spin state transition caused by inhomogeneity is considered to play an important role in the reversal of the magnetization and the SEB effect.


An update of cancer mortality among chrysotile asbestos miners in Balangero, northern Italy.
The mortality experience of a cohort of chrysotile miners employed since 1946 in Balangero, northern Italy was updated to the end of 1987 giving a total of 427 deaths out of 27,010 man-years at risk. A substantial excess mortality for all causes (standardised mortality ratio (SMR) = 149) was found, mainly because of high rates for some alcohol related deaths (hepatic cirrhosis, accidents). For mortality from cancer, however, the number of observed deaths (82) was close to that expected (76.2). The SMR was raised for oral cancer (SMR 231 based on six deaths), cancer of the larynx (SMR 267 based on eight deaths), and pleura (SMR 667 based on two deaths), although the excess only reached statistical significance for cancer of the larynx. Rates were not increased for lung, stomach, or any other type of cancer. No consistent association was seen with duration or cumulative dust exposure (fibre-years) for oral cancer, but the greatest risks for laryngeal and pleural cancer were in the highest category of duration and degree of exposure to fibres. Although part of the excess mortality from laryngeal cancer is probably attributable to high alcohol consumption in this group of workers, the data suggest that exposure to chrysotile asbestos (or to the fibre balangeroite that accounts for 0.2-0.5% of total mass in the mine) is associated with some, however moderate, excess risk of laryngeal cancer and pleural mesothelioma. The absence of excess mortality from lung cancer in this cohort is difficult to interpret.


Capability of ischemia-modified albumin to predict serious cardiac outcomes in the short term among patients with potential acute coronary syndrome.
Ischemia-modified albumin (IMA) has been suggested as a marker of cardiac ischemia. Little, however, is known about its capacity to predict short-term serious cardiac outcomes (death, myocardial infarction, congestive heart failure, serious arrhythmia, or refractory ischemic cardiac pain) in patients arriving at the emergency department with symptoms that may indicate cardiac ischemia. We screened 546 patients over a 4-week period, of whom 189 fulfilled our entry criteria by presenting to an emergency department with potential cardiac-ischemia symptoms within 6 hours after chest pain, seeing an emergency physician who chose to order a troponin I test, and having no serious cardiac outcome before the troponin result became available. We followed the study patients for 72 hours to determine if any experienced a serious cardiac outcome. We calculated the likelihood ratios (LRs) of IMA findings predicting serious cardiac outcomes that could not be diagnosed at presentation with current techniques. Of the 189 patients, 24 had a serious cardiac outcome within 72 hours after their arrival at the emergency department. The likelihood ratios for IMA measurement within 6 hours after chest pain predicting a serious cardiac outcome within the next 72 hours were 1.35 (95% confidence interval [CI] 0.315-5.79) for IMA < or = 80 U/mL and 0.98 (95% CI 0.86- 1.11) for IMA > 80 U/mL. These data suggest that in patients presenting with chest pain who have not yet experienced a serious cardiac event, IMA is a poor predictor of serious cardiac outcomes in the short term.


A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease.
We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dual-function BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC50's ranged from 3.2 to 17 muM). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition.


Role of gender and race mismatch and graft failure in patients undergoing liver transplantation.
Previous data have suggested an increased risk of graft failure in male recipients of female livers, and in nonwhite recipients of orthotopic liver transplantation. United Network for Organ Sharing records of liver transplantations from 1992 through 2000 with at least one follow-up visit were reviewed. Analysis of these data was performed with proportional hazards regression, controlling for follow-up time, age, gender, ethnicity, number of comorbidities, functional status at time of transplant, and status 1 designation. Separate analyses comparing transplants among whites and blacks only and matched versus mismatched transplants for male and female recipients were performed. The results revealed that gender-mismatched patients (n = 13,992) had a higher likelihood of graft failure when compared with gender matched transplants (n = 18,522) (12.2% versus 11.3% respectively, P =.013). After controlling for the above potential confounders, gender-mismatched patients were found to have a 6.9% increase in likelihood of graft failure, (P =.042). Female recipients receiving male organs had no significant change in the risk of graft failure (11.5%; P =.368). A worse outcome was found in male recipients receiving female organs (12.9%; P =.0003). Graft failure rate among patients with donors matched by race (white to white or nonwhite to nonwhite; n = 21,818) was 11.6% versus 11.9%, and among unmatched patients (n = 10,697), the difference was not significant (P =.33). Multivariate regression analysis controlling for potential confounders confirmed that this difference was not significant (P =.21). Mismatch between black donors and white recipients was found to increase the risk of liver graft failure (27.4%, P = <.0001), independently of gender, number of comorbidities, and functional status at time of transplant.


Asking questions during breast cancer consultations: does being alone or being accompanied make a difference?
Companions often accompany patients to cancer consultations. The number of questions asked by patients and companions is an indicator of their active participation. The present study aims to provide first descriptive evidence on the characteristics of unaccompanied and accompanied Italian breast cancer patients that attend the first consultation after surgery and to analyse companions contribution to the type and quantity of questions asked during the consultation. Seventy consultations of female patients with breast cancer were audio taped. Questions were transcribed and coded by content. Companion's questions were also classified in terms of function. Socio-demographic and clinical data, patients' role preference and confidence in decision making measures were gathered for each patient. Post consultation satisfaction with decision and the perceived level of shared decision making were collected either for the patient and the companion. 69% of patients were accompanied, usually by one close family member, either husband or adult child. Non employed or retired patients and those with a preference for passive role in decision making were more likely to be accompanied. Unaccompanied patients and accompanied patients had comparable levels of anxiety, emotional distress and depression and were equally active in asking questions. These levels were far greater than those reported for other cancer patients in the literature. Companions did not increase significantly the number of questions per consultation. Accompanied and non accompanied patients differed more in socio-demographic than clinical characteristics. Companions sustained the patient and shared information without reducing the level of patient involvement.


CoSIA: an R Bioconductor package for CrOss Species Investigation and Analysis.
High throughput sequencing technologies have enabled cross-species comparative transcriptomic studies; however, there are numerous challenges for these studies due to biological and technical factors. We developed CoSIA (Cross-Species Investigation and Analysis), an Bioconductor R package and Shiny app that provides an alternative framework for cross-species transcriptomic comparison of non-diseased wild-type RNA sequencing gene expression data from Bgee across tissues and species (human, mouse, rat, zebrafish, fly, and nematode) through visualization of variability, diversity, and specificity metrics.


Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system.
Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.


Implementing Aided Augmentative Communication Systems With Persons Having Complex Communicative Needs.
Augmentative and alternative communication (AAC) systems can support communication skills for people with significant developmental disabilities who experience complex communication needs (CCNs). There is a need to tailor best practices in AAC assessment and intervention to create individualized communication systems with this population. In this article, we outline the important components of AAC systems that can be implemented in authentic settings. However, given the limited evidence on AAC interventions specific to people with CCNs, we also identify some priority areas for future inquiry. Among these involve strategies to enhance decision making regarding (a) matching communication mode(s) to learner skills and contextual demands, (b) identifying communicative opportunities and obligations, (c) individualizing aided communication display features, (d) selection of vocabulary specificity, and (e) considering dosage parameters needed to acquire and maintain a communicative repertoire. In addition, we briefly discuss the use of telehealth to enhance intervention capability.


Applications of Systematic Molecular Scaffold Enumeration to Enrich Structure-Activity Relationship Information.
Establishing structure-activity relationships (SARs) in hit identification during early stage drug discovery is important in accelerating hit confirmation and expansion. We describe the development of EnCore, a systematic molecular scaffold enumeration protocol using single atom mutations, to enhance the application of objective scaffold definitions and to enrich SAR information from analysis of high-throughput screening output. A list of 43 literature medicinal chemistry compound series, each containing a minimum of 100 compounds, published in the Journal of Medicinal Chemistry was collated to validate the protocol. Analysis using the top representative Level 1 scaffolds this list of literature compound series demonstrated that EnCore could mimic the scaffold exploration conducted when establishing SAR. When EnCore was applied to analyze an HTS library containing over 200 000 compounds, we observed that over 70% of the molecular scaffolds matched extant scaffolds within the library after enumeration. In particular, over 60% of the singleton scaffolds with only one representative compound were found to have structurally related compounds after enumeration. These results illustrate the potential of EnCore to enrich SAR information. A case study using literature cyclooxygenase-2 inhibitors further demonstrates the advantage of EnCore application in establishing SAR from structurally related scaffolds. EnCore complements literature enumeration methods in enabling changes to the physicochemical properties of molecular scaffolds and structural modifications to aliphatic rings and linkers. The enumerated scaffold clusters generated would constitute a comprehensive collection of scaffolds for scaffold morphing and hopping.


