A subgroup of pleural mesothelioma expresses ALK protein and may be targetable by combined rapamycin and crizotinib therapy.
Malignant pleural mesothelioma (MPM) is a neoplasm with inferior prognosis and notorious chemotherapeutic resistance. Targeting aberrantly overexpressed kinases to cure MPM is a promising therapeutic strategy. Here, we examined ALK, MET and mTOR as potential therapeutic targets and determined the combinatorial efficacy of ALK and mTOR targeting on tumor cell growth in vivo. First, ALK overexpression, rearrangement and mutation were studied in primary MPM by qRT-PCR, FISH, immunohistochemistry and sequence analysis; mTOR and MET expression by qRT-PCR and immunohistochemistry. Overexpression of full-length ALK transcripts was observed in 25 (19.5%) of 128 primary MPM, of which ten expressed ALK protein. ALK overexpression was not associated with gene rearrangement, amplification or kinase-domain mutation. mTOR protein was detected in 28.7% MPM, co-expressed with ALK or MET in 5% and 15% MPM, respectively. The ALK/MET inhibitor crizotinib enhanced the anti-tumor effect of the mTOR-inhibitor rapamycin in a patient-derived MPM xenograft with co-activated ALK/mTOR: combined therapy achieved tumor shrinkage in 4/5 tumors and growth stagnation in one tumor. Treatment effects on proliferation, apoptosis, autophagy and pathway signaling were assessed using Ki-67 immunohistochemistry, TUNEL assay, LC3B immunofluorescence, and immunoblotting. Co-treatment significantly suppressed cell proliferation and induced autophagy and caspase-independent, necrotic cell death. Rapamycin/crizotinib simultaneously inhibited mTORC1 (evidenced by S6 kinase and RPS6 dephosphorylation) and ALK signaling (ALK, AKT, STAT3 dephosphorylation), and crizotinib suppressed the adverse AKT activation induced by rapamycin. In conclusion, co-treatment with rapamycin and crizotinib is effective in suppressing MPM tumor growth and should be further explored as a therapeutic alternative in mesothelioma.


Interaction of Hydrophobic Tungsten Cluster Complexes with a Phospholipid Bilayer.
Nanoconstructions composed of lipid vesicles and inorganic units (nanoparticles, metal complexes) arouse much interest across materials science and nanotechnology as hybrid materials combining useful functionalities from both parts. Ideally, these units are to be embedded into the bilayer to keep the biophysical performance of lipid vesicles having inorganic moieties screened from the environment. This can be achieved by doping a lipid bilayer with cluster complexes of transition metals. In this work, we report the preparation of nanoparticles from trinuclear W3S4 cluster complexes and egg phosphatidylcholine. A systematic study of their properties was performed by the differential scanning calorimetry, NMR spectroscopy, dynamic light scattering, and transmission electron microscopy. Phospholipids and clusters have been found to spontaneously self-assemble into novel cluster-lipid hybrid materials. The behavior of clusters in the hydrophobic lipid environment is determined by the structure of the ligands and cluster-to-lipid ratio. Intact cluster complexes bearing compact hydrophobic ligands are embedded into the hydrophobic midplane of a lipid bilayer, whereas cluster complexes bearing larger ligands drive the aggregation of lipids and cluster complexes. Considering these differences, it could be possible to obtain different self-assembled associates such as cluster-doped liposomes or lipid-covered crystals. These cluster-lipid hybrids can be a platform for the design of new materials for nanotechnology.


Early kinematic outcome after treatment of cranial cruciate ligament rupture by tibial plateau levelling osteotomy in the dog.
To establish the effect of tibial plateau levelling osteotomy (TPLO) on two selected pelvic limb kinematic variables in dogs treated for clinical cranial cruciate ligament rupture (CCLR). Thirteen dogs that had incurred CCLR and were treated by TPLO walked on a treadmill whilst kinematic data on pelvic limb paw motion were acquired using motion capture equipment. Data were subject to secondary processing using matrix analysis software and statistical analysis. Pelvic limb stance duration significantly increased during the 12 week study period, recovering to near-normal values. Range of pelvic limb paw velocity also significantly increased but did not reach normal values by 12 weeks postoperatively. The improvement in stance duration to near normality may aid in explaining the widely-held subjective impression that TPLO frequently provides an excellent outcome in the early stages after repair of the cruciate deficient canine stifle joint. Both stance length and range of paw velocity provide useful objective measures to compare outcome following surgery for CCLR.


The dynamic of asymptomatic Plasmodium falciparum infections following mass drug administrations with dihydroarteminisin-piperaquine plus a single low dose of primaquine in Savannakhet Province, Laos.
The increase in multidrug resistant Plasmodium falciparum infections threatens the malaria elimination goals in countries within the Greater Mekong Sub-region. A multi-pronged approach assuring access to basic malaria control measures, including insecticide-treated bed nets and early diagnosis and treatment was followed by mass drug administrations (MDA) in southern Savannakhet Province, Laos. The main objective of this study was to evaluate the effectiveness and safety of mass drug administrations as well as their effects on the dynamic of asymptomatic P. falciparum infections in 4 malaria endemic villages. Two villages were randomized to early MDA consisting of 3 rounds of a 3-day course of dihydroartemisinin-piperaquine with a single low dose of primaquine. In the other 2 villages MDA was deferred by 1 year. A total of 1036 residents were enrolled in early MDA villages and 883 in control villages (deferred-MDA). Tri-monthly parasitaemia surveys using uPCR were conducted for a year in the 4 villages. Eighty-four percent (872/1036) of the residents participated in the MDAs, of whom 90% (781/872) completed 3 rounds of MDA (9 doses). In intervention villages, the prevalence of asymptomatic P. falciparum infections decreased by 85% after MDA from 4.8% (95% CI 3.4-6.4) at baseline (month 0 or M0) to 0.7% (95% CI 0.3-1.6) at month 12. In control villages there was a decrease of 33% in P. falciparum prevalence between M0: 17.5% (95% CI 15.9-20.3) and M12: 11.6% (95% CI 9.3-14.2). In bivariate and multivariate analyses P. falciparum infections were significantly reduced with early MDA (adjusted incidence rate ratios (AIRR): 0.08, CI 0.01-0.091) and completion of 3 MDA rounds (AIRR: 0.06; CI 0.01-0.66). A quarter of participants (226/872) reported adverse events of which 99% were mild. The study found a significant reduction in P. falciparum prevalence and incidence following MDA. MDA was safe, well tolerated, feasible, and achieved high population coverage and adherence. MDAs must be integrated in multi-pronged approaches such as vector control and preventive measures with a focus on specific risk groups such as mobile, migrant population and forest goers for a sustained period to eliminate the remaining parasite reservoirs. Trial registration ClinicalTrials.gov Identifier: NCT01872702.


A search for O-polypeptidyl-ribonucleic acids in rabbit-reticulocyte ribosomes by electrophoresis in phenol-acetic acid-water systems.
1. When solutions of ;soluble' or transfer RNA (s-RNA) and of cytochrome c in phenol-acetic acid-water were mixed, intractable coacervates were formed. The addition to the solutions of various strong electrolytes prevented coacervation and allowed electrophoretic separation on filter paper. Protein migrates cationically, leaving RNA at or near the origin. The separation is aided by adsorption of RNA to the paper. Special arrangements were necessary to prevent contamination of the paper by ultraviolet-absorbing electrode-reaction products. 2. Binding of alkali-metal cations to RNA and some other associations were observed in such solvent systems. Possible effects of ionic association on mobilities are discussed. 3. Rabbit-reticulocyte ribosomes were subjected to electrophoresis as above, after their nascent-protein moiety had been labelled with [(14)C]valine in the intact cell. Most of the radioactivity migrated with the ribosomal protein; such protein as remained near the origin with the RNA had valine of lower specific radioactivity. 4. Molecular-sieve chromatography in phenol-acetic acid-water indicated that the nascent-protein moiety was not of markedly lower molecular weight than the average for the ribosomal proteins. 5. These results are very tentatively taken to mean that the nascent-protein moiety of ribosomes so prepared is not O-polypeptidyl-s-RNA. It is postulated that, in the course of adding each amino acid residue, the growing polypeptide chain is transferred from ester linkage with s-RNA to linkage with ribosomal protein through its carboxyl group, perhaps by ester linkage to an alcoholic group. The two types of intermediate, O-polypeptidyl-s-RNA and polypeptidyl-protein, would be found in different proportions, depending on the isolation procedure used. Some implications and possible tests of this hypothesis are discussed.


Effect of bodily fluids from honey bee (Apis mellifera) larvae on growth and genome-wide transcriptional response of the causal agent of American Foulbrood disease (Paenibacillus larvae).
Paenibacillus larvae, the causal agent of American Foulbrood disease (AFB), affects honey bee health worldwide. The present study investigates the effect of bodily fluids from honey bee larvae on growth velocity and transcription for this Gram-positive, endospore-forming bacterium. It was observed that larval fluids accelerate the growth and lead to higher bacterial densities during stationary phase. The genome-wide transcriptional response of in vitro cultures of P. larvae to larval fluids was studied by microarray technology. Early responses of P. larvae to larval fluids are characterized by a general down-regulation of oligopeptide and sugar transporter genes, as well as by amino acid and carbohydrate metabolic genes, among others. Late responses are dominated by general down-regulation of sporulation genes and up-regulation of phage-related genes. A theoretical mechanism of carbon catabolite repression is discussed.


Laser speckle interferometry for plate bending problems.
A method is proposed whereby the spatial speckles created in front of a plate with an optically rough surface when illuminated by a coherent laser beam is used to generate slope contour fringes. This is done by photographing the speckles contained in a parallel plane in front of the plate before and after deformation via double exposure. The resulting speckle interferogram is then optically Fourier transformed to yield the fringe pattern of slope contours. It is shown that the method is analogous to the Ligtenberg reflection moiré method with a grating of continuously variable pitch and orientation. The method can be applied to plates made of almost any material.


