Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people.
To determine time to treatment intensification in people with type 2 diabetes treated with one, two, or three oral antidiabetes drugs (OADs) and associated levels of glycemic control. This was a retrospective cohort study based on 81,573 people with type 2 diabetes in the U.K. Clinical Practice Research Datalink between January 2004 and December 2006, with follow-up until April 2011. In people with HbA1c ≥7.0, ≥7.5, or ≥8.0% (≥53, ≥58, or ≥64 mmol/mol), median time from above HbA1c cutoff to intensification with an additional OAD was 2.9, 1.9, or 1.6 years, respectively, for those taking one OAD and >7.2, >7.2, and >6.9 years for those taking two OADs. Median time to intensification with insulin was >7.1, >6.1, or 6.0 years for those taking one, two, or three OADs. Mean HbA1c at intensification with an OAD or insulin for people taking one, two, or three OADs was 8.7, 9.1, and 9.7%. In patients taking one, two, or three OADs, median time from treatment initiation to intensification with an OAD or insulin exceeded the maximum follow-up time of 7.2 years. The probability of patients with poor glycemic control taking one, two, or three OADs, intensifying at end of follow-up with an OAD, was 21.1-43.6% and with insulin 5.1-12.0%. There are delays in treatment intensification in people with type 2 diabetes despite suboptimal glycemic control. A substantial proportion of people remain in poor glycemic control for several years before intensification with OADs and insulin.


Do the mechanical and chemical properties of InvisalignTM appliances change after use? A retrieval analysis.
To investigate the mechanical and chemical alterations of Invisalign appliances after intraoral aging. Samples of Invisalign appliances (Align Technology, San Jose, California, USA) were collected following routine treatment for a mean period of 44±15 days (group INV), whereas unused aligners of the same brand were used as reference (group REF). A small sample from the central incisors region was cut from each appliance and the buccal surface was analysed by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy (n = 5). Then the appliances were cut (n = 25) and embedded in acrylic resin, ground/polished in a grinding polishing machine, and the prepared surfaces were subjected to Instrumented Indentation Testing under 4.9 N load. Force-indentation depth curves were recorded for each group and the following parameters were calculated according to ISO 14577-1; 2002 specification: indentation modulus (E IT), elastic to total work ratio also known as elastic index (ηIT), Martens Hardness (HM), and indentation creep (C IT) The mean values of the mechanical properties were statistically analysed by unpaired t-test (a = 0.05). ATR-FTIR analysis confirmed the urethane based structure of the appliances, without important chemical differences attributed to the aging process. INV group showed significantly lower E IT (REF: 2466±20, INV: 2216±168MPa), HM (REF: 119±1, INV: 110±6 N mm-2) and higher ηIT (REF: 40.0±0.3, INV: 41.5±1.2%), and C IT (REF: 3.7±0.2 INV: 4.0±0.1%). The increase in ηIT indicates that INV is a more brittle than REF, whereas the increase in C IT, a decrease in creep resistance. Despite the lack of detectable chemical changes, intraoral aging adversely affected the mechanical properties of the Invisalign appliance.


Vitreous rebleed following sutureless vitrectomy: Incidence and risk factors.
This study aims to evaluate the incidence and risk factors for vitreous rebleed (VRB) following 25-gauge sutureless vitrectomy for vitreous hemorrhage (VH) in diabetic retinopathy. A retrospective review of 190 diabetic patients having undergone vitrectomy for VH at a tertiary eye care center was analyzed. Demographic data of patients along with risk factors such as blood sugar levels (BSL), blood pressure (BP), anticoagulant use, and pan-retinal photocoagulation status (PRP) were tabulated. Depending on the commencement of VRB, patients were divided into immediate rebleed-within 2 weeks and delayed rebleed-beyond 2-4 weeks. Forty-one patients had VRB, out of which 18 patients had immediate VRB and 23 patients had delayed VRB. The average duration between vitrectomy and VRB was 3.28 months. Twenty-eight patients were male and 13 were females. Average age at presentation was 53.8 years. Thirty-four patients (82.9%) were found to have high BSL and 28 patients (68.3%) had high BP and they developed rebleed (P < 0.01) after an initial hemorrhage-free period (average = 5.15 months). Fifteen patients (36.6%) underwent first time PRP intraoperatively, and they had immediate rebleed (P < 0.01) without any hemorrhage-free period (average = 0.9 months). Eight patients (19.5%) were on perioperative anticoagulants; however, their statistical significance did not persist in the multivariable model. There were neither age nor gender predilection toward rebleed (P > 0.05). The incidence rate of VRB was found to be 21.6%. Age and gender did not contribute to rebleed. Intraoperative PRP was a risk factor for immediate rebleed. Poor glycemic and BP control was a risk factor for delayed rebleed.