Serum titres of Pneumocystis carinii antibody in health care workers caring for patients with AIDS.
Pneumocystis carinii pneumonia was thought to occur from reactivation of latent infection, but recent studies with the polymerase chain reaction have failed to detect P carinii in normal subjects. If pneumocystis pneumonia is therefore caused by new infection the source and mode of transmission of P carinii remains unknown. Natural exposure to P carinii was detected by measuring antibodies by indirect immunofluorescence in 24 health care workers working continuously with patients with AIDS and 24 control health care workers exclusively treating elderly patients. P carinii antibody titres were significantly higher in the health care workers exposed to AIDS than in the control group (median titre 1:32 v 1:16 respectively). Three control subjects had no antibodies compared with none of the subjects exposed to AIDS, and 10 of the 12 highest titres came from the exposed group. Raised P carinii antibody titres in health care workers caring for patients with AIDS suggest that patients infected with HIV may be a potentially infectious source of P carinii for susceptible subjects.


Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway.
Various endocrine disrupting chemicals (EDCs) are exogenous compounds found in the environment and have the potential to interfere with the endocrine system and hormonal regulation. Among EDCs, bisphenol A (BPA) and 1,1,1-trichloro-2,2-bis(4-methoxyphenol)-ethane [methoxychlor (MXC)] have estrogenic activity resulting in a variety of dysfunctions in the E2-mediated response by binding to estrogen receptors (ERs), causing human health problems such as abnormal reproduction and carcinogenesis. In this study, we investigated the effects of BPA and MXC on cell proliferation facilitated by ER signaling in human breast cancer cells. MCF-7 cells are known to be ERα-positive and to be a highly E2-responsive cancer cell line; these cells are, therefore, a useful in vitro model for detecting estrogenic activity in response to EDCs. We evaluated cancer cell proliferation following BPA and MXC treatment using an MTT assay. We analyzed alterations in the expression of genes associated with the cell cycle in MCF-7 cells by semi-quantitative reverse-transcription PCR following treatment with BPA or MXC compared to EtOH. To determine whether BPA and MXC stimulate cancer cell growth though ER signaling, we co-treated the cells with agonists (propyl pyrazoletriol, PPT; and diarylpropionitrile, DPN) or an antagonist (ICI 182,780) of ER signaling and reduced ERα gene expression via siRNA in MCF-7 cells before treatment with EDCs. These studies confirmed the carcinogenicity of EDCs in vitro. As a result, BPA and MXC induced the cancer cell proliferation by the upregulation of genes that promote the cell cycle and the downregulation of anti-proliferative genes, especially ones affecting the G1/S transition via ERα signaling. These collective results confirm the carcinogenicity of these EDCs in vitro. Further studies are required to determine whether EDCs promote carcinogenesis in vivo.


The pathophysiology of triose phosphate isomerase dysfunction in Alzheimer's disease.
Alzheimer's disease (AD), the most prevalent neurodegenerative disease worldwide, has two main hallmarks: extracellular deposits of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles composed by tau protein. Most AD cases are sporadic and are not dependent on known genetic causes; aging is the major risk factor for AD. Therefore, the oxidative stress has been proposed to initiate the uncontrolled increase in Aβ production and also to mediate the Aβ's deleterious effects on brain cells, especially on neurons from the cortex and hippocampus. The production of free radicals in the presence of nitric oxide (NO) yields to the peroxynitrite generation, a very reactive agent that nitrotyrosinates the proteins irreversibly. The nitrotyrosination produces a loss of protein physiological functions, contributing to accelerate AD progression. One of the most nitrotyrosinated proteins in AD is the enzyme triosephosphate isomerase (TPI) that isomerises trioses, regulating glucose consumption by both phosphate pentose and glycolytic pathways and thereby pyruvate production. Hence, any disturbance in the glucose supply could affect the proper brain function, considering that the brain has a high rate of glucose consumption. Besides this directly affecting to the energetic metabolism of the neurons, TPI modifications, such as mutation or nitrotyrosination, increase methylglyoxal production, a toxic precursor of advanced glycated end-products (AGEs) and responsible for protein glycation. Moreover, nitro-TPI aggregates interact with tau protein inducing the intraneuronal aggregation of tau. Here we review the relationship between modified TPI and AD, highlighting the relevance of this protein in AD pathology and the consequences of protein nitro-oxidative modifications.


Use of Medical Devices in Hospice for Symptom Management.
Home health services in the United States(US) have been on a rise. Hospice patients cope with diverse physical and pain symptoms; medical devices are used for symptom management to improve their quality-of-care at end-of-life. Using the National Home and Hospice Care Survey (NHHCS), the study summarizes medical device use for symptom management and tracks various demographic variables for home hospice patients. A cross-sectional analysis of data using the 2007 NHHCS was conducted. There were 4733 hospice discharges which corresponded to 2,505,011 individuals in US with sampling weights. The data was analyzed using chi square tests and confounding factors adjusted with logistic regression. Eighty-nine percent of hospice discharges were evaluated for pain at first assessment. The regression model for pain at first assessment was significantly associated with use of patient controlled analgesia (OR = 1.82, 95% CI = 1.28, 2.59) and urinary catheters (OR = 1.16, 95% CI = 1.02, 1.33). Patient with dyspnea were associated with significant use of oxygen (OR = 3.00, 95% CI = 2.64, 3.40) and metered dose inhaler (OR = 2.43, 95% CI = 1.92, 3.07). There was negligible use of total parenteral nutrition (TPN) noted in the study. In conclusion, the study highlights medical device use in home hospice care for end-of-life symptom management. It noted the significant use of IV infusion pumps and patient controlled analgesia. Conversely, there is little use of TPN or CPAP in patients with anorexia or dyspnea. While missing data on critical symptom evaluations regrettably raises questions about the validity of the study, the NHHCS serves as an important reservoir of data on the growing population of home hospice patients.


Inhibition of both mesothelioma cell growth and Cdk4 activity following treatment with a TATp16INK4a peptide.
Disruption of the 9p21 locus is common in mesothelioma and leads to loss of both the p16INK4a and the p14ARF gene products. This study tested the hypothesis that reexpression of p16INK4a carried out using the TAT delivery system that carries the protein transduction domain of the HIV TAT will result in mesothelioma cell death. A synthetic TATp16INK4a peptide and a charge matched control were transduced into mesothelioma cells in vitro and in vivo. Cells were assayed for Cdk4 inhibition, cell cycle arrest, and cell death. Treatment of mesothelioma cells with TATp16INK4a for 48 hours resulted in cell death. Apoptosis and G1 cell cycle arrest was also observed. Following transduction of cells with TATp16INK4a there was complete but transient hypophosphorylation of pRb. Similar effects were observed in mesothelioma xenografts. Therapeutic strategies which introduce either TATp16INK4a peptide, or small molecule mimetic, could be an effective strategy for mesothelioma treatment.


Exploring the paradox: A cross-sectional study of academic dishonesty among Australian nursing students.
Universities' responsibility to ensure academic integrity is frustrated by software and communication tools that facilitate content reuse coupled with a growing international essay writing economy. A wide range of behaviours constitute academic dishonesty and while a complex phenomenon to examine, existing evidence suggests that there is sufficient proliferation (both in volume and variety) of these behaviours among Australian university students to warrant concern. This proliferation presents faculty and staff with new challenges in ensuring academic integrity. This paper reports findings of a nationwide cross-sectional survey of 361 students enrolled in an Australian nursing degree program and describes the extent of academic dishonesty among those surveyed. An online survey adapted from previous work was used to collect data on academic dishonesty, professional dishonesty and social desirability bias. Analysis of this data enabled identification of the prevalence of dishonesty, relationships between individual characteristics and dishonest behaviours, associations between academic and professional dishonesty, and the impact of deterrents to such behaviour. Plagiarism was the most frequently reported form of academic misconduct. Most participants indicated that threat of severe punishment and signing of verification statements would deter undesirable academic behaviour. Despite this, a relatively high proportion of students reported engaging in at least one form of academic misconduct, the likelihood of which was higher among younger age groups. Of concern was that a correlation was found between academic and professional misconduct, the most common being the recording of inaccurate or fabricated vital signs and breaching client privacy. In health professional education, there is a tendency to assume that the nobility of these disciplines would result in a lower incidence of cheating behaviours. The findings of this study support existing literature that refutes this assumption. This study found troubling rates of academic and professional misconduct among the surveyed population.