Do mindfulness-based programmes improve the cognitive skills, behaviour and mental health of children and adolescents? An updated meta-analysis of randomised controlled trials.
Mindfulness-based programmes (MBPs) are an increasingly popular approach to improving mental health in young people. Our previous meta-analysis suggested that MBPs show promising effectiveness, but highlighted a lack of high-quality, adequately powered randomised controlled trials (RCTs). This updated meta-analysis assesses the-state-of the-art of MBPs for young people in light of new studies. It explores MBP's effectiveness in active vs passive controls; selective versus universal interventions; and studies that included follow-up. We searched for published and unpublished RCTs of MBPs with young people (<19 years) in PubMed Central, PsycINFO, Web of Science, EMBASE, ICTRP, ClinicalTrials.gov, EThOS, EBSCO and Google Scholar. Random-effects meta-analyses were conducted, and standardised mean differences (Cohen's d) were calculated. Sixty-six RCTs, involving 20 138 participants (9552 receiving an MBP and 10 586 controls), were identified. Compared with passive controls, MBPs were effective in improving anxiety/stress, attention, executive functioning, and negative and social behaviour (d from 0.12 to 0.35). Compared against active controls, MBPs were more effective in reducing anxiety/stress and improving mindfulness (d=0.11 and 0.24, respectively). In studies with a follow-up, there were no significant positive effects of MBPs. No consistent pattern favoured MBPs as a universal versus selective intervention. The enthusiasm for MBPs in youth has arguably run ahead of the evidence. While MBPs show promising results for some outcomes, in general, the evidence is of low quality and inconclusive. We discuss a conceptual model and the theory-driven innovation required to realise the potential of MBPs in supporting youth mental health.


Use of medical care biases associations between Parkinson disease and other medical conditions.
To examine how use of medical care biases the well-established associations between Parkinson disease (PD) and smoking, smoking-related cancers, and selected positively associated comorbidities. We conducted a population-based, case-control study of 89,790 incident PD cases and 118,095 randomly selected controls, all Medicare beneficiaries aged 66 to 90 years. We ascertained PD and other medical conditions using ICD-9-CM codes from comprehensive claims data for the 5 years before PD diagnosis/reference. We used logistic regression to estimate age-, sex-, and race-adjusted odds ratios (ORs) between PD and each other medical condition of interest. We then examined the effect of also adjusting for selected geographic- or individual-level indicators of use of care. Models without adjustment for use of care and those that adjusted for geographic-level indicators produced similar ORs. However, adjustment for individual-level indicators consistently decreased ORs: Relative to ORs without adjustment for use of care, all ORs were between 8% and 58% lower, depending on the medical condition and the individual-level indicator of use of care added to the model. ORs decreased regardless of whether the established association is known to be positive or inverse. Most notably, smoking and smoking-related cancers were positively associated with PD without adjustment for use of care, but appropriately became inversely associated with PD with adjustment for use of care. Use of care should be considered when evaluating associations between PD and other medical conditions to ensure that positive associations are not attributable to bias and that inverse associations are not masked.


Effects of somatostatin and related peptides on the membrane potential and input resistance of rat ventral subicular neurons, in vitro.
The effects of bath-applied somatostatin (SS), and related peptides on the membrane potential and input resistance of 117 ventral subicular neurons were investigated by intracellular recording in rat brain slices. Electrophysiological properties, which included burst-firing in response to depolarizing current pulses, indicated that the neurons studied were of the pyramidal type. For the 89 cells analyzed quantitatively, membrane potential was -69.1 +/- 0.3 mV (mean +/- S.E.) and input resistance was 23.9 +/- 0.5 megohms. SS (5 microM) caused a hyperpolarization of 3.4 +/- 0.3 mV (n = 9) and reduced input resistance by 16 +/- 3.1% (n = 6). SS D-Trp8, somatostatin, octreotide, CGP 23996 and MK 678 shared these effects, but somatostatin was inactive. SS effects persisted when bathing solutions contained tetrodotoxin, reduced calcium and elevated magnesium concentrations and when both of these treatments were combined. They were unaltered by antagonists at gamma-aminobutyric acid receptors or at ionotropic glutamate receptors. The effects of MK 678, SS, SS D-Trp8 and somatostatin were concentration-dependent, and these peptides were equipotent at 500 nM and at 5 microM. For MK 678, the EC50 was 316 nM for the hyperpolarization and 90 nM for the reduction in input resistance. We conclude that SS acts directly on pyramidal neurons of the rat subiculum to cause a hyperpolarization and a decrease in input resistance. We suggest that these effects are mediated by the SSTR2 receptor subtype.


An analysis of sagittal spinal alignment in 100 asymptomatic middle and older aged volunteers.
A radiographic evaluation of 100 adult volunteers over age 40 and without a history of significant spinal abnormality was done to determine indices of sagittal spinal alignment. To determine the sagittal contours of the spine in a population of adults older than previously reported in the literature and to correlate age and overall sagittal balance to other measures of segmental spinal alignment. Previous studies of sagittal alignment have focused on adolescent and young adult populations before the onset of degenerative changes that may affect sagittal alignment. Radiographic measurements were collected and subjected to statistical analysis. Mean sagittal vertical axis fell 3.2 +/- 3.2 cm behind the front of the sacrum. Total lumbar lordosis (T12-S1) averaged -64 degrees +/- 10 degrees. Lordosis increased incrementally with distal progression through the lumbar spine. Lordosis at L5-S1 and the position of the apices of the thoracic and lumbar curves were most closely correlated to sagittal vertical axis. Increasing age correlated to a more forward sagittal vertical axis with loss of distal lumbar lordosis but without an increase in thoracic or thoracolumbar kyphosis. The majority of asymptomatic individuals are able to maintain their sagittal alignment despite advancing age. Loss of distal lumbar lordosis is most responsible for sagittal imbalance in those individuals who do not maintain sagittal alignment. Spinal fusion for deformity should take into account the anticipated loss of lordosis that may occur with age.


MSCV-based retroviral plasmids expressing 3xFLAG-Sp-dCas9 for enChIP analysis.
Engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) is a technology for purifying specific genomic regions to facilitate identification of their associated molecules, including proteins, RNAs, and other genomic regions. In enChIP, the target genomic region is tagged with engineered DNA-binding molecules, for example, a variant of the clustered regularly interspaced short palindromic repeats (CRISPR) system consisting of a guide RNA (gRNA) and a catalytically inactive form of Cas9 (dCas9). In this study, to increase the flexibility of enChIP and expand the range of target cells, we generated murine stem cell virus (MSCV)-based retroviral plasmids for expressing dCas9. We constructed MSCV-based retroviral plasmids expressing Streptococcus pyogenes dCas9 fused to a 3xFLAG-tag (3xFLAG-Sp-dCas9) and various drug resistance genes. We showed that by using these plasmids, it is feasible to purify target genomic regions with yields comparable to those reported using other systems. These systems might give enChIP users greater flexibility in choosing optimal systems for drug selection of transduced cells.


Does mechanism of injury predict trauma center need?
To determine the predictive value of the mechanism-of-injury step of the American College of Surgeons Field Triage Decision Scheme for determining trauma center need. Emergency medical services (EMS) providers caring for injured adult patients transported to the regional trauma center in three midsized communities over two years were interviewed upon emergency department (ED) arrival. Included was any injured patient, regardless of injury severity. The interview collected patient physiologic condition, apparent anatomic injury, and mechanism of injury. Using the 1999 Scheme, patients who met the physiologic or anatomic steps were excluded. Patients were considered to need a trauma center if they had nonorthopedic surgery within 24 hours, had intensive care unit admission, or died prior to hospital discharge. Data were analyzed by calculating positive likelihood ratios (+LRs) and 95% confidence intervals (CIs) for each mechanism-of-injury criterion. A total of 11,892 provider interviews were conducted. Of those, one was excluded because outcome data were not available, and 2,408 were excluded because they met the other steps of the Field Triage Decision Scheme. Of the remaining 9,483 cases, 2,363 met one of the mechanism-of-injury criteria, 204 (9%) of whom needed the resources of a trauma center. Criteria with a +LR ≥ 5 were death of another occupant in the same vehicle (6.8; CI: 2.7-16.7), fall >20 feet (5.3; CI: 2.4-11.4), and motor vehicle crash (MVC) extrication time >20 minutes (5.1; CI: 3.2-8.1). Criteria with a +LR between >2 and <5 were intrusion >12 inches (4.2; CI: 2.9-5.9), ejection (3.2; CI: 1.3-8.2), and deformity >20 inches (2.5; CI: 1.9-3.2). The criteria with a +LR ≤ 2 were MVC speed >40 mph (2.0; CI: 1.7-2.4), pedestrian/bicyclist struck at a speed >5 mph (1.2; CI:1.1-1.4), bicyclist/pedestrian thrown or run over (1.2; CI: 0.9-1.6), motorcycle crash at a speed >20 mph (1.2; CI: 1.1-1.4), rider separated from motorcycle (1.0; CI: 0.9-1.2), and MVC rollover (1.0; CI: 0.7-1.5). Death of another occupant, fall distance, and extrication time were good predictors of trauma center need when a patient did not meet the anatomic or physiologic conditions. Intrusion, ejection, and vehicle deformity were moderate predictors. Key words: wounds and injury; triage; emergency medical services; emergency medical technicians; predictors; mechanism of injury; trauma center.


Magic-angle phosphorus NMR of functional mitochondria: in situ monitoring of lipid response under apoptotic-like stress.
Using a noninvasive, solid-state magic-angle spinning nuclear magnetic resonance (MAS NMR) approach, we track ex vivo the behavior of individual membrane components in isolated, active mitochondria (model system: potato tubers) during physiological processes. The individual phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) membrane constituents were identified as distinct lines by applying MAS (31)P NMR on extracted lipid membranes. However, the CL NMR signal appeared to be very broad in functional mitochondria, indicating a tight complex formation with membrane protein. Calcium stress induced severe membrane degradation without recovery of a single CL NMR resonance. This suggests that calcium overload destroys the outer mitochondrial membrane and does not modify strongly the CL protein complexes in the inner membrane; a conclusion confirmed by respiratory controls. Conversely, mitochondrial membrane disruption on time degradation or mechanical stress generates clearly visible identical CL NMR signals, similar to those observed in rehydrated lipid extracts. Similarly, noninvasive based NMR tracking of lipids in response to diverse physiological stimuli can easily be used for other organelles and whole living cells.