Cancer epigenetics drug discovery and development: the challenge of hitting the mark.
Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved "first generation" of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area.


Responses of neurons in inferior colliculus to variations in sound-source azimuth.
This study aimed to classify the responses of single units in the auditory midbrain to acoustic stimuli presented in the free field in order to characterize those units likely to have a role in sound localization in the horizontal plane. The responses of 131 single units in the inferior colliculus of the cat and the brush-tailed possum were studied using tone and noise-burst stimuli presented from a speaker capable of movement at any point along a plane 10 degrees above the horizontal plane. Speaker positions along this plane are referred to as speaker azimuths; those on the same side as the recorded inferior colliculus as ipsilateral, and on the opposite side as contralateral, azimuths. For each unit, spike counts were measured as a function of azimuth either at the best frequency (BF) or using noise bursts. These functions are referred to as azimuth functions and were usually measured for at least two intensities, between 10 and 70 dB above threshold. The recording sites of most units were identified histologically with the aid of microlesions and were related to the major subdivisions of the inferior colliculus: the central nucleus (ICC), the lateral part of the external nucleus (ICX), and the rostroventral process (R-ICX). Two units were located in the pericentral nucleus and two in the dorsal nucleus of the lateral lemniscus. Two major classes of neuron were identified: omnidirectional and directionally sensitive. Omnidirectional units exhibited azimuth functions that were either flat or that declined gradually at progressively ipsilateral azimuths. For the latter units, discharge rates at all points monotonically increased with stimulus intensity. There was no indication, for either type of omnidirectional unit, of significant binaural interaction. A good correlation was found between the summed proportions of excitatory-excitatory (EE) and monaural (EO) units observed in dichotic studies (46-55%) and the proportion of omnidirectional units in the present study (47%). A subgroup of directionally sensitive units (36% of the total) displayed azimuth functions for which the azimuthal position of the discharge border or peak firing azimuth remained essentially unaltered over a range of stimulus intensities. These azimuth-selective units are likely to have a role in the detection of the location of stimuli in the horizontal plane and appear to include units that would be considered excitatory-inhibitory (EI) or delay sensitive in dichotic studies. The azimuths over which directionally sensitive units showed their marked directional effects were influenced by the position of the contralateral pinna.(ABSTRACT TRUNCATED AT 400 WORDS)


Fitness Restoration of a Genetically Tractable Enterococcus faecalis V583 Derivative To Study Decoration-Related Phenotypes of the Enterococcal Polysaccharide Antigen.
Commensal and generally harmless in healthy individuals, Enterococcus faecalis causes opportunistic infections in immunocompromised patients. Plasmid-cured E. faecalis strain VE14089, derived from sequenced reference strain V583, is widely used for functional studies due to its improved genetic amenability. Although strain VE14089 has no major DNA rearrangements, with the exception of an ∼20-kb integrated region of pTEF1 plasmid, the strain presented significant growth differences from the V583 reference strain of our collection (renamed VE14002). In the present study, genome sequencing of strain VE14089 identified additional point mutations. Excision of the integrated pTEF1 plasmid region and sequential restoration of wild-type alleles showing nonsilent mutations were performed to obtain the VE18379 reference-derivative strain. Recovery of the growth ability of the restored VE18379 strain at a level similar to that seen with the reference strain points to GreA and Spx as bacterial fitness determinants. Virulence potential in Galleria mellonella and intestinal colonization in mouse demonstrated host adaptation of the VE18379 strain equivalent to VE14002 host adaptation. We further demonstrated that deletion of the 16.8-kb variable region of the epa locus recapitulates the key role of Epa decoration in host adaptation, providing a genetic system to study the role of specific epa-variable regions in host adaptation independently of other genetic variations.IMPORTANCEE. faecalis strain VE14089 was derived from V583 cured of its plasmids. Although VE14089 had no major DNA rearrangements, it presented significant growth and host adaptation differences from the reference strain V583 of our collection. To construct a strain with better fitness, we sequenced the genome of VE14089, identified single nucleotide polymorphisms (SNPs), and repaired the genes that could account for these changes. Using this reference-derivative strain, we provide a novel genetic system to understand the role of the variable region of epa in the enterococcal lifestyle.