Can computed tomography angiography of the brain replace lumbar puncture in the evaluation of acute-onset headache after a negative noncontrast cranial computed tomography scan?
The primary goal of evaluation for acute-onset headache is to exclude aneurysmal subarachnoid hemorrhage (SAH). Noncontrast cranial computed tomography (CT), followed by lumbar puncture (LP) if the CT is negative, is the current standard of care. Computed tomography angiography (CTA) of the brain has become more available and more sensitive for the detection of cerebral aneurysms. This study addresses the role of CT/CTA versus CT/LP in the diagnostic workup of acute-onset headache. This article reviews the recent literature for the prevalence of SAH in emergency department (ED) headache patients, the sensitivity of CT for diagnosing acute SAH, and the sensitivity and specificity of CTA for cerebral aneurysms. An equivalence study comparing CT/LP and CT/CTA would require 3,000 + subjects. As an alternative, the authors constructed a mathematical probability model to determine the posttest probability of excluding aneurysmal or arterial venous malformation (AVM) SAH with a CT/CTA strategy. SAH prevalence in ED headache patients was conservatively estimated at 15%. Representative studies reported CT sensitivity for SAH to be 91% (95% confidence interval [CI] = 82% to 97%) and sensitivity of CTA for aneurysm to be 97.9% (95% CI = 88.9% to 99.9%). Based on these data, the posttest probability of excluding aneurysmal SAH after a negative CT/CTA was 99.43% (95% CI = 98.86% to 99.81%). CT followed by CTA can exclude SAH with a greater than 99% posttest probability. In ED patients complaining of acute-onset headache without significant SAH risk factors, CT/CTA may offer a less invasive and more specific diagnostic paradigm. If one chooses to offer LP after CT/CTA, informed consent for LP should put the pretest risk of a missed aneurysmal SAH at less than 1%.


Interventions to increase attendance for diabetic retinopathy screening.
Despite evidence supporting the effectiveness of diabetic retinopathy screening (DRS) in reducing the risk of sight loss, attendance for screening is consistently below recommended levels. The primary objective of the review was to assess the effectiveness of quality improvement (QI) interventions that seek to increase attendance for DRS in people with type 1 and type 2 diabetes.Secondary objectives were:To use validated taxonomies of QI intervention strategies and behaviour change techniques (BCTs) to code the description of interventions in the included studies and determine whether interventions that include particular QI strategies or component BCTs are more effective in increasing screening attendance;To explore heterogeneity in effect size within and between studies to identify potential explanatory factors for variability in effect size;To explore differential effects in subgroups to provide information on how equity of screening attendance could be improved;To critically appraise and summarise current evidence on the resource use, costs and cost effectiveness. We searched the Cochrane Library, MEDLINE, Embase, PsycINFO, Web of Science, ProQuest Family Health, OpenGrey, the ISRCTN, ClinicalTrials.gov, and the WHO ICTRP to identify randomised controlled trials (RCTs) that were designed to improve attendance for DRS or were evaluating general quality improvement (QI) strategies for diabetes care and reported the effect of the intervention on DRS attendance. We searched the resources on 13 February 2017. We did not use any date or language restrictions in the searches. We included RCTs that compared any QI intervention to usual care or a more intensive (stepped) intervention versus a less intensive intervention. We coded the QI strategy using a modification of the taxonomy developed by Cochrane Effective Practice and Organisation of Care (EPOC) and BCTs using the BCT Taxonomy version 1 (BCTTv1). We used Place of residence, Race/ethnicity/culture/language, Occupation, Gender/sex, Religion, Education, Socioeconomic status, and Social capital (PROGRESS) elements to describe the characteristics of participants in the included studies that could have an impact on equity of access to health services.Two review authors independently extracted data. One review author entered the data into Review Manager 5 and a second review author checked them. Two review authors independently assessed risks of bias in the included studies and extracted data. We rated certainty of evidence using GRADE. We included 66 RCTs conducted predominantly (62%) in the USA. Overall we judged the trials to be at low or unclear risk of bias. QI strategies were multifaceted and targeted patients, healthcare professionals or healthcare systems. Fifty-six studies (329,164 participants) compared intervention versus usual care (median duration of follow-up 12 months). Overall, DRS attendance increased by 12% (risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14; low-certainty evidence) compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted (RD 0.17, 95% CI 0.11 to 0.22) and general QI interventions (RD 0.12, 95% CI 0.09 to 0.15) were effective, particularly where baseline DRS attendance was low. All BCT combinations were associated with significant improvements, particularly in those with poor attendance. We found higher effect estimates in subgroup analyses for the BCTs 'goal setting (outcome)' (RD 0.26, 95% CI 0.16 to 0.36) and 'feedback on outcomes of behaviour' (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients, and 'restructuring the social environment' (RD 0.19, 95% CI 0.12 to 0.26) and 'credible source' (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting healthcare professionals.Ten studies (23,715 participants) compared a more intensive (stepped) intervention versus a less intensive intervention. In these studies DRS attendance increased by 5% (RD 0.05, 95% CI 0.02 to 0.09; moderate-certainty evidence).Fourteen studies reporting any QI intervention compared to usual care included economic outcomes. However, only five of these were full economic evaluations. Overall, we found that there is insufficient evidence to draw robust conclusions about the relative cost effectiveness of the interventions compared to each other or against usual care.With the exception of gender and ethnicity, the characteristics of participants were poorly described in terms of PROGRESS elements. Seventeen studies (25.8%) were conducted in disadvantaged populations. No studies were carried out in low- or middle-income countries. The results of this review provide evidence that QI interventions targeting patients, healthcare professionals or the healthcare system are associated with meaningful improvements in DRS attendance compared to usual care. There was no statistically significant difference between interventions specifically aimed at DRS and those which were part of a general QI strategy for improving diabetes care. This is a significant finding, due to the additional benefits of general QI interventions in terms of improving glycaemic control, vascular risk management and screening for other microvascular complications. It is likely that further (but smaller) improvements in DRS attendance can also be achieved by increasing the intensity of a particular QI component or adding further components.


Treatment of stage D2 prostatic carcinoma with combined gonadal and adrenal suppression in a 60-year-old man.
A 60-year-old man with stage D2 prostatic carcinoma received treatment with a new luteinizing hormone-releasing hormone superagonist. After a seven-month remission; relapse of the disease occurred and an adrenal-suppressing dose of dexamethasone was added. The resulting combined gonadal and adrenal suppression led to another remission that lasted five months. This case supports other observations of the importance of adrenal androgen production in the pathobiology of prostatic carcinoma.


Understanding the current sexual health service provision for mental health consumers by nurses in mental health settings: Findings from a Survey in Australia and England.
Nurses in mental health settings avoid talking to consumers about sexual health concerns. It is unclear whether this avoidance prevents the provision of sexual healthcare. The present study gathered information about how mental health nurses respond to sexual health issues within their routine practice, what issues they address, and their view on their role in promoting sexual health for consumers. A cross-sectional study using an electronic survey questionnaire, originally generated from a previous study in the united kingdom, was employed. The study occurred in four National Health Service Trusts in England and a national call for participants in Australia. Participants were nurse clinicians (n = 303) who self-selected by completing surveys available via email and newsletters containing links to the survey. The results demonstrated that mental health nurses do not routinely include sexual health in their practice and are poorly prepared in knowing what to do with a sexual health issue, and what services to assist consumers to use. In conclusion, it has been well established in the literature that mental health consumers experience high sexual health needs that potentially impact on health and recovery. Mental health nurses are ideally placed to promote sexual health and refer consumers to sexual health and family planning services. Training to improve the confidence and responsiveness of mental health nurses to sexual health is an urgent need.