The Influence of Torque Tightening on the Position Stability of the Abutment in Conical Implant-Abutment Connections.
The influence of repeated system-specific torque tightening on the position stability of the abutment after de- and reassembly of the implant components was evaluated in six dental implant systems with a conical implant-abutment connection. An established experimental setup was used in this study. Rotation, vertical displacement, and canting moments of the abutment were observed; they depended on the implant system (P = .001, P < .001, P = .006, respectively). Repeated torque tightening of the abutment screw does not eliminate changes in position of the abutment.


Long-term outcome of hepatitis B virus-related Chronic Hepatitis under protracted nucleos(t)ide analogues.
Long-term outcome of patients with chronic hepatitis B virus (HBV) infection under continuous nucleos(t)ide analogues (NUCs) has been poorly elucidated. We enrolled 121 anti-HBe-positive patients into a prospective surveillance programme while on (>36 months) NUCs therapy. HBV-DNA clearance, add-on therapy and safety were evaluated. Development of cirrhosis, events of liver decompensation and hepatocellular carcinoma (HCC) during the follow-up were the main endpoints, as the complication-free survival. At baseline, 74 patients (61%) had chronic hepatitis, the remainders a cirrhotic liver. HBV-DNA levels >38 000 IU/mL were discovered in 103 patients. At enrolment, 79 patients were naïve to NUCs treatment. Lamivudine monotherapy (n = 70) or a different NUC (n = 51) was administered. At month 6 of therapy, HBV-DNA clearance was documented in 88 patients (73%). Treatment schedule was modified in 52 patients due to breakthrough or suboptimal response. During a mean follow-up of 6 ± 3 years, viral clearance was achieved in the majority of patients. Ten of 74 patients (13.5%) with chronic hepatitis progressed to cirrhosis, 1 patient developed a HCC. In the 47 patients with cirrhosis at presentation, HCC occurred in 14 (30%) and liver decompensation in 5 (11%). The 5 and 10-year event-free survivals were, respectively, 89.3% (95% CI, 81.7 -96.9) and 75.6% (95% CI, 61.5 -89.7) for patients with chronic hepatitis, and 70.2% (95% CI, 56.3 -84.1) and 40.4% (95% CI, 16.9 -63.9) for those with cirrhosis. Protracted, effective treatment with oral NUCs affects the natural history of chronic HBV infection by reducing the incidence of cirrhosis and risk of complications, but does not guarantee against the development of HCC in cirrhosis at presentation.


India Biodiversity Portal: An integrated, interactive and participatory biodiversity informatics platform.
This paper describes a growing biodiversity platform, launched in 2008, which organizes knowledge on the biodiversity of India. The main objective and originality of the India Biodiversity Portal (IBP) is to aggregate curated biodiversity data of different kinds (e.g. distribution maps, temporal distribution or life history) in an integrated platform where amateurs and experts can easily interact. Since its launch, the platform has seen an exceptional increase in both user activity and biodiversity data. Currently the portal has descriptions of over 20,400 species, and has aggregated approximately 1,280,000 observations covering more than 30,000 species, which already constitutes a unique source of information for scientists and stakeholders in conservation. Over 8500 users have registered on the portal. The amount of data generated and to be generated in the next few years by this portal will certainly help the effective implementation of biodiversity conservation and management in one of the most ecologically diverse countries in the world.


Comparative metabolism of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by cultured F344 rat oral tissue and esophagus.
The metabolism and DNA binding of N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cultured F344 rat oral tissue and esophagus were investigated over a range of concentrations. The metabolites present in the culture media were separated by high performance liquid chromatography and were identified by comparison to standards. alpha-Hydroxylation of NNN, an esophageal carcinogen, was the major pathway for metabolism of this nitrosamine in both tissues. The metabolites formed from 2'-hydroxylation were between 3.0 and 3.9 times those formed from 5'-hydroxylation. 2'-Hydroxylation results in a pyridyloxobutylating species. DNA from esophagus cultured with [5-3H]NNN contained a pyridyloxobutylated adduct which upon acid hydrolysis released 3.8 pmol [5-3H]-4-hydroxy-1-(3-pyridyl)-1-butanone/mumol guanine. DNA from oral tissue cultured under the same conditions, where the extent of metabolism was the same, contained no measurable [5-3H]NNN DNA adduct. This suggests that factors, as yet unknown, cause the DNA of oral cavity tissue to be protected from pyridyloxobutylation by NNN. The metabolism of NNK by alpha-hydroxylation was as much as 10-fold less than the metabolism of NNN by this pathway in both tissues. alpha-Hydroxylation of NNK results in either a methylating species or a pyridyloxobutylating species. DNA from oral tissue cultured with [C3H3]NNK contained between 1.7 and 4.3 pmol 7-methylguanine/mumol guanine, respectively. No pyridyloxobutylated DNA (less than 0.2 pmol/mumol guanine) was detected in oral tissue incubated with [5-3H]NNK. The DNA from esophagi incubated with [C3H3]NNK contained no 7-methylguanine (less than 0.4 pmol/mumol guanine). The level of pyridyloxobutylation of DNA from esophagi incubated with [5-3H]NNK was 0.17 pmol/mumol guanine. The ability of the esophagus to metabolize NNN to a greater extent than NNK to a reactive species which pyridyloxobutylates DNA may be important in determining the carcinogenicity of NNN in the esophagus. In contrast, the metabolism of NNK to a methylating species by oral cavity tissue suggests that this tobacco-specific nitrosamine is important in tobacco-related oral cavity carcinogenesis.


Digital image analysis of growth and starvation responses of a surface-colonizing Acinetobacter sp.
Surface growth of an Acinetobacter sp. cultivated under several nutrient regimens was examined by using continuous-flow slide culture, phase-contrast microscopy, scanning confocal laser microscopy, and computer image analysis. Irrigation of attached coccoid stationary-phase Acinetobacter sp. cells with high-nutrient medium resulted in a transition from coccoid to bacillar morphology. Digital image analysis revealed that this transition was biphasic. During phase I, both the length and the width of cells increased. In contrast, cell width remained constant during phase II, while both cell length and cell area increased at a rate greater than in phase I. Cells were capable of growth and division without morphological transition when irrigated with a low-nutrient medium. Rod-shaped cells reverted to cocci by reduction-division when irrigated with starvation medium. This resulted in conservation of cell area (biomass) with an increase in cell number. In addition, the changes in cell morphology were accompanied by changes in the stability of cell attachment. During phase I, coccoid cells remained firmly attached. Following transition in high-nutrient medium, bacillar cells displayed detachment, transient attachment, and drifting behaviors, resulting in a spreading colonization pattern. In contrast, cells irrigated with a low-nutrient medium remained firmly attached to the surface and eventually formed tightly packed microcolonies. It is hypothesized that the coccoid and bacillar Acinetobacter sp. morphotypes and associated behavior represent specialized physiological adaptations for attachment and colonization in low-nutrient systems (coccoid morphotype) or dispersion under high-nutrient conditions (bacillar morphotype).


Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition.
Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992-2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00-1.26), with no detected heterogeneity across countries (phomogeneity = 0.42). This risk increased linearly with duration of use (ptrend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97-1.43), which was heterogeneous across countries (phomogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.


Semi-Supervised Multi-Organ Segmentation through Quality Assurance Supervision.
Human in-the-loop quality assurance (QA) is typically performed after medical image segmentation to ensure that the systems are performing as intended, as well as identifying and excluding outliers. By performing QA on large-scale, previously unlabeled testing data, categorical QA scores (e.g. "successful" versus "unsuccessful") can be generated. Unfortunately, the precious use of resources for human in-the-loop QA scores are not typically reused in medical image machine learning, especially to train a deep neural network for image segmentation. Herein, we perform a pilot study to investigate if the QA labels can be used as supplementary supervision to augment the training process in a semi-supervised fashion. In this paper, we propose a semi-supervised multi-organ segmentation deep neural network consisting of a traditional segmentation model generator and a QA involved discriminator. An existing 3-D abdominal segmentation network is employed, while the pre-trained ResNet-18 network is used as discriminator. A large-scale dataset of 2027 volumes are used to train the generator, whose 2-D montage images and segmentation mask with QA scores are used to train the discriminator. To generate the QA scores, the 2-D montage images were reviewed manually and coded 0 (success), 1 (errors consistent with published performance), and 2 (gross failure). Then, the ResNet-18 network was trained with 1623 montage images in equal distribution of all three code labels and achieved an accuracy 94% for classification predictions with 404 montage images withheld for the test cohort. To assess the performance of using the QA supervision, the discriminator was used as a loss function in a multi-organ segmentation pipeline. The inclusion of QA-loss function boosted performance on the unlabeled test dataset from 714 patients to 951 patients over the baseline model. Additionally, the number of failures decreased from 606 (29.90%) to 402 (19.83%). The contributions of the proposed method are three-fold: We show that (1) the QA scores can be used as a loss function to perform semi-supervised learning for unlabeled data, (2) the well trained discriminator is learnt by QA score rather than traditional "true/false", and (3) the performance of multi-organ segmentation on unlabeled datasets can be fine-tuned with more robust and higher accuracy than the original baseline method. The use of QA-inspired loss functions represents a promising area of future research and may permit tighter integration of supervised and semi-supervised learning.


Vitamin K intake and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial.
Vitamin K inhibits prostate cancer cells, and an altered expression of vitamin K-dependent proteins in prostate tumors has been linked to their aggressiveness and progression. However, little is known about the effect of vitamin K intake on prostate cancer in human populations. We evaluated the associations of dietary intake of phylloquinone (vitamin K-1), menaquinones (vitamin K-2), and total vitamin K with the development of prostate cancer among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. Dietary intake of vitamin K was assessed with the Dietary Questionnaire (DQX) at baseline and the Dietary History Questionnaire (DHQ) at the third anniversary of randomization by using high-performance liquid chromatography-based food-composition data obtained from the USDA and published studies. During a median follow-up of 11.8 y, 2978 cases of prostate cancer (including 490 advanced cases) were identified from the 28,356 men who completed DQX. Similarly, 2973 cases of prostate cancer (including 647 advanced cases) were documented from the 48,090 men who completed DHQ. Cox proportional hazards regression was used to estimate prostate cancer risk in relation to the dietary intake of vitamin K. After adjustment for confounders, dietary intakes of phylloquinone, menaquinones, and total vitamin K, assessed with either the DQX or DHQ, were not significantly associated with the risk of advanced, nonadvanced, and total prostate cancer. These results remained virtually the same when vitamin K intake was modeled as a categorical (divided into quintiles) or continuous (per IQR increase) variable or after outliers of total vitamin K intake (defined as a value that falls above the sum of third quartile and twice the IQR) were excluded. The present study does not suggest that vitamin K intake influences the occurrence of total and advanced prostate cancer in the general US population.


Physical inaccessibility negatively impacts the treatment participation of persons with disabilities.
This research assessed the impact that physical inaccessibility of provider locations has on the substance abuse treatment participation of two groups of persons with disabilities. A random sample of treatment providers in the Mid-Atlantic region were surveyed and asked if they had declined services to persons with spinal cord (SCI) or traumatic brain (TBI) injuries due to the inaccessibility of their practices. Over half of those who had been approached by persons with SCI and nearly half of those approached by persons with TBI were unable to provide services due to physical barriers. The inability to serve such individuals was not related to practice affiliation (public or private) or practice type (hospital based, non-medical residential, or outpatient). These findings support earlier research indicating the treatment participation of persons with disabilities is negatively affected by physical accessibility concerns.


Lead toxicosis of captive vultures: case description and responses to chelation therapy.
Lead, a serious threat for raptors, can hamper the success of their conservation. This study reports on experience with accidental lead intoxication and responses to chelation therapy in captive Cinereous (Aegypius monachus) and Egyptian (Neophron percnopterus) Vultures. Soil contamination by lead-based paint sanded off the steel aviary resulted in poisoning of eight Cinereous and two Egyptian Vultures. A male Egyptian Vulture developed signs of apathy, polydipsia, polyuria, regurgitation, and stupor, and died on the next day. Liver, kidney and blood lead concentrations were 12.2, 8.16 and 2.66 μg/g, respectively. Laboratory analyses confirmed severe liver and kidney damage and anaemia. Blood Pb levels of Pb-exposed Cinereous Vultures were 1.571 ± 0.510 μg/g shortly after intoxication, decreased to 0.530 ± 0.165 μg/g without any therapy in a month and to 0.254 ± 0.097 μg/g one month after CaNa(2)EDTA administration. Eight months later, blood lead levels decreased to close to the background of the control group. Blood parameters of healthy Pb-non-exposed Cinereous Vultures were compared with those of the exposed group prior to and after chelation therapy. Iron levels in the lead-exposed pre-treatment birds significantly decreased after chelation. Haematocrit levels in Pb-exposed birds were significantly lower than those of the controls and improved one month after chelation. Creatine kinase was higher in pre-treatment birds than in the controls but normalised after therapy. Alkaline phosphatase increased after chelation. A marked increase in the level of lipid peroxidation measured as thiobarbituric acid reactive species was demonstrated in birds both prior to and after chelation. The ferric reducing antioxidant power was significantly lower in pre-treatment vultures and returned to normal following chelation therapy. Blood metallothionein levels in lead-exposed birds were higher than in controls. Reduced glutathione dropped after CaNa(2)EDTA therapy, while oxidised glutathione was significantly lower in both pre- and post-treatment birds. A chick in an egg produced by a Cinereous Vulture female two months after lead toxicosis died on day 40 of artificial incubation. Lead concentrations in foetal tissues were consistent with levels causing avian mortality. The reported blood parameters and reproduction impairment in captive birds may have implications for professionals dealing with lead exposure in wild birds.


Comparative in vitro and in vivo activities of piperacillin combined with the beta-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam.
Tazobactam (YTR-830H), a novel beta-lactamase inhibitor, was compared with clavulanic acid and sulbactam for enhancement of the activity of piperacillin against beta-lactamase-producing, piperacillin-resistant clinical isolates. Piperacillin MICs were determined in media containing a fixed concentration of 2 or 4 micrograms of the inhibitors per ml. The higher concentration was generally more effective. Tazobactam was superior to sulbactam in enhancing the spectrum and potency of piperacillin. Although the calvulanic acid combination was more potent, tazobactam was effective for a similar spectrum of resistant gram-negative clinical isolates containing beta-lactamase. MICs were reduced to the susceptible range for Escherichia coli, Klebsiella pneumoniae, Proteus spp., Salmonella spp., and Shigella spp. Combinations with tazobactam and sulbactam, but not clavulanic acid, were effective against Morganella spp. Some antagonism of the activity of piperacillin was observed with clavulanic acid but not with tazobactam or sulbactam. The inhibitors were similarly effective with piperacillin against beta-lactamase-positive Staphylococcus spp. and the Bacteroides fragilis group. Piperacillin-tazobactam was more effective against a broader spectrum of gram-negative enteric bacteria than ticarcillin plus clavulanic acid was. Combinations with tazobactam or clavulanic acid had a broader spectrum of activity than combinations with sulbactam against bacteria that produce characterized plasmid-mediated enzymes of clinical significance. In particular, piperacillin with tazobactam or clavulanic acid, but not with sulbactam, inhibited TEM-1, TEM-2, and SHV-1 enzymes. In vitro activity was reflected in vivo. Tazobactam and clavulanic acid were superior to sulbactam in enhancing the therapeutic efficacy of piperacillin in mice infected with beta-lactamase-positive E. coli, K. pneumoniae, Proteus mirabilis, and Staphylococcus aureus. Only combinations with tazobactam and sulbactam were effective against the Morganella infection. Tazobactam has a good potential for enhancing the clinical efficacy of piperacillin.


A Review of State Licensing Regulations to Determine Alignment with Best Practices to Prevent Human Norovirus Infections in Child-Care Centers.
Close, frequent contact between children and care providers in child-care centers presents many opportunities to spread human noroviruses. We compared state licensing regulations for child-care centers with national guidelines written to prevent human noroviruses. We reviewed child-care licensing regulations for all 50 U.S. states and the District of Columbia in effect in June 2015 to determine if these regulations fully, partially, or did not address 14 prevention practices in four topic areas: (1) hand hygiene, (2) exclusion of ill people, (3) environmental sanitation, and (4) diapering. Approximately two-thirds (8.9) of the 14 practices across all state regulations were partially or fully addressed, with few (2.6) fully addressed. Practices related to exclusion of ill people and diapering were fully addressed most often, while practices related to hand hygiene and environmental sanitation were fully addressed least often. Regulations based on guidelines for best practices are one way to prevent the spread of human noroviruses in child-care facilities, if the regulations are enforced. Our findings show that, in mid-2015, many state child-care regulations did not fully address these guidelines, suggesting the need to review these regulations to be sure they are based on best practices.


Nonculture methods for diagnosis of disseminated candidiasis.
Two of the nonculture approaches to the diagnosis of DC, enzymatic-fluorometric determination of serum D-arabinitol and detection of marker antigens in antigenemia (enolase and CWMP), have been commercialized and have shown promise in limited clinical trials. These approaches are not new but are the culmination of efforts made over 10 or more years. Clearly, further fine-tuning of both metabolite and antigen detection is needed to simplify the methods and to improve their sensitivity and specificity so that they will be valuable in guiding clinical treatment decisions. An alternative approach, detection of DC by DNA amplification methods such as PCR, is a special case of a compelling technology and one that is capable of standardization across microbial genera. The availability of simplified PCR diagnostic methods for DC remains a tantalizing prospect. Nevertheless, the development of methods to release DNA from very small numbers of Candida organisms in the blood in a form that is sufficiently free of inhibitors of PCR will require further intensive effort. The maturation of these converging laboratory approaches to nonculture diagnosis of DC leads to more optimism about the eventual use of these methods in clinical laboratories.


Expressed emotion as a predictor of outcome among bipolar patients undergoing family therapy.
Levels of expressed emotion (EE) in relatives are consistent predictors of relapse among bipolar and other mood disordered patients followed naturalistically. However, few studies have examined whether levels of EE predict the course of illness for patients engaged in psychosocial interventions. This study examined whether EE levels among caregivers moderated the success of family-based psychosocial interventions for patients with bipolar disorder. EE was examined as a predictor of symptomatic outcome in two groups: (1) bipolar patients receiving family-focused psychoeducational treatment (FFT) or integrated family and individual treatment (IFIT), and (2) bipolar patients receiving crisis management (CM), a less intensive intervention designed to emulate community care. Bipolar patients (N = 125) began the study in an acute illness episode, were stabilized on standard pharmacotherapy regimens, and followed for up to 2 years. Family EE status was not associated with time to relapse in either group. However, patients with high EE relatives reported higher levels of depression over the 2-year term of follow-up, regardless of treatment condition. An examination of the dimensions of EE (critical comments and emotional overinvolvement) indicated that a higher frequency of critical comments predicted higher levels of mania and depression at follow-up. Additionally, the association between EE criticism and levels of mania symptoms was stronger among patients in CM than among patients in family treatment. The participants were recruited from two separate treatment protocols. Patients in the IFIT protocol were not randomly assigned to treatments. EE is a predictor of symptom severity among bipolar patients undergoing pharmacological and psychosocial treatments, but family intervention may mitigate this association.