Appropriate antibiotic use for patients with complicated urinary tract infections in 38 Dutch Hospital Departments: a retrospective study of variation and determinants.
Appropriate antibiotic use in patients with complicated urinary tract infections can be measured by a valid set of nine quality indicators (QIs). We evaluated the performance of these QIs in a national setting and investigated which determinants influenced appropriate antibiotic use. For the latter, we distinguished patient, department and hospital characteristics, including organizational interventions aimed at improving the quality of antibiotic use (antibiotic stewardship elements). A retrospective, observational multicentre study included 1964 patients (58% male sex) with a complicated urinary tract infection treated at Internal Medicine and Urology departments of 19 Dutch university and non-university hospitals. Data of 50 patients per department were extracted from medical charts. QI performance scores were calculated using previously constructed algorithms. Department and hospital characteristics were collected using questionnaires filled in by an internal medicine physician and an urologist. Regression analysis was performed to identify determinants of QI performance. Clustering at department and hospital level was taken into account through inclusion of random effects in a multi-level model. Median QI performance of departments varied between 31% ('Treat urinary tract infection in men according to local guideline') and 77% ('Perform urine culture'). The patient characteristics non-febrile urinary tract infection, female sex and presence of a urinary catheter were negatively associated with performance on many QIs. The presence of an infectious diseases physician and an antibiotic formulary were positively associated with 'Prescribe empirical therapy according to guideline'. No other department or hospital characteristics, including stewardship elements, were consistently associated with better QI performance. A large inter-department variation was demonstrated in the appropriateness of antibiotic use. In particular certain patient characteristics (more than department or hospital characteristics) influenced the quality of antibiotic use. Some, but not all antibiotic stewardship elements did translate into better QI performance.


Smoothelin, a novel cytoskeletal protein specific for smooth muscle cells.
The characterization of a novel 59-kD cytoskeletal protein is described. It is exclusively observed in smooth muscle cells by Northern blotting and immunohistochemical analysis and therefore designated "smoothelin." A human smooth muscle cDNA library was screened with the monoclonal antibody R4A, and a full-size cDNA of the protein was selected. The cDNA was sequenced and appeared to contain a 1,113-bp open reading frame. Based on the cDNA sequence, the calculated molecular weight of the polypeptide was 40 kD and it was demonstrated to contain two N-glycosylation sites. Computer assisted analysis at the protein level revealed a 56-amino acid domain with homologies of approximately 40% with a sequence bordering the actin-binding domains of dystrophin, utrophin, beta-spectrin and alpha-actinin. In situ hybridization demonstrated that human smoothelin is encoded by a single copy gene which is located on chromosome 22. Immunohistochemistry and Western blotting revealed synthesis of smoothelin in smooth muscle of species evolutionarily as far apart as human and teleost. Northern blotting indicated that sequence as well as size of the mRNA (approximately 1,500 bases) are conserved among vertebrates. Cell fractionation studies and differential centrifugation showed that the protein cannot be extracted with Triton X-100, which indicates that it is a part of the cytoskeleton. Transfection of the human cDNA into smooth muscle cells and COS7 cells produced a protein of 59 kD, which assembled into a filamentous network. However, in rat heart-derived myoblasts association with stress fibers was most prominent. Smoothelin was not detected in primary or long term smooth muscle cell cultures. Also, transcription of smoothelin mRNA was almost instantly halted in smooth muscle tissue explants. We conclude that smoothelin is a new cytoskeletal protein that is only found in contractile smooth muscle cells and does not belong to one of the classes of structural proteins presently known.


On-line sample preconcentration with chemical derivatization of bacterial biomarkers by capillary electrophoresis: a dual strategy for integrating sample pretreatment with chemical analysis.
Simple, selective yet sensitive methods to quantify low-abundance bacterial biomarkers derived from complex samples are required in clinical, biological, and environmental applications. In this report, a new strategy to integrate sample pretreatment with chemical analysis is investigated using on-line preconcentration with chemical derivatization by CE and UV detection. Single-step enantioselective analysis of muramic acid (MA) and diaminopimelic acid (DAP) was achieved by CE via sample enrichment by dynamic pH junction with ortho-phthalaldehyde/N-acetyl-L-cysteine labeling directly in-capillary. The optimized method resulted in up to a 100-fold enhancement in concentration sensitivity compared to conventional off-line derivatization procedures. The method was also applied toward the detection of micromolar levels of MA and DAP excreted in the extracellular medium of Escherichia coli bacterial cell cultures. On-line preconcentration with chemical derivatization by CE represents a unique approach for conducting rapid, sensitive, and high-throughput analyses of other classes of amino acid and amino sugar metabolites with reduced sample handling, where the capillary functions simultaneously as a concentrator, microreactor, and chiral selector.


The effect of an ultra-endurance running race on mucosal and humoral immune function.
There are reports of the effect of endurance exercise on mucosal immune function and of the effect of short duration exercise on humoral immune function. However, little is known of the effect of endurance exercise on humoral immune function and the related risk of infection. This study examined the effects of an ultra-endurance running race on salivary immunoglobulin-A (s-IgA), serum IgA, leukocyte subset concentrations and the incidence of upper respiratory tract infections (URTI). Thirteen male and 4 female competitors provided saliva samples and blood before and at several times after the running race. Self-reported symptoms of URTI were also recorded for 2 weeks before and 2 weeks after the race. Salivary IgA secretion rate (P=0.005) and ratio to osmolality (P=0.006) were lower immediately postrace and decreased further for at least 2 more h. s-IgA secretion rate had not returned to normal the next morning (P=0.009). Serum IgA concentration was lower post- than prerace (P=0.003) and was even lower the next morning (P<0.001). Leukocyte concentration was elevated postrace (P<0.001), mainly because of an increase in neutrophils (P<0.001) and both remained high the morning after the race (P<0.001). Lymphocyte concentration decreased postrace (P<0.001) and was still depressed the next morning (P=0.032). The incidence of symptoms of URTI was the same in the two 2-week periods before and after the race. These findings support the hypotheses that an ultra-endurance run may adversely affect mucosal immunity and cause significant changes in the concentration of leukocyte subsets.


Human cutaneous T cell lymphoma and leukemia cell lines produce and respond to T cell growth factor.
Three cell lines of mature T cell origin derived from patients with cutaneous T cell lymphoma-leukemias (CTCL) were found to be constitutive producers of T cell growth factor (L-TCGF). These are the first reported human cell lines which constitutively produce TCGF. Biologically active TCGF could also be eluted from the surface of these cells using an acid glycine buffer under conditions that maintained cell viability, and subcellular fractionation showed that almost all the TCGF activity was associated with the plasma membrane. Over 30 other human hematopoietic cell lines derived from other disorders were unable to produce TCGF even after induction, and their acid eluates did not contain TCGF activity. L-TCGF from CTCL lines had the same biological activity as TCGF obtained from normal leukocytes (N-TCGF) in that they both supported the long-term growth of normal T cells only after the cells were previously activated by antigen or lectin. Both L-TCGF and N-TCGF increased the rate of proliferation of TCGF-independent and TCGF-dependent CTCL cell lines. The same three factor-independent cell lines that released TCGF adsorbed TCGF in a cell-concentration, time-, and temperature-dependent manner. Since the CTCL cell lines produce TCGF, adsorb TCGF, and increase their proliferative rate in response to TCGF or a related molecule, it is suggested that this endogenously produced factor plays a role in maintaining the abnormal proliferation of these cells in culture as permanently growing cell lines independent of exogenous TCGF. However, this does not mean that this is an essential aspect of neoplastic transformation. Since it is unusual to develop these cell lines in the absence of the continuous need for added TCGF, "autostimulation" may be one of the many unusual variant phenotypic properties sometimes associated with neoplastic cells that gives them a selective advantage for in vitro growth.