The effects of muscle fatigue on bone strain.
There is anecdotal evidence that bone strains may increase to the point that bone becomes susceptible to rapid failure when muscles become fatigued. To determine whether neuromuscular response could be a factor in accelerating bone failure, we tested the hypothesis that muscle fatigue causes a significant increase in peak principal and shear strains in bone. Ten adult foxhounds were subjected to rigorous exercise that caused muscular fatigue while myoelectrical activity of the quadriceps and hamstrings and strain on the distal tibia were monitored simultaneously. Ground reaction forces on the dog hindlimbs were measured before and after strain gauges had been applied to the tibia. The data show a significant shift to lower median myoelectrical frequencies in the quadriceps, indicating muscular fatigue, following the 20 min exercise period. In conjunction with this shift, peak principal and shear strains increased on both compressive and tensile cortices of the tibia and shear strain on the tensile cortex increased significantly (P = 0.02). The largest changes were along the anterior and anterolateral surfaces of the tibia, where peak principal strain increased by an average of 26-35% following muscular fatigue. The cross-sectional strain distribution was calculated at the gauge site at peak strain at the beginning of the exercise period and at peak strain after 20 min of exercise. These data show a change in strain distribution when muscle becomes fatigued. Strains on the posterior cortex of the bone showed the greatest change. Correlation analysis demonstrated a significant inverse association between median myoelectrical frequency and bone strain after 20 min of exercise (Spearman r2 = 1.00; P = 0.05). These data show that muscle fatigue may be associated with increased bone strain.


Cloning and expression of the cDNA for human gamma-glutamyl carboxylase.
The cDNA for human gamma-glutamyl carboxylase, which accomplishes the post-translational modification required for the activity of all of the vitamin K-dependent proteins, was cloned. The enzyme is a 758-residue integral membrane protein and appears to have three transmembrane domains near its amino terminus. The hydrophilic COOH-terminal half of the carboxylase has 19.3 percent identity with soybean seed lipoxygenase. Expression of the cloned cDNA resulted in an increase in carboxylase activity in microsomes of transfected cells compared to mock-transfected cells.


Computation of radiation pressure force exerted on arbitrary shaped homogeneous particles by high-order Bessel vortex beams using MLFMA.
Due to special characteristics of nondiffraction and self reconstruction, the Bessel beams have attracted wide attention in optical trapping and appear to be a dramatic alternative to Gaussian beams. We present in this paper an efficient approach based on the surface integral equations (SIE) to compute the radiation pressure force (RPF) exerted on arbitrary shaped homogeneous particles by high-order Bessel vortex beam (HOBVB). The incident beam is described by vector expressions perfectly satisfy Maxwell's equations. The problem is formulated with the combined tangential formulation (CTF) and solved iteratively with the aid of the multilevel fast multipole algorithm (MLFMA). Then RPF is computed by vector flux of the Maxwell's stress tensor over a spherical surface tightly enclosing the particle and analytical expression for electromagnetic fields of incident beam in near region are used. The numerical predictions are compared with the results of the rigorous method for spherical particle to validate the accuracy of the approach. Some numerical results on relative large particles of complex shape, such as biconcave cell-like particles with different geometry parameters are given, showing powerful capability of our approach. These results are expected to provide useful insights into the RPF exerted on complex shaped particles by HOBVB.


Nematodes from Swainson's spurfowl Pternistis swainsonii and an Orange River francolin Scleroptila levaillantoides in Free State Province, South Africa, with a description of Tetrameres swainsonii n. sp. (Nematoda: Tetrameridae).
Five Swainson's spurfowl collected in Free State Province, South Africa, were examined for helminth parasites, and the nematodes Acuaria gruveli, Cyrnea parroti, Gongylonema congolense, Subulura dentigera, Subulura suctoria and a new Tetrameres species were recovered. Their respective prevalence was 100, 20, 80, 20, 20 and 20%. These nematodes are all new parasite records for Swainson's spurfowl, and Acuaria gruveli constitutes a new geographical record as well. A single specimen of Cyrnea eurycerca was found in an Orange River francolin, representing a new host and geographical record for this parasite. The new species, for which the name Tetrameres swainsonii is proposed, can be differentiated from its congeners by a combination of the following characters of males: two rows of body spines, a single spicule which is 1152-1392 microm long, and eight pairs of caudal spines arranged in two ventral and two lateral rows of four spines each. The single female has the globular shape typical of the genus.


Different techniques for management of common bile duct stones: a single centre experience.
Local experience on the combined technique of endoscopic sphincterotomy followed by endo: scopic balloon dilation is scarce. This study clarified whether this crombined technique will offer any advantages, with respect to therapeutic outcome and complications rate, as compared with endoscopic sphincterotomy (ES) and endoscopic balloon dilatation (EBD) alone for the extraction of large and/or multiple common bile duct stones. For a total of 76 patients, extraction of large and/or multiple common bile duct (CBD) stones during endoscopic retrograde cholangiopancreatography was performed. According to the used technique, they were categorized into 3 groups; Endoscopic sphincterotomy, endoscopic balloon dilatation or combined technique. The success rate of complete stone removal and the incidence of procedure-related complications were compared among the three groups. Success rate after one session was recorded to be comparable among the three groups. Relative Risk Ratio assessment of success rate after single session among the three groups showed no statistically significant difference. Regarding bleeding, only 3 (10%) cases were recorded in the ES group with no cases in the, other 2 groups. No significant difference was noted among the three groups regarding other complication. The combined technique of ES followed by EBD is an effective and safe technique enables extraction of multiple and/or relatively large stones. It could be a reasonable alternative option when standard techniques are inadequate to remove bile duct stones.


Definition of miRNAs expression profile in glioblastoma samples: the relevance of non-neoplastic brain reference.
Glioblastoma is the most aggressive brain tumor that may occur in adults. Regardless of the huge improvements in surgery and molecular therapy, the outcome of neoplasia remains poor. MicroRNAs are small molecules involved in several cellular processes, and their expression is altered in the vast majority of tumors. Several studies reported the expression of different miRNAs in glioblastoma, but one of the most critical point in understanding glioblastoma miRNAs profile is the comparison of these studies. In this paper, we focused our attention on the non-neoplastic references used for determining miRNAs expression. The aim of this study was to investigate if using three different non-neoplastic brain references (normal adjacent the tumor, commercial total RNA, and epileptic specimens) could provide discrepant results. The analysis of 19 miRNAs was performed using Real-Time PCR, starting from the set of samples described above and the expression values compared. Moreover, the three different normal RNAs were used to determine the miRNAs profile in 30 glioblastomas. The data showed that different non-neoplastic controls could lead to different results and emphasize the importance of comparing miRNAs profiles obtained using the same experimental condition.


Pain and health related functioning among employees.
Although employees report high rates of pain, little is known about the effects of pain on health related functioning among them. This study examined the effects of pain on employees' health related functioning by bodily locations of pain, number of painful locations, and whether pain was acute or chronic. Cross sectional questionnaire survey. Data on pain and health related functioning as measured with the eight subscales of the short form 36 health survey (SF-36) were obtained in the years 2001 and 2002. Municipal employees of the City of Helsinki, Finland. All employees who reached the age of 40, 45, 50, 55, and 60 years during each study year. Response rate was 66% (n = 5829). Compared with those reporting no pain, those with pain had considerably poorer functioning on all SF-36 subscales. The lowest scores for health related functioning were seen in the physical domain of health, whereas the mental domain was less affected. The association of pain with functioning was practically independent of the bodily location of pain. Whether pain was acute or chronic had only a modest effect on functioning. Widest variation in functioning was found by the number of painful locations. Among employees pain complaints, irrespective of the location, are associated with a decreased level of functioning. The number of painful locations is likely to be the most useful measure to identify employees with a high risk of poor functioning.


Factors associated with the support of pricking (female genital cutting type IV) among Somali immigrants - a cross-sectional study in Sweden.
Pricking, classified as female genital cutting (FGC) type IV by the World Health Organization, is an under-researched area gaining momentum among diaspora communities. Our aim was to explore factors associated with being supportive of pricking among Somalis in Sweden. In a cross-sectional design, attitudes and knowledge regarding FGC, and measures of socioeconomic status, acculturation, and social capital, were assessed by a 49-item questionnaire in four municipalities in Sweden. Data were collected in 2015 from 648 Somali men and women, ≥ 18 years old, of which 113 supported the continuation of pricking. Logistic regression was used for the analysis. Those more likely to support the continuation of pricking were older, originally from rural areas, and newly arrived in Sweden. Further, those who reported that they thought pricking was: acceptable, according to their religion (aOR: 10.59, 95% CI: 5.44-20.62); not a violation of children's rights (aOR: 2.86, 95% CI: 1.46-5.61); and did not cause long-term health complications (aOR: 5.52, 95% CI: 2.25-13.52) had higher odds of supporting pricking. Religion was strongly associated with the support of pricking among both genders. However, for men, children's rights and the definition of pricking as FGC or not were important aspects in how they viewed pricking, while, for women, health complications and respectability were important. Values known to be associated with FGC in general are also related to pricking. Hence, there seems to be a change in what types of FGC are supported rather than in their perceived values.


Disposition of ketoconazole, an oral antifungal, in humans.
The pharmacology of ketoconazole was studied in patients with fungal infections. After administration of 50-, 100-, and 200-mg doses of ketoconazole, there was a linear increase in the area under the curve of serum concentrations; this was not apparent when higher doses of ketoconazole were given. An increase in the area under the curve occurred in patients receiving 200 mg daily who were restudied after 1 to 12 months of therapy. However, normalized area under the curve appeared to decrease after higher doses were administered chronically. The half life ranged from 2.0 to 3.3 h. Peak serum concentrations up to 50 micrograms/ml were detected in this study, and potentially therapeutic concentrations were detectable up to 26 h after high doses. Ketoconazole penetrated the saliva and inflamed joint fluid and meninges, although variably, and could be demonstrated in some other tissue compartments. In the presence of renal failure, ketoconazole disposition was not altered, whereas in the presence of hepatic insufficiency, an alteration in disposition was suggested. The interactions of ketoconazole and other drugs were studied. Of note, antacids did not significantly affect ketoconazole pharmacokinetics (nor did meals), and ketoconazole and warfarin did not appear to affect the pharmacokinetics of the other.


Continental-scale distributions of dust-associated bacteria and fungi.
It has been known for centuries that microorganisms are ubiquitous in the atmosphere, where they are capable of long-distance dispersal. Likewise, it is well-established that these airborne bacteria and fungi can have myriad effects on human health, as well as the health of plants and livestock. However, we have a limited understanding of how these airborne communities vary across different geographic regions or the factors that structure the geographic patterns of near-surface microbes across large spatial scales. We collected dust samples from the external surfaces of ∼1,200 households located across the United States to understand the continental-scale distributions of bacteria and fungi in the near-surface atmosphere. The microbial communities were highly variable in composition across the United States, but the geographic patterns could be explained by climatic and soil variables, with coastal regions of the United States sharing similar airborne microbial communities. Although people living in more urbanized areas were not found to be exposed to distinct outdoor air microbial communities compared with those living in more rural areas, our results do suggest that urbanization leads to homogenization of the airborne microbiota, with more urban communities exhibiting less continental-scale geographic variability than more rural areas. These results provide our first insight into the continental-scale distributions of airborne microbes, which is information that could be used to identify likely associations between microbial exposures in outdoor air and incidences of disease in crops, livestock, and humans.


The alexithymic brain: the neural pathways linking alexithymia to physical disorders.
Alexithymia is a personality trait characterized by difficulties in identifying and describing feelings and is associated with psychiatric and psychosomatic disorders. The mechanisms underlying the link between emotional dysregulation and psychosomatic disorders are unclear. Recent progress in neuroimaging has provided important information regarding emotional experience in alexithymia. We have conducted three brain imaging studies on alexithymia, which we describe herein. This article considers the role of emotion in the development of physical symptoms and discusses a possible pathway that we have identified in our neuroimaging studies linking alexithymia with psychosomatic disorders. In terms of socio-affective processing, alexithymics demonstrate lower reactivity in brain regions associated with emotion. Many studies have reported reduced activation in limbic areas (e.g., cingulate cortex, anterior insula, amygdala) and the prefrontal cortex when alexithymics attempt to feel other people's feelings or retrieve their own emotional episodes, compared to nonalexithymics. With respect to primitive emotional reactions such as the response to pain, alexithymics show amplified activity in areas considered to be involved in physical sensation. In addition to greater hormonal arousal responses in alexithymics during visceral pain, increased activity has been reported in the insula, anterior cingulate cortex, and midbrain. Moreover, in complex social situations, alexithymics may not be able to use feelings to guide their behavior appropriately. The Iowa gambling task (IGT) was developed to assess decision-making processes based on emotion-guided evaluation. When alexithymics perform the IGT, they fail to learn an advantageous decision-making strategy and show reduced activity in the medial prefrontal cortex, a key area for successful performance of the IGT, and increased activity in the caudate, a region associated with impulsive choice. The neural machinery in alexithymia is therefore activated more on the physiologic, motor-expressive level and less in the cognitive-experiential domains of the emotional response system. Affects may play an important role in alleviating intrinsic physiologic reactions and adapting to the environment. Deficient development of emotional neural structures may lead to hypersensitivity to bodily sensations and unhealthy behaviors, a possible mechanism linking alexithymia to psychosomatic disorders.


HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation.
We have determined the molecular genetic basis of congenital adrenal hyperplasia due to 21-hydroxylase (21-OHase) deficiency. This common disorder of cortisol biosynthesis is HLA-linked. The haplotype HLA-(A3);Bw47;DR7 is strongly associated with 21-OHase deficiency and always carries a null allele at the locus encoding the C4A (Rodgers) form of the fourth component (C4) of complement. It seemed likely that this haplotype carries a deletion encompassing the genes encoding both C4A and 21-OHase. We hypothesized that the HLA-linked defect involved a structural gene for the adrenal microsomal cytochrome P-450 specific for steroid 21-hydroxylation. Using a plasmid with a 520-base-pair bovine adrenal cDNA insert encoding the middle third of the cytochrome P-450 polypeptide, we compared hybridization patterns in DNA from normal and 21-OHase-deficient individuals. Normal human DNA yielded two fragments that hybridized with the probe after digestion with either restriction endonuclease EcoRI [12- and 14-kilobase (kb) fragments] or Taq I (3.7 and 3.2 kb). One of these bands (the first mentioned in each digest) was absent in DNA from a cell line derived from a patient homozygous for HLA-Bw47. DNA from six unrelated patients homozygous for 21-OHase deficiency who were heterozygous for HLA-Bw47 yielded diminished relative intensity of the 3.7-kb Taq I band in five patients, consistent with a heterozygous deletion, and complete disappearance of the 3.7-kb band in one. This deletion segregated with HLA-Bw47 in a large pedigree carrying 21-OHase deficiency and HLA-Bw47. Thus, 21-OHase deficiency sometimes results from the deletion of a specific cytochrome P-450 gene and sometimes, presumably, from smaller mutations. This gene is probably located very near the C4A gene.


HbS-oman heterozygote: a new dominant sickle syndrome.
Hemoglobin (Hb) S-Oman has two mutations in the beta-chains. In addition to the classic betaS mutation (beta6 Glu --> Val), it contains a second mutation in the same chain (beta121 Glu --> Lys) identical to that of HbOARAB. We have studied a pedigree of heterozygous carriers of HbS-Oman that segregates into two types of patients: those expressing about 20% HbS-Oman and concomitant -/ thalassemia and those with about 14% of HbS-Oman and concomitant -/- thalassemia. The higher expressors of S-Oman have a sickle cell anemia (SS) clinical syndrome of moderate intensity, while the lower expressors have no clinical syndrome, and are comparable to the solitary case first described in Oman. In addition, the higher expressors exhibit a unique form of irreversibly sickled cell reminiscent of a "yarn and knitting needle" shape, in addition to folded and target cells. The CSAT of S-Oman is identical to that of S-Antilles, another supersickling hemoglobin, whose carriers express the abnormal hemoglobin at 40% to 50%, with a very similar clinical picture to HbS-Oman. Because the level of expression is so different and the clinical picture so similar, and based on the hemolysates CSAT's, we conclude that HbS-Oman produces pathology beyond its sickling tendencies. A clue for this additional pathogenesis is found in the fact that homozygous HbOARAB, which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbOARAB is combined with HbS, it makes the phenotype of this double heterozygote as severe as SS. Properties of HbS-Oman red blood cells (RBCs) include reticulocytes that are much denser than normal (similar to those of SC and CC disease), a decrease in the Km for Ca2+ needed to activate the Gardos' channel (making this transporter more sensitive to Ca2+), increased association of HbS-Oman with the RBC membrane, the presence of dense cells by isopycnic gradient, the presence of folded cells, and abundant nidus of polymerization under the membrane. Other properties include a clear increase in volume and N-ethylmaleimide-stimulated K:Cl cotransport in RBCs expressing more than 20% HbS-Oman. We conclude that the pathology of heterozygous S-Oman is the product of the sickling properties of the beta6 Val mutation which are enhanced by the second mutation at beta121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at beta121. We speculate that this pathology results from the abnormal association of the highly positively charged HbS-Oman (3 charges different from normal hemoglobin) with the RBC membrane.


Proteome analysis of the xylose-fermenting mutant yeast strain TMB 3400.
Xylose fermentation in yeast has been a target of research for years, yet not all the factors that may affect xylose fermentation performance of yeast strains are known. In this study, the mutant S. cerevisiae strain TMB 3400, which has good xylose fermentation properties, was compared with its parental strain to examine the factors behind the improved xylose utilization at protein level. The proteome of the parental and the mutant strains were characterized by difference in gel electrophoresis (DiGE) to quantitatively identify proteins that are expressed at altered levels in the mutant. The most significant changes detected by proteome analysis were the 6-10-fold increased levels of xylose reductase, xylitol dehydrogenase and transketolase (Tkl1) in the mutant, which is in accordance with previous knowledge about xylose metabolism in yeast. The level of acetaldehyde dehydrogenase (Ald6) was also significantly increased. In addition, several proteins homologous to proteins from yeast species other than S. cerevisiae were identified in both strains, demonstrating the genetic heterogeneity of industrial yeast strains. The results were also compared with a previously reported transcription analysis performed with identical experimental set-up; however, very little correlation between the two datasets was observed. The results of the proteome analysis were in good agreement with a parallel study in which rationally designed overexpression of XR, XDH and the non-oxidative pentose phosphate pathway resulted in similar improvement in xylose utilization, which demonstrates the usefulness of proteome analysis for the identification of target genes for further metabolic engineering strategies in industrial yeast strains.