Harnessing translational research in wheat for climate resilience.
Despite being the world's most widely grown crop, research investments in wheat (Triticum aestivum and Triticum durum) fall behind those in other staple crops. Current yield gains will not meet 2050 needs, and climate stresses compound this challenge. However, there is good evidence that heat and drought resilience can be boosted through translating promising ideas into novel breeding technologies using powerful new tools in genetics and remote sensing, for example. Such technologies can also be applied to identify climate resilience traits from among the vast and largely untapped reserve of wheat genetic resources in collections worldwide. This review describes multi-pronged research opportunities at the focus of the Heat and Drought Wheat Improvement Consortium (coordinated by CIMMYT), which together create a pipeline to boost heat and drought resilience, specifically: improving crop design targets using big data approaches; developing phenomic tools for field-based screening and research; applying genomic technologies to elucidate the bases of climate resilience traits; and applying these outputs in developing next-generation breeding methods. The global impact of these outputs will be validated through the International Wheat Improvement Network, a global germplasm development and testing system that contributes key productivity traits to approximately half of the global wheat-growing area.


Comparison of control strategies for the cervical muscles of an average female head-neck finite element model.
Objective: ViVA OpenHBM is the first open source Human Body Model (HBM) for crash safety assessment. It represents an average size (50th percentile) female and was created to assess whiplash protection systems in a car. To increase the biofidelity of the current model, further enhancements are being made by implementing muscle reflex response capabilities as cervical muscles alter the head and neck kinematics of the occupant during low-speed rear crashes. The objective of this study was to assess how different neck muscle activation control strategies affect head-neck kinematics in low speed rear impacts.Methods: The VIVA OpenHBM head-neck model, previously validated to PMHS data, was used for this study. To represent the 34 cervical muscles, 129 beam elements with Hill-type material models were used. Two different muscle activation control strategies were implemented: a control strategy to mimic neural feedback from the vestibular system and a control strategy to represent displacement feedback from muscle spindles. To identify control gain values for these controller strategies, parameter calibrations were conducted using optimization. The objective of these optimizations was to match the head linear and angular displacements measured in volunteer tests.Results: Muscle activation changed the head kinematics by reducing the peak linear displacements, as compared to the model without muscle activation. For the muscle activation model mimicking the human vestibular system, a good agreement was observed for the horizontal head translation. However, in the vertical direction there was a discrepancy of head kinematic response caused by buckling of the cervical spine. In the model with a control strategy that represents muscle spindle feedback, improvements in translational head kinematics were observed and less cervical spine buckling was observed. Although, the overall kinematic responses were better in the first strategy.Conclusions: Both muscle control strategies improved the head kinematics compared to the passive model and comparable to the volunteer kinematics responses with overall better agreement achieved by the model with active muscles mimicking the human vestibular system.


Partial migration in fishes: definitions, methodologies and taxonomic distribution.
Partial migration, where populations are composed of both migratory and resident individuals, is extremely widespread across the animal kingdom. Researchers studying fish movements have long recognized that many fishes are partial migrants, however, no detailed taxonomic review has ever been published. In addition, previous work and synthesis has been hampered by a varied lexicon associated with this phenomenon in fishes. In this review, definitions and important concepts in partial migration research are discussed, and a classification system of the different forms of partial migration in fishes introduced. Next, a detailed taxonomic overview of partial migration in this group is considered. Finally, methodological approaches that ichthyologists can use to study this fascinating phenomenon are reviewed. Partial migration is more widespread amongst fishes than previously thought, and given the array of techniques available to fish biologists to study migratory variation the future of the field looks promising.


[FeFe]-Hydrogenase H-cluster mimics mediated by naphthalene monoimide derivatives of peri-substituted dichalcogenides.
Synthetic models of the active site of [FeFe]-hydrogenase containing naphthalene monoimide (NMI) of peri-substituted dichalcogenides as bridging linkers have been prepared and characterized using different spectroscopic methods. The influence of the imide functionality and the chalcogen atoms on the redox properties and the catalytic behaviour of complexes 7-10 was studied using cyclic voltammetry. The results revealed that the imide functionality has improved the chemical stability of the reduced species and the replacement of the S atoms by Se caused a cathodic shift in the oxidation peaks. Moreover, the optical properties of compounds 1, 2, 4, and 5 and the respective diiron complexes 7-10 were investigated by UV-Vis absorption and fluorescence spectroscopy assisted by quantum chemical simulations. The structures of complexes 6-9 were confirmed by X-ray diffraction analysis.


Intra versus Inter Cross-resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer.
Current treatments for castration resistant prostate cancer (CRPC) largely fall into two classes: androgen receptor (AR)-targeted therapies such as the next-generation antiandrogen therapies (NGAT), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients still succumb to the disease due to the development of resistance. Further complicating the situation is lack of a well-defined treatment sequence and potential for cross-resistance between therapies. We have developed several models representing CRPC with acquired therapeutic resistance. Here, we utilized these models to assess putative cross-resistance between treatments. We find that resistance to enzalutamide induces resistance to abiraterone and vice versa, but resistance to neither alters sensitivity to taxanes. Acquired resistance to docetaxel induces cross-resistance to cabazitaxel but not to enzalutamide or abiraterone. Correlating responses with known mechanisms of resistance indicates that AR variants are associated with resistance to NGATs, whereas the membrane efflux protein ABCB1 is associated with taxane resistance. Mechanistic studies show that AR variant-7 (AR-v7) is involved in NGAT resistance but not resistance to taxanes. Our findings suggest the existence of intra cross-resistance within a drug class (i.e., within NGATs or within taxanes), whereas inter cross-resistance between drug classes does not develop. Furthermore, our data suggest that resistance mechanisms differ between drug classes. These results may have clinical implications by showing that treatments of one class can be sequenced with those of another, but caution should be taken when sequencing similar classed drugs. In addition, the development and use of biomarkers indicating resistance will improve patient stratification for treatment. Mol Cancer Ther; 17(10); 2197-205. ©2018 AACR.


Optical propagation in uniaxial crystals orthogonal to the optical axis: paraxial theory and beyond.
We describe monochromatic light propagation in uniaxial crystals by means of an exact solution of Maxwell's equations. We subsequently develop a paraxial scheme for describing a beam traveling orthogonal to the optical axis. We show that the Cartesian field components parallel and orthogonal to the optical axis are extraordinary and ordinary, respectively, and hence uncoupled. The ordinary component exhibits a standard Fresnel behavior, whereas the extraordinary one exhibits interesting anisotropic diffraction dynamics. We interpret the anisotropic diffraction as a composition of two spatial geometrical affinities and a single Fresnel propagation step. As an application, we obtain the analytical expression of the extraordinary Gaussian beam. We then derive the first nonparaxial correction to the paraxial beam, thus giving a scheme for describing slightly nonparaxial fields. We find that nonparaxiality couples the Cartesian components of the field and that the resultant longitudinal component is greater than the correction to the transverse component orthogonal to the optical axis. Finally, we derive the analytical expression for the nonparaxial correction to the paraxial Gaussian beam.


Amphiphilic hyaluronic acid derivatives toward the design of micelles for the sustained delivery of hydrophobic drugs.
The idea of this study was to combine hyaluronic acid (HA) viscosupplementation and a local/controlled delivery of a hydrophobic anti-inflammatory drug. To this aim, we investigated the ability of an octenyl succinic anhydride (OSA) modified HA (OSA-HA), to act as a solubility enhancer and as a platform for slow release of hydrophobic drug(s). This novel HA derivative could act as a viscosupplementation agent and, for this reason, a rheological study was conducted along with calorimetric analysis. Differential scanning calorimetry (DSC) results revealed that the ability of HA to sequester water is enhanced by the introduction of lipophilic functions within HA molecules, resulting in a decrease of the fraction of free water able to freeze compared to the unmodified HA. Moreover, OSA-HA solutions appear to be an appropriate tool to be used in viscosupplementation therapy owing to their suitable viscoelastic features. Our results indicate that OSA-HA is able to self-assemble into micelles, load a hydrophobic drug and release the active molecule with controlled kinetics. In particular, the analysis of release profiles showed that, in all cases, drug diffusion into the gel is faster compared to gel/drug dissolution, being the dissolution contribution more relevant as the OSA-HA concentration increases.


High-Cost Patients Had Substantial Rates Of Leaving Medicare Advantage And Joining Traditional Medicare.
Medicare Advantage payment regulations include risk-adjusted capitated reimbursement, which was implemented to discourage favorable risk selection and encourage the retention of members who incur high costs. However, the extent to which risk-adjusted capitation has succeeded is not clear, especially for members using high-cost services not previously considered in assessments of risk selection. We examined the rates at which participants who used three high-cost services switched between Medicare Advantage and traditional Medicare. We found that the switching rate from 2010 to 2011 away from Medicare Advantage and to traditional Medicare exceeded the switching rate in the opposite direction for participants who used long-term nursing home care (17 percent versus 3 percent), short-term nursing home care (9 percent versus 4 percent), and home health care (8 percent versus 3 percent). These results were magnified among people who were enrolled in both Medicare and Medicaid. Our findings raise questions about the role of Medicare Advantage plans in serving high-cost patients with complex care needs, who account for a disproportionately high amount of total health care spending.