Painful neuropathy and foot ulceration in diabetic patients.
To examine the prevalence of painful symptoms in neuropathic patients with or without foot ulceration. It has been suggested that there are two clinical presentations of sensory diabetic neuropathy with little overlap: painful (acute or chronic) and painless with recurrent foot ulceration. We examined three groups of diabetic patients matched for age and duration of diabetes--24 without neuropathy on clinical grounds (mean age 56.1 yr [range 38-76 yr], diabetes duration 12.6 yr [0.4-40 yr]), 30 with neuropathy (mean age 55.3 yr [range 21-73 yr], diabetes duration 17.3 yr [range 0.2-61 yr]), and 40 with neuropathic foot ulceration (mean age 58.1 yr [range 41-72 yr], diabetes duration 18.5 yr [range 1-46 yr])--and compared them with 20 healthy subjects (mean age 50 yr [range 37-69 yr]). For evaluation of neuropathy, the neuropathy symptom score, neuropathy disability score, and vibration perception threshold were measured. No difference existed between the neuropathic and foot ulcer groups in the neuropathy symptom score (4.2 +/- 3.9 [mean +/- SD] vs. 2.5 +/- 2.1, NS) and neuropathy disability score (15.1 +/- 5.7 vs. 16.8 +/- 6.1, NS), but the vibration perception threshold was lower in the neuropathic group (30.1 +/- 13.4 vs. 40.5 +/- 13.8 V, P < 0.001). Painful symptoms (neuropathy symptom score > 3), either in the past or during the time the study was conducted, had been experienced by none of the control subjects, 7 (29%) of the nonneuropathic group, 18 (60%) of the neuropathic group, and 17 (43%) of the foot ulcer group (NS for the last two groups), and were present at the time of examination in 13 (43%) of the neuropathic group and in 13 (33%) of the foot ulcer group (NS in all groups). Duration of symptoms was < 12 mo in 12 (40%) neuropathic and 15 (38%) foot ulcer patients (NS). We conclude that painful symptoms are frequent in diabetic neuropathy, irrespective of the presence or absence of foot ulceration and that these symptoms can occur at any stage of the disease. These results suggest that there is a spectrum of neuropathic syndromes from the painful to the patients with foot ulceration, and that much overlap exists.


Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.
Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.


CD34+ hematopoietic stem cells mobilization, paralleled with multiple cytokines elevated in patients with HBV-related acute-on-chronic liver failure.
Recent studies indicate that bone marrow (BM)-derived stem cells contribute to liver regeneration. But limited information is available on the dynamic and mechanisms of mobilization of BM-derived hematopoietic stem cells (HSCs) after acute-on-chronic liver failure (ACLF). The purpose of this study was to assess the mobilization of BM-derived CD34+ HSCs in ACLF patients, and elucidate the association of stress-induced cytokines in HSCs mobilization and/or liver repair in ACLF patients. Thirty patients with HBV-related ACLF, 30 patients undergoing chronic hepatitis B, and 20 healthy controls were enrolled. The percentages of peripheral blood CD34+ cells were determined by two-color flow cytometry. The hepatic commitment of mobilized CD34+ cells was investigated by RT-PCR. The serum levels of stress-induced cytokines were determined by enzyme-linked immunosorbent assays. A significant increase of circulating CD34+ cells was observed in ACLF patients. RT-PCR analyses showed that the mobilized CD34+ cells expressed both CD34 mRNA and liver-specific markers including cytokeratin 19 and α-fetoprotein. In parallel with mobilization of BM-derived CD34+ cells, elevated serum levels of hepatocyte growth factor, interleukin-6, stem cell factor, granulocyte colony-stimulating factor and matrix metalloproteinase 9 were observed in ACLF patients. We demonstrated that ACLF led to mobilization of CD34+ cells, which had a hepatic differentiation potential.


Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis.
To compare the effectiveness and safety of three types of stents (sirolimus eluting, paclitaxel eluting, and bare metal) in people with and without diabetes mellitus. Collaborative network meta-analysis. Electronic databases (Medline, Embase, the Cochrane Central Register of Controlled Trials), relevant websites, reference lists, conference abstracts, reviews, book chapters, and proceedings of advisory panels for the US Food and Drug Administration. Manufacturers and trialists provided additional data. Network meta-analysis with a mixed treatment comparison method to combine direct within trial comparisons between stents with indirect evidence from other trials while maintaining randomisation. Overall mortality was the primary safety end point, target lesion revascularisation the effectiveness end point. 35 trials in 3852 people with diabetes and 10,947 people without diabetes contributed to the analyses. Inconsistency of the network was substantial for overall mortality in people with diabetes and seemed to be related to the duration of dual antiplatelet therapy (P value for interaction 0.02). Restricting the analysis to trials with a duration of dual antiplatelet therapy of six months or more, inconsistency was reduced considerably and hazard ratios for overall mortality were near one for all comparisons in people with diabetes: sirolimus eluting stents compared with bare metal stents 0.88 (95% credibility interval 0.55 to 1.30), paclitaxel eluting stents compared with bare metal stents 0.91 (0.60 to 1.38), and sirolimus eluting stents compared with paclitaxel eluting stents 0.95 (0.63 to 1.43). In people without diabetes, hazard ratios were unaffected by the restriction. Both drug eluting stents were associated with a decrease in revascularisation rates compared with bare metal stents in people both with and without diabetes. In trials that specified a duration of dual antiplatelet therapy of six months or more after stent implantation, drug eluting stents seemed safe and effective in people both with and without diabetes.


Comparison of noise sources in dual- and single-beam Fourier-transform near-infrared spectrometry.
We report the results of noise source investigations and stability tests in both dual- and single-beam Fourier-transform near-infrared operation. The noise sources are divided into two parts: intrinsic and extrinsic. The intrinsic noise sources, which include detector system noise, are common for both modes of operation. The extrinsic sources, which include variations in ambient conditions (room temperature, atmospheric gaseous components, and source scintillations), are shown to be smaller in dual-beam operation than in single-beam operation by a factor of 2-10. The results are based on interferograms measured in specified time intervals. The root-mean-square values are calculated at each retardation point. The values obtained near the centerburst and average values obtained for the dual-beam operation are compared with the intrinsic noise value obtained for single-beam operation. The dual-beam advantage is observed in both open-beam and liquid cell measurements, and it corresponds well with earlier results based on multivariate calibration techniques applied on aqueous solutions.


Emotional Loneliness Is Associated With a Risk of Dementia in a General Japanese Older Population: The Hisayama Study.
To investigate the association of loneliness and its component subscales with the risk of dementia in a general Japanese older population. A total of 1,141 community-dwelling Japanese residents aged ≥65 years without dementia were prospectively followed up for a median 5.0 years. We evaluated any loneliness and its component subscales-namely, social and emotional loneliness-by using the 6-item de Jong Gierveld Loneliness Scale. Cox proportional hazards models were used to estimate hazard ratios (HRs) of each loneliness type on the risk of dementia controlling for demographic factors, lifestyle factors, physical factors, social isolation factors, and depression. During the follow-up, 114 participants developed dementia. The age- and sex-adjusted incidence rate of dementia was significantly greater in participants with any loneliness and emotional loneliness than those without. The multivariable-adjusted HRs (95% confidence intervals) of participants with any loneliness and emotional loneliness on incident dementia were 1.61 (1.08-2.40) and 1.65 (1.07-2.54), respectively, as compared to those without. However, there was no significant association between social loneliness and dementia risk. In subgroup analyses of social isolation factors, excess risks of dementia associated with emotional loneliness were observed in participants who had a partner, lived with someone, or rarely communicated with relatives or friends, but such association was not significant in participants who had no partner, lived alone, or frequently communicated with friends or relatives. The present study suggested that loneliness, especially emotional loneliness, was a significant risk factor for the development of dementia in the general older population in Japan.


Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies.
SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.


Results from the Mars Pathfinder camera.
Images of the martian surface returned by the Imager for Mars Pathfinder (IMP) show a complex surface of ridges and troughs covered by rocks that have been transported and modified by fluvial, aeolian, and impact processes. Analysis of the spectral signatures in the scene (at 440- to 1000-nanometer wavelength) reveal three types of rock and four classes of soil. Upward-looking IMP images of the predawn sky show thin, bluish clouds that probably represent water ice forming on local atmospheric haze (opacity approximately 0.5). Haze particles are about 1 micrometer in radius and the water vapor column abundance is about 10 precipitable micrometers.


Characterization of the stunting syndrome agent: physicochemical properties.
Stunting syndrome is an enteric disease of turkeys causing diarrhea, reduced weight gain, poor feed efficiency, and maldigestion. The etiologic agent is a newly identified, but unclassified, virus termed the stunting syndrome agent (SSA). The SSA is a pleomorphic, enveloped virus ranging from 60 to 95 nm in diameter. The objectives of this study were to characterize the physicochemical properties of SSA. SSA hemagglutinated rat erythrocytes at 4 C and room temperature. Treatment of SSA with ether resulted in loss of infectivity. SSA was resistant to pH changes between pH 3.0 and pH 9.0 at 37 C for 1 hr. The virus was inactivated at pH > or = 10. SSA was resistant to treatment with trypsin, chymotrypsin, pancreatin, phospholipase C, and sodium deoxycholate. Treatment of SSA with trypsin, chymotrypsin, and pancreatin resulted in enhanced viral infectivity. The viral genome extracted from purified SSA was sensitive to RNAse treatment. Using oligo d(T)16-18 and random hexamers as primers, the SSA genome was amplified using the reverse transcription-polymerase chain reaction conditions but was not amplified using polymerase chain reaction conditions. The enrichment of viral genome was achieved following poly-A+ selection. These studies provide evidence that the SSA is a positive-sense, single-stranded RNA virus having many characteristics (stability at acidic pH, resistant to proteolytic enzymes and bile salt) consistent with other enveloped enteric viruses.