Birth centers in Australia: a national population-based study of perinatal mortality associated with giving birth in a birth center.
Perinatal mortality is a rare outcome among babies born at term in developed countries after normal uncomplicated pregnancies; consequently, the numbers involved in large databases of routinely collected statistics provide a meaningful evaluation of these uncommon events. The National Perinatal Data Collection records the place of birth and information on the outcomes of pregnancy and childbirth for all women who give birth each year in Australia. Our objective was to describe the perinatal mortality associated with giving birth in "alongside hospital" birth centers in Australia during 1999 to 2002 using nationally collected data. This population-based study included all 1,001,249 women who gave birth in Australia during 1999 to 2002. Of these women, 21,800 (2.18%) gave birth in a birth center. Selected perinatal outcomes (including stillbirths and neonatal deaths) were described for the 4-year study period separately for first-time mothers and for women having a second or subsequent birth. A further comparison was made between deaths of low-risk term babies born in hospitals compared with deaths of term babies born in birth centers. The total perinatal death rate attributed to birth centers was significantly lower than that attributed to hospitals (1.51/1,000 vs 10.03/1,000). The perinatal mortality rate among term births to primiparas in birth centers compared with term births among low-risk primiparas in hospitals was 1.4 versus 1.9 per 1,000; the perinatal mortality rate among term births to multiparas in birth centers compared with term births among low-risk multiparas in hospitals was 0.6 versus 1.6 per 1,000. This study using Australian national data showed that the overall rate of perinatal mortality was lower in alongside hospital birth centers than in hospitals irrespective of the mother's parity.


Oral vs. intravenous empirical antimicrobial therapy in febrile neutropenic patients receiving childhood cancer chemotherapy.
To compare the use of intravenous vs. oral antibiotic therapy. All febrile neutropenic patients younger than 18 years old with low risk of complications and receiving chemotherapy were selected. The study was conducted from 2002 to 2005 at the Pediatric Oncology Unit of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Patients were divided into group A and group B and were randomly assigned to receive oral or intravenous therapy. The empirical antimicrobial treatment used for group A consisted in oral ciprofloxacin plus amoxicillin-clavulanate and intravenous placebo, and group B received cefepime and oral placebo. A total of 91 consecutive episodes of febrile neutropenia in 58 children were included in the study. For patients of group A, treatment failure rate was 51.2%; the mean length of hospital stay was 8 days (range 2-10 days). For patients treated with intravenous antibiotic therapy, treatment failure rate was 45.8%; the mean length of hospital stay was 7 days (range 3-10 days). There was no difference in the outcome in oral vs. intravenous therapy. There is need of larger randomized trials before oral empirical therapy administered to this population should be considered the new standard of treatment.


Ex vivo transcriptional profiling reveals a common set of genes important for the adaptation of Pseudomonas aeruginosa to chronically infected host sites.
The opportunistic bacterium Pseudomonas aeruginosa is a major nosocomial pathogen causing both devastating acute and chronic persistent infections. During the course of an infection, P. aeruginosa rapidly adapts to the specific conditions within the host. In the present study, we aimed at the identification of genes that are highly expressed during biofilm infections such as in chronically infected lungs of patients with cystic fibrosis (CF), burn wounds and subcutaneous mouse tumours. We found a common subset of differentially regulated genes in all three in vivo habitats and evaluated whether their inactivation impacts on the bacterial capability to form biofilms in vitro and to establish biofilm-associated infections in a murine model. Additive effects on biofilm formation and host colonization were discovered by the combined inactivation of several highly expressed genes. However, even combined inactivation was not sufficient to abolish the establishment of an infection completely. These findings can be interpreted as evidence that either redundant traits encode functions that are essential for in vivo survival and chronic biofilm infections and/or bacterial adaptation is considerably achieved independently of transcription levels. Supplemental screens, will have to be applied in order to identify the minimal set of key genes essential for the establishment of chronic infectious diseases.


Complications of tension-band wiring of olecranon fractures.
We encountered a high incidence of complications related to the technique of tension-band wire fixation of displaced fractures of the olecranon in a five-year retrospective study of twenty patients (twenty fractures). All had been treated with primary open reduction using the AO technique of tension-band wiring. Twenty patients were followed at least to union as determined radiographically. The most frequent complication was symptomatic prominence of the Kirschner wires at the elbow in sixteen patients. There was skin breakdown in four patients, and infection developed in one. Measurable proximal migration of the Kirschner wires, however, occurred in only three patients. Prominence of the Kirschner wires usually was due to improper seating at the time of surgery (twelve of sixteen patients). Most complications that are related to this method of fixation may be avoided by careful attention to surgical technique.


Metabolic labeling in middle-down proteomics allows for investigation of the dynamics of the histone code.
Middle-down mass spectrometry (MS), i.e., analysis of long (~50-60 aa) polypeptides, has become the method with the highest throughput and accuracy for the characterization of combinatorial histone posttranslational modifications (PTMs). The discovery of histone readers with multiple domains, and overall the cross talk of PTMs that decorate histone proteins, has revealed that histone marks have synergistic roles in modulating enzyme recruitment and subsequent chromatin activities. Here, we demonstrate that the middle-down MS strategy can be combined with metabolic labeling for enhanced quantification of histone proteins and their combinatorial PTMs in a dynamic manner. We used a nanoHPLC-MS/MS system consisting of hybrid weak cation exchange-hydrophilic interaction chromatography combined with high resolution MS and MS/MS with ETD fragmentation. After spectra identification, we filtered confident hits and quantified polypeptides using our in-house software isoScale. We first verified that middle-down MS can discriminate and differentially quantify unlabeled from heavy labeled histone N-terminal tails (heavy lysine and arginine residues). Results revealed no bias toward identifying and quantifying unlabeled versus heavy labeled tails, even if the heavy labeled peptides presented the typical skewed isotopic pattern typical of long protein sequences that hardly get 100% labeling. Next, we plated epithelial cells into a media with heavy methionine-(methyl-13CD3), the precursor of the methyl donor S-adenosylmethionine and stimulated epithelial to mesenchymal transition (EMT). We assessed that results were reproducible across biological replicates and with data obtained using the more widely adopted bottom-up MS strategy, i.e., analysis of short tryptic peptides. We found remarkable differences in the incorporation rate of methylations in non-confluent cells versus confluent cells. Moreover, we showed that H3K27me3 was a critical player during the EMT process, as a consistent portion of histones modified as H3K27me2K36me2 in epithelial cells were converted into H3K27me3K36me2 in mesenchymal cells. We demonstrate that middle-down MS, despite being a more scarcely exploited MS technique than bottom-up, is a robust quantitative method for histone PTM characterization. In particular, middle-down MS combined with metabolic labeling is currently the only methodology available for investigating turnover of combinatorial histone PTMs in dynamic systems.


Houston hurricane Harvey health (Houston-3H) study: assessment of allergic symptoms and stress after hurricane Harvey flooding.
In August 2017, Hurricane Harvey caused unprecedented flooding across the greater Houston area. Given the potential for widespread flood-related exposures, including mold and sewage, and the emotional and mental toll caused by the flooding, we sought to evaluate the short- and long-term impact of flood-related exposures on the health of Houstonians. Our objectives were to assess the association of flood-related exposures with allergic symptoms and stress among Houston-area residents at two time points: within approximately 30 days (T1) and 12 months (T2) after Hurricane Harvey's landfall. The Houston Hurricane Harvey Health (Houston-3H) Study enrolled a total of 347 unique participants from four sites across Harris County at two times: within approximately 1-month of Harvey (T1, n = 206) and approximately 12-months after Harvey (T2, n = 266), including 125 individuals who participated at both time points. Using a self-administered questionnaire, participants reported details on demographics, flood-related exposures, and health outcomes, including allergic symptoms and stress. The majority of participants reported hurricane-related flooding in their homes at T1 (79.1%) and T2 (87.2%) and experienced at least one allergic symptom after the hurricane (79.4% at T1 and 68.4% at T2). In general, flood-exposed individuals were at increased risk of upper respiratory tract allergic symptoms, reported at both the T1 and T2 time points, with exposures to dirty water and mold associated with increased risk of multiple allergic symptoms. The mean stress score of study participants at T1 was 8.0 ± 2.1 and at T2, 5.1 ± 3.2, on a 0-10 scale. Participants who experienced specific flood-related exposures reported higher stress scores when compared with their counterparts, especially 1 year after Harvey. Also, a supplementary paired-samples analysis showed that reports of wheezing, shortness of breath, and skin rash did not change between T1 and T2, though other conditions were less commonly reported at T2. These initial Houston-3H findings demonstrate that flooding experiences that occurred as a consequence of Hurricane Harvey had lasting impacts on the health of Houstonians up to 1 year after the hurricane.