A Recombinant Respiratory Syncytial Virus Vaccine Candidate Attenuated by a Low-Fusion F Protein Is Immunogenic and Protective against Challenge in Cotton Rats.
Although respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, a safe and effective vaccine is not yet available. Live-attenuated vaccines (LAVs) are the most advanced vaccine candidates in RSV-naive infants. However, designing an LAV with appropriate attenuation yet sufficient immunogenicity has proven challenging. In this study, we implemented reverse genetics to address these obstacles with a multifaceted LAV design that combined the codon deoptimization of genes for nonstructural proteins NS1 and NS2 (dNS), deletion of the small hydrophobic protein (ΔSH) gene, and replacement of the wild-type fusion (F) protein gene with a low-fusion RSV subgroup B F consensus sequence of the Buenos Aires clade (BAF). This vaccine candidate, RSV-A2-dNS-ΔSH-BAF (DB1), was attenuated in two models of primary human airway epithelial cells and in the upper and lower airways of cotton rats. DB1 was also highly immunogenic in cotton rats and elicited broadly neutralizing antibodies against a diverse panel of recombinant RSV strains. When vaccinated cotton rats were challenged with wild-type RSV A, DB1 reduced viral titers in the upper and lower airways by 3.8 log10 total PFU and 2.7 log10 PFU/g of tissue, respectively, compared to those in unvaccinated animals (P < 0.0001). DB1 was thus attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. DB1 is the first RSV LAV to incorporate a low-fusion F protein as a strategy to attenuate viral replication and preserve immunogenicity. RSV is a leading cause of infant hospitalizations and deaths. The development of an effective vaccine for this high-risk population is therefore a public health priority. Although live-attenuated vaccines have been safely administered to RSV-naive infants, strategies to balance vaccine attenuation with immunogenicity have been elusive. In this study, we introduced a novel strategy to attenuate a recombinant RSV vaccine by incorporating a low-fusion, subgroup B F protein in the genetic background of codon-deoptimized nonstructural protein genes and a deleted small hydrophobic protein gene. The resultant vaccine candidate, DB1, was attenuated, highly immunogenic, and protective against RSV challenge in cotton rats.


Rapid delivery of paclitaxel with an organic solvent-free system based on a novel cell penetrating peptide for suppression of tumor growth.
Paclitaxel (PTX) is widely used to treat ovarian, breast, lung, pancreatic, cervical and other cancers, however, the cell uptake and utilization of PTX is greatly limited by its slow penetration rate and poor solubility in water. Therefore, it is of great interest to develop an efficient method for PTX delivery to improve its cellular uptake and utilization. A novel cell penetrating peptide, RRRRRWW (R7), is developed to accelerate the translocation of PTX into HeLa cells in the organic solvent-free system to suppress tumor growth. There is no significant cytotoxicity induced by the peptide alone even after 24 h incubation at 1 mM at 37 °C for both cancer cells and normal cells. In contrast, 30 min treatment with the R7/PTX complex leads to a significant decrease in the cell viability. The intracellular PTX concentration of the R7/PTX complex group is 3 fold that of the free PTX group. The in vivo animal experiments show that the tumor is dramatically suppressed by a tail vein injection of the R7/PTX complex. This system provides a novel approach for the delivery of PTX into tumor cells to efficiently suppress tumor growth.


Correlating early evolution of parasitic platyhelminths to Gondwana breakup.
Investigating patterns and processes of parasite diversification over ancient geological periods should involve comparisons of host and parasite phylogenies in a biogeographic context. It has been shown previously that the geographical distribution of host-specific parasites of sarcopterygians was guided, from Palaeozoic to Cainozoic times, mostly by evolution and diversification of their freshwater hosts. Here, we propose phylogenies of neobatrachian frogs and their specific parasites (Platyhelminthes, Monogenea) to investigate coevolutionary processes and historical biogeography of polystomes and further discuss all the possible assumptions that may account for the early evolution of these parasites. Phylogenetic analyses of concatenated rRNA nuclear genes (18S and partial 28S) supplemented by cophylogenetic and biogeographic vicariance analyses reveal four main parasite lineages that can be ascribed to centers of diversity, namely Australia, India, Africa, and South America. In addition, the relationships among these biogeographical monophyletic groups, substantiated by molecular dating, reflect sequential origins during the breakup of Gondwana. The Australian polystome lineage may have been isolated during the first stages of the breakup, whereas the Indian lineage would have arisen after the complete separation of western and eastern Gondwanan components. Next, polystomes would have codiverged with hyloid sensu stricto and ranoid frog lineages before the completion of South American and African plate separation. Ultimately, they would have undergone an extensive diversification in South America when their ancestral host families diversified. Therefore, the presence of polystome parasites in specific anuran host clades and in discrete geographic areas reveals the importance of biogeographic vicariance in diversification processes and supports the occurrence and radiation of amphibians over ancient and recent geological periods.


Th17 lymphocytes in respiratory syncytial virus infection.
Infection by respiratory syncytial virus (RSV) affects approximately 33 million infants annually worldwide and is a major cause of hospitalizations. Helper T lymphocytes (Th) play a central role in the immune response during such infections. However, Th lymphocytes that produce interleukin 17 (IL-17), known as Th17 lymphocytes, in addition to been protective can also cause pathology that accompany this type of infection. The protective effects of Th17 is associated with better prognosis in most infected individuals but heightened Th17 responses causes inflammation and pathology in others. Studies employing animal models haves shown that activated Th17 lymphocytes recruit neutrophils and facilitate tertiary lymphoid structure development in infected lungs. However, IL-17 also inhibits the ability of CD8+ lymphocytes to clear viral particles and acts synergistically with the innate immune system to exacerbate inflammation. Furthermore, IL-17 enhances IL-13 production which, in turn, promotes the activation of Th2 lymphocytes and excessive mucus production. Studies of these animal models have also shown that a lack of, or inadequate, responses by the Th1 subset of T lymphocytes enhances Th17-mediated responses and that this is detrimental during RSV co-infection in experimental asthma. The available evidence, therefore, indicates that Th17 can play contradictory roles during RSV infections. The factors that determine the shift in the balance between beneficial and adverse Th17 mediated effects during RSV infection remains to be determined.


Unmet care needs of advanced cancer patients and their informal caregivers: a systematic review.
This systematic review aimed to identify the unmet care needs and their associated variables in patients with advanced cancer and informal caregivers, alongside summarizing the tools used for needs assessment. Ten electronic databases were searched systematically from inception of each database to December 2016 to determine eligible studies. Studies that considered the unmet care needs of either adult patients with advanced cancer or informal caregivers, regardless of the study design, were included. The Mixed Methods Appraisal Tool was utilized for quality appraisal of the included studies. Content analysis was used to identify unmet needs, and descriptive analysis was adopted to synthesize other outcomes. Fifty studies were included, and their methodological quality was generally robust. The prevalence of unmet needs varied across studies. Twelve unmet need domains were identified in patients with advanced cancer, and seven among informal caregivers. The three most commonly reported domains for patients were psychological, physical, and healthcare service and information. The most prominent unmet items of these domains were emotional support (10.1-84.4%), fatigue (18-76.3%), and "being informed about benefits and side-effects of treatment" (4-66.7%). The most commonly identified unmet needs for informal caregivers were information needs, including illness and treatment information (26-100%) and care-related information (21-100%). Unmet needs of patients with advanced cancer were associated with their physical symptoms, anxiety, and quality of life. The most commonly used instruments for needs assessment among patients with advanced cancer were the Supportive Care Needs Survey (N = 8) and Problems and Needs in Palliative Care questionnaire (N = 5). The majority of the included studies investigated unmet needs from the perspectives of either patients or caregivers with a cross-sectional study design using single time-point assessments. Moreover, significant heterogeneity, including differences in study contexts, assessment methods, instruments for measurement, need classifications, and reporting methods, were identified across studies. Both advanced cancer patients and informal caregivers reported a wide range of context-bound unmet needs. Examining their unmet needs on the basis of viewing patients and their informal caregivers as a whole unit will be highly optimal. Unmet care needs should be comprehensively evaluated from the perspectives of all stakeholders and interpreted by using rigorously designed mixed methods research and longitudinal studies within a given context.


Robotic Versus Laparoscopic Partial Mesorectal Excision for Cancer of the High Rectum: A Single-Center Study with Propensity Score Matching Analysis.
The role of robotic surgery for partial mesorectal excision (PME) in patients with high rectal cancer (RC) remains unexplored. This study aimed to compare the operative and postoperative outcomes of robotic (R-PME) versus laparoscopic (L-PME) PME for high RC. This was a single-center propensity score cohort study of consecutive patients diagnosed with RC in the high rectum (>10 to 15 cm from the anal verge) who underwent surgery between September 2012 and May 2019. Of 131 selected patients (50 R-PME and 81 L-PME), 88 were matched using propensity score (44 per group). Operative and postoperative variables were similar between R-PME and L-PME patients, except for operative time (220 min and 190 min, respectively; p < 0.0001). No conversion was needed. Overall morbidity was 15.9%; 4 patients (4.5%) developed anastomotic leakage. The mean hospital stay was 7.25 days for R-PME vs. 7.64 days for L-PME (p = 0.597). R0 resection was achieved in 100% of R-PME and 90.9% of L-PME (p = 0.116). Only 3 patients (1 R-PME, 2 L-PME) received a permanent stoma (p = 1). No group differences were observed for overall or disease-free survival rates at 5 years. The costs of R-PME were significantly higher than those of L-PME. Minimally invasive surgery can be performed safely for PME in high RC. No difference can be detected between R-PME and L-PME for both short- and long-term outcomes, leaving the choice of the surgical approach to the surgeon's experience. Specific health economic studies are needed to evaluate the cost-effectiveness of robotic surgery for RC.


Cross-correlations and joint gaussianity in multivariate level crossing models.
A variety of phenomena in physical and biological sciences can be mathematically understood by considering the statistical properties of level crossings of random Gaussian processes. Notably, a growing number of these phenomena demand a consideration of correlated level crossings emerging from multiple correlated processes. While many theoretical results have been obtained in the last decades for individual Gaussian level-crossing processes, few results are available for multivariate, jointly correlated threshold crossings. Here, we address bivariate upward crossing processes and derive the corresponding bivariate Central Limit Theorem as well as provide closed-form expressions for their joint level-crossing correlations.


Ectopic decidual reaction mimicking peritoneal tubercles: a report of three cases.
Ectopic decidual reaction is commonly seen in the ovary and cervix; however, peritoneal localization is rare. Peritoneal deciduosis is usually an incidental histological finding. It may present a diagnostic dilemma by mimicking grossly peritoneal carcinomatosis or tubercles and deciduoid mesothelioma, microscopically. We report three cases of ectopic decidual reaction discovered incidentally during caesarian sections, as whitish yellow nodules resembling tubercles. Histology revealed extensive decidualisation. To the best of our knowledge, this is the first report of ectopic decidua mimicking peritoneal tubercles.