A mouse model provides evidence that genetic background modulates anemia and liver injury in erythropoietic protoporphyria.
Erythropoietic protoporphyria is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin (PP) overproduction by erythrocytes. In humans, it is responsible for painful skin photosensitivity and, occasionally, liver failure due to accumulation of PP in the liver. The ferrochelatase deficiency mouse mutation is the best animal model available for human erythropoietic protoporphyria. The original description, based on mice with a BALB/cByJCrl genetic background, reported a disease resembling the severe form of the human disease, with anemia, jaundice, and liver failure. Using congenic strains, we investigated the effect of genetic background on the severity of the phenotype. Compared with BALB/cByJCrl, C57BL/6JCrl mice developed moderate but increasing anemia and intense liver accumulation of PP with severe hepatocyte damage and loss. Bile excretory function was not affected, and bilirubin remained low. Despite the highest PP concentration in erythrocytes, anemia was mild and there were few PP deposits in the liver in SJL/JOrlCrl homozygotes. Discriminant analysis using six hematologic and biochemical parameters showed that homozygotes of the three genetic backgrounds could be clustered in three well-separated groups. These three congenic strains provide strong evidence for independent genetic control of bone marrow contribution of PP overproduction to development of liver disease and biliary PP excretion. They provide a tool to investigate the physiological mechanisms involved in these phenotypic differences and to identify modifying genes.


Inhibition of NF-kappa B by S-nitrosylation.
It is not clear if redox regulation of transcription is the consequence of direct redox-related modifications of transcription factors, or if it occurs at some other redox-sensitive step. One obstacle has been the inability to demonstrate redox-related modifications of transcription factors in vivo. The redox-sensitive transcriptional activator NF-kappaB (p50-p65) is a case in point. Its activity in vitro can be inhibited by S-nitrosylation of a critical thiol in the DNA-interacting p50 subunit, but modulation of NF-kappaB activity by nitric oxide synthase (NOS) has been attributed to other mechanisms. Herein we show that cellular NF-kappaB activity is in fact regulated by S-nitrosylation. We observed that both S-nitrosocysteine and cytokine-activated NOS2 inhibited NF-kappaB in human respiratory cells or murine macrophages. This inhibition was reversed by addition of the denitrosylating agent dithiothreitol to cellular extracts, whereas NO bioactivity did not affect the TNFalpha-induced degradation of IkappaBalpha or the nuclear translocation of p65. Recapitulation of these conditions in vitro resulted in S-nitrosylation of recombinant p50, thereby inhibiting its binding to DNA, and this effect was reversed by dithiothreitol. Further, an increase in S-nitrosylated p50 was detected in cells, and the level was modulated by TNFalpha. Taken together, these data suggest that S-nitrosylation of p50 is a physiological mechanism of NF-kappaB regulation.


Comparison of cidofovir and the measles, mumps, and rubella vaccine in the treatment of recurrent respiratory papillomatosis.
We conducted a retrospective study of the use of cidofovir and the measles, mumps, and rubella (MMR) vaccineas adjunctive treatments to lesion debridement in patients with recurrent respiratory papillomatosis (RRP). Our study population was made up of 15 children-7 boys and 8 girls, aged 1 to 16 years at diagnosis (mean: 6.2)-with pathologically confirmed RRP who had been followed for at least 1 year. In addition to demographic data, we compiled information on disease severity, the type of adjunctive treatment administered to each patient, the frequency of debridements, the length of observation, and remission rates. Of the 15 patients, 5 had been treated with cidofovirafter debridement (cidofovir-only group), 6 were treated with MMR vaccine after debridement (MMR-only group), 3 were treated with one and later switched to the other based on parental preference, and 1 received neither treatment, only debridement. The initial mean Derkay disease severity scores were 12.6 for the cidofovir-only group and 11.0 for the MMR-only group (p = 0.61). The cidofovir-only patients underwent an average of 11.8 adjunctive treatments and the MMR-only patients an average of 17.7 (p = 0.33). The average duration of observation was 44.0 months in the cidofovir-only group and 64.7 months in the MMR-only group (p = 0.29). Remission rates were 20% in the cidofovir-only group and 50% in the MMR-only group (p = 0.54). Our study found insufficient evidence of any significant differences between cidofovir and the MMR vaccinein terms of the number and frequency of adjunctive treatments and the rates of remission.


Access to an optimal treatment. Current situation.
Access to an optimal treatment is determined by several factors, like availability, pricing/funding, and acceptability. In Latin America (LA), one of the regions with more disparities particularly on healthcare in the world, access is affected by other factors, including socio-demographic factors like poverty, living in rural regions, and/or health coverage. Regarding rheumatoid arthritis (RA), an inadequate access to specialists leads to diagnosis and treatment delays diminishing the probability of remission or control. Unfortunately, in almost every LA country, there are cities with more than 100,000 inhabitants without rheumatologists; furthermore, a primary care reference system is present in only about half the countries. In the public health system, coverage of biologic disease-modifying antirheumatic drugs occurs for less than 10 % of the patients in about half of the countries. Also, as healthcare providers based their funding decisions mainly in direct costs instead of on patient-centered healthcare quality indicators, access to new drugs is more complicated in this region than in high-income countries. More accurate epidemiological data from LA need to be obtained in order to improve the management of patients with rheumatic diseases in general and RA in particular.


A synchroton X-ray study of the changes occurring in the corneal stroma during processing for electron microscopy.
Using a high-intensity synchroton X-ray source, the structural changes occurring in the corneal stroma were monitored during each stage of several different processing runs for the transmission electron microscope (TEM) and scanning electron microscope (SEM). The parameters studied were interfibrillar spacing, intermolecular spacing, D-periodicity and fibril diameter. The processing schedule that produced the least changes in spacings for TEM specimens involved extended fixation in glutaraldehyde followed by low-temperature embedding in Lowicryl K4M resin. However, interfibrillar material was better preserved after embedding in LR White resin or Nanoplast. Almost every processing stage for electron microscopy produced significant changes in one or more structural parameters in the cornea. Glutaraldehyde fixation significantly increased the intermolecular spacings, while resin infiltration and resin polymerization each resulted in shrinkage of all the spacings monitored. Critical-point drying for SEM specimens resulted in considerable shrinkage in all three spacings, but was still preferable to air drying, which caused reduction in the order of the fibril packing, resulting in loss of the interfibrillar X-ray pattern. Perhaps the most drastic effect was caused by post-fixation in osmium tetroxide, which resulted in loss of the intermolecular pattern, and also increased the amount of shrinkage in the interfibrillar spacings and the D-periodicity which occurred during later stages of processing.


Using protein-fatty acid complexes to improve vitamin D stability.
Liprotides are complexes between lipids and partially denatured proteins in which the protein forms a stabilizing shell around a fatty acid micelle core. We have previously shown that liprotides stabilize small aliphatic molecules such as retinal and tocopherol by sequestering these molecules in the fatty acid core. This opens up the use of liprotides to formulate food additives. Here, we expand our investigations to the large and bulky molecule vitamin D3 (vitD), motivated by the population-wide occurrence of vitD deficiency. We prepared liprotides using different proteins and fatty acids and evaluated their ability to protect vitD upon exposure to heating or intense UV light. Additionally, we determined the stability of liprotides toward pH, Ca(2+), and BSA. The best results were obtained with liprotides made from α-lactalbumin and oleate. These liprotides were able to completely solubilize vitD, increase the stability toward UV light 9-fold, and increase the long-term stability at 37°C up to 1,000-fold. Native α-lactalbumin binds Ca(2+), making Ca(2+) potentially disruptive toward liprotides. However, liprotides prepared by incubation at 80°C were stable toward Ca(2+), in contrast to those made at 20°C. Nevertheless, the fatty acid binding protein BSA reduced the ability of both liprotides to protect vitD; the amount of vitD remianing after 20d at 20°C decreased from 79±3% in the absence of BSA to 49±4 and 23±3% in the presence of BSA for liprotides made at 80 and 20°C, respectively. Both classes of liprotides were able to release their vitD content, as demonstrated by the transfer of vitD encapsulated in liprotides to phospholipid vesicles. Importantly, liprotides were not stable at pH 6 and below, limiting the useful pH range of the liprotides to >pH 6. Our results indicate that vitD may be encapsulated and stabilized for enrichment of clear beverages at neutral pH to improve the intake and bioavailability of vitD.


Respiratory system mechanics in mice measured by end-inflation occlusion.
Characterization of pulmonary function parameters in mice will facilitate the dissection of genetic mechanisms underlying airway hyperresponsiveness. We evaluated acetylcholine (ACh)-induced respiratory system resistance (Rrs) and elastance (Ers) in A/J and C3H/HeJ mice and compared these results with the previously used airway pressure-time index (APTI). A low-dead-space ventilatory system was designed to ventilate anesthetized mice with constant inspiratory flow. The end-inflation occlusion method was used to measure Rrs and Ers at baseline and after intravenous ACh (12.5-75.0 micrograms/kg) challenge. ACh induced a dose-dependent rise in Rrs and Ers in A/J mice, whereas minimal changes were observed in C3H/HeJ mice. A/J mice had a higher baseline Rrs, yet the response to ACh was independent of baseline Rrs. Additionally, sequential ACh challenges led to augmented responses. Rrs, Ers, and APTI were strongly correlated, and each was useful to detect differences in interstrain cholinergic-induced airway responsiveness. The Rrs detected the smallest differences between the strains of mice studied.


Baseline C-Reactive Protein Levels and Life Prognosis in Parkinson Disease.
C-reactive protein (CRP) is a biomarker of inflammation, and high levels of CRP correlate with vascular death. Chronic inflammation is considered to be involved in neurodegeneration, although there is no evidence linking it with the process of neurodegenerative diseases. To determine the role of baseline CRP levels in the prognosis of patients with Parkinson disease (PD). A cohort of 313 patients with a mean age of 69.1 and mean PD duration of 7.9 years was retrospectively followed for a mean observation time of 1,753 days. CRP was measured when patients were not diagnosed with any infections, and levels were repetitively measured to investigate a tendency of "regression to mean." The primary outcome measure was a survival time from study enrollment to death. During the observation period 56 patients died. Baseline CRP was log-linearly associated with a risk of death in PD. Mean survival time was 3,149 (95% confidence interval; 3,009-3,289) days in patients with CRP ≤ 0.8mg/L (lower two thirds) and 2,620 (2,343-2,897) days in those with CRP > 0.8 mg/L (top third, p < 0.001, log-rank test). The adjusted hazard ratio (HR) per two-fold higher CRP concentration for all deaths was 1.29 (1.10-1.52), and after excluding PD-unrelated deaths, such as cancer or stroke, HR was 1.23 (1.01-1.49) (adjusted for age, sex, PD duration, modified Hohen-Yahr stages, MMSE scores, and serum albumin). Baseline CRP concentrations were associated with the risk of death and predicted life prognosis of patients with PD. The associations were independent from PD duration, PD severity, cognitive function, ages, and nutritional conditions, suggesting the possibility that subclinical chronic inflammation is associated with a neurodegenerative process in PD.


Wearable sensors and systems. From enabling technology to clinical applications.
It is now more than 50 years since the time when clinical monitoring of individuals in the home and community settings was first envisioned. Until recently, technologies to enable such vision were lacking. However, wearable sensors and systems developed over the past decade have provided the tools to finally implement and deploy technology with the capabilities required by researchers in the field of patients' home monitoring. As discussed, potential applications of these technologies include the early diagnosis of diseases such as congestive heart failure, the prevention of chronic conditions such as diabetes, improved clinical management of neurodegenerative conditions such as Parkinson's disease, and the ability to promptly respond to emergency situations such as seizures in patients with epilepsy and cardiac arrest in subjects undergoing cardiovascular monitoring. Current research efforts are now focused on the development of more complex systems for home monitoring of individuals with a variety of preclinical and clinical conditions. Recent research on the clinical assessment of wearable technology promises to deliver methodologies that are expected to lead to clinical adoption within the next five to ten years. In particular, combining home robots and wearable technology is likely to be a key step toward achieving the goal of effectively monitoring patients in the home. These efforts to merge home robots and wearable technology are expected to enable a new generation of complex systems with the ability to monitor subjects' status, facilitate the administration of interventions, and provide an invaluable tool to respond to emergency situations.


Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination.
The multikinase inhibitor sunitinib malate (SUT) has been reported to reduce levels of myeloid suppressor cells and Treg cells in cancer patients, hypothetically diminishing intrinsic impediments for active immunization against tumor-associated antigens in such individuals. The goal of this study was to identify longitudinal immune molecular and cellular changes associated with tumor regression and disease-free status after the treatment of established day 7 s.c. MO5 (B16.OVA) melanomas with SUT alone (1 mg/day via oral gavage for 7 days), vaccination using ovalbumin (OVA) peptide-pulsed dendritic cell [vaccine (VAC)] alone, or the combination of SUT and VAC (SUT/VAC). We observed superior anti-tumor efficacy for SUT/VAC combination approaches, particularly when SUT was applied at the time of the initial vaccination or the VAC boost. Treatment effectiveness was associated with the acute loss of (and/or failure to recruit) cells bearing myeloid-derived suppressor cells or Treg phenotypes within the tumor microenvironment (TME) and the corollary, prolonged enhancement of Type-1 anti-OVA CD8(+) T cell responses in the tumor-draining lymph node and the TME. Enhanced Type-1 T cell infiltration of tumors was associated with treatment-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and CXCR3 ligand chemokines in vascular/peri-vascular cells within the TME, with SUT/VAC therapy benefits conditionally negated upon adminsitration of CXCR3 or VCAM-1 blocking antibodies. These data support the ability of a short 7 day course of SUT to (re)condition the TME to become more receptive to the recruitment and prolonged therapeutic action of (VAC-induced) anti-tumor Tc1 cells.


Large outbreak of isoniazid-monoresistant tuberculosis in London, 1995 to 2006: case-control study and recommendations.
We conducted a case–control study to examine risk factors for isoniazid-monoresistant Mycobacterium tuberculosis in an ongoing outbreak in London. Cases were defined as individuals with an isoniazid-monoresistant strain diagnosed from 1995 to the third quarter of 2006 with an indistinguishable restriction fragment length polymorphism (RFLP) or mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeats (VNTR) pattern who were resident in or had epidemiological links with London. Controls were all other individuals reported with tuberculosis to the Health Protection Agency London regional epidemiology unit or the HPA London TB Register during 2000 to 2005. Of 293 cases, 153 (52%) were sputum smear-positive compared with 3,266 (18%) of controls. Cases were more likely to be young adults (aged between 15 and 34 years), born in the United Kingdom (OR: 2.4; 95% CI: 1.7–3.4) and of white (OR: 2.9; 95% CI: 1.8–4.8) or black Caribbean (OR: 12.5; 95% CI: 7.7–20.4) ethnicity, a prisoner at the time of diagnosis (OR: 20.2; 95% CI: 6.7–60.6), unemployed (OR: 4.1; 95% CI: 3.0–5.6), or a drug dealer or sex worker (OR: 187.1; 95% CI: 28.4–1,232.3). A total of 113 (39%) of cases used drugs and 54 (18%) were homeless. Completion of treatment gradually improved in cases from 55% among those diagnosed up to the end of 2002 compared with 65% by the end of 2006. Treatment completion increased from 79% to 83% in controls from 2000 to 2005. There are complex social challenges facing many cases in this outbreak that need to be addressed if medical interventions are to be successful.