Dopaminergic receptor blockade changes a functional connectivity network centred on the amygdala.
Resting-state connectivity has become an increasingly important measure in characterizing the functional integrity of brain circuits in neuro-psychiatric conditions. One approach that has recently gained prominence in this regard-and which we use in this study-is to investigate how resting-state connectivity depends on the integrity of certain neuromodulator systems. Here, we use a pharmacological challenge in combination with functional magnetic resonance imaging to investigate the impact of dopaminergic receptor blockade on whole brain functional connectivity in twenty healthy human subjects. Administration of the D2-receptor antagonist haloperidol led to a profound change in functional integration in network nodes linked to the amygdala. Compared to placebo and baseline measurements, network-based statistics and pairwise connectivity analyses revealed reduced connectivity and decreased link strength between the amygdala and the bilateral posterior cingulate cortex and other cortical areas. This was complemented by less extensive but very circumscribed enhanced connectivity between the amygdala and the right putamen during D2-receptor blockade. It will be interesting to investigate whether these pharmacologically induced shifts in resting-state connectivity will similarly be evident in clinical conditions that involve a dysfunction of the dopaminergic system. Our findings might also aid in interpreting alterations in more complex states, such as those seen psychiatric conditions and their treatment. Hum Brain Mapp 37:4148-4157, 2016. © 2016 Wiley Periodicals, Inc.


Impact of acute temperature and air pollution exposures on adult lung function: A panel study of asthmatics.
Individuals with respiratory conditions, such as asthma, are particularly susceptible to adverse health effects associated with higher levels of ambient air pollution and temperature. This study evaluates whether hourly levels of fine particulate matter (PM2.5) and dry bulb globe temperature (DBGT) are associated with the lung function of adult participants with asthma. Global positioning system (GPS) location, respiratory function (measured as forced expiratory volume at 1 second (FEV1)), and self-reports of asthma medication usage and symptoms were collected as part of the Exposure, Location, and Lung Function (ELF) study. Hourly ambient PM2.5 and DBGT exposures were estimated by integrating air quality and temperature public records with time-activity patterns using GPS coordinates for each participant (n = 35). The relationships between acute PM2.5, DBGT, rescue bronchodilator use, and lung function collected in one week periods and over two seasons (summer/winter) were analyzed by multivariate regression, using different exposure time frames. In separate models, increasing levels in PM2.5, but not DBGT, were associated with rescue bronchodilator use. Conversely DBGT, but not PM2.5, had a significant association with FEV1. When DBGT and PM2.5 exposures were placed in the same model, the strongest association between cumulative PM2.5 exposures and the use of rescue bronchodilator was identified at the 0-24 hours (OR = 1.030; 95% CI = 1.012-1.049; p-value = 0.001) and 0-48 hours (OR = 1.030; 95% CI = 1.013-1.057; p-value = 0.001) prior to lung function measure. Conversely, DBGT exposure at 0 hours (β = 3.257; SE = 0.879; p-value>0.001) and 0-6 hours (β = 2.885; SE = 0.903; p-value = 0.001) hours before a reading were associated with FEV1. No significant interactions between DBGT and PM2.5 were observed for rescue bronchodilator use or FEV1. Short-term increases in PM2.5 were associated with increased rescue bronchodilator use, while DBGT was associated with higher lung function (i.e. FEV1). Further studies are needed to continue to elucidate the mechanisms of acute exposure to PM2.5 and DBGT on lung function in asthmatics.


FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.
On October 6, 2006, the U.S. Food and Drug Administration granted regular approval to vorinostat (Zolinza(R); Merck & Co., Inc., Whitehouse Station, NJ), a histone deacetylase inhibitor, for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The pivotal study supporting approval was a single-arm open-label phase II trial that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). Patients received vorinostat at a dose of 400 mg orally once daily, which could be reduced for toxicity to 300 mg daily or 300 mg 5 days a week. The median age of patients was 61 years. Sixty-one patients (82%) had stage IIB or higher CTCL and 30 patients (41%) had Sézary syndrome. The median duration of protocol treatment was 118 days. The primary efficacy endpoint was objective response assessed by the Severity-Weighted Assessment Tool. The objective response rate was 30% (95% confidence interval [CI], 19.7%-41.5%), the estimated median response duration was 168 days, and the median time to tumor progression was 202 days. An additional single-center study enrolled 33 patients with similar baseline and demographic features as the pivotal trial. Thirteen of the 33 received vorinostat (400 mg/day). The response rate in these 13 patients was 31% (95% CI, 9.1%-61.4%). The most common clinical adverse events (AEs) of any grade were diarrhea (52%), fatigue (52%), nausea (41%), and anorexia (24%). Grade 3 or 4 clinical AEs included fatigue (4%) and pulmonary embolism (5%). Hematologic laboratory abnormalities included thrombocytopenia (26%) and anemia (14%). Chemistry laboratory abnormalities included increased creatinine (16%), increased serum glucose (69%), and proteinuria (51%). Most abnormalities were National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 or 2. Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia, and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine.


The effect of islet amyloid polypeptide (amylin) and calcitonin gene-related peptide on glucose removal in the anaesthetized rat and on insulin secretion from rat pancreatic islets in vitro.
The effect of intravenous infusion of islet amyloid polypeptide (IAPP/amylin) and calcitonin gene-related peptide (CGRP) on blood glucose and plasma insulin in the basal and glucose-stimulated state was investigated in the anaesthetized rat. Both peptides had no effect on basal blood glucose or plasma insulin but following an intravenous bolus of glucose, CGRP-treated rats were hyperglycaemic and hyperinsulinaemic compared with control animals which were similar to IAPP-treated rats. IAPP had no effect on glucose-stimulated islet insulin secretion. These results suggest that CGRP, but not IAPP, alters glucose removal in vivo.


Limb Bone Structural Proportions and Locomotor Behavior in A.L. 288-1 ("Lucy").
While there is broad agreement that early hominins practiced some form of terrestrial bipedality, there is also evidence that arboreal behavior remained a part of the locomotor repertoire in some taxa, and that bipedal locomotion may not have been identical to that of modern humans. It has been difficult to evaluate such evidence, however, because of the possibility that early hominins retained primitive traits (such as relatively long upper limbs) of little contemporaneous adaptive significance. Here we examine bone structural properties of the femur and humerus in the Australopithecus afarensis A.L. 288-1 ("Lucy", 3.2 Myr) that are known to be developmentally plastic, and compare them with other early hominins, modern humans, and modern chimpanzees. Cross-sectional images were obtained from micro-CT scans of the original specimens and used to derive section properties of the diaphyses, as well as superior and inferior cortical thicknesses of the femoral neck. A.L. 288-1 shows femoral/humeral diaphyseal strength proportions that are intermediate between those of modern humans and chimpanzees, indicating more mechanical loading of the forelimb than in modern humans, and by implication, a significant arboreal locomotor component. Several features of the proximal femur in A.L. 288-1 and other australopiths, including relative femoral head size, distribution of cortical bone in the femoral neck, and cross-sectional shape of the proximal shaft, support the inference of a bipedal gait pattern that differed slightly from that of modern humans, involving more lateral deviation of the body center of mass over the support limb, which would have entailed increased cost of terrestrial locomotion. There is also evidence consistent with increased muscular strength among australopiths in both the forelimb and hind limb, possibly reflecting metabolic trade-offs between muscle and brain development during hominin evolution. Together these findings imply significant differences in both locomotor behavior and ecology between australopiths and later Homo.


Presence of an aromatase inhibitor, possibly heat shock protein 90, in dominant follicles of cattle.
In cattle, it has been suggested that follicular fluid has direct modulatory effects on follicular growth and maturation. In the first part of this study, an in vitro test using aromatase activity of follicular wall fragments as an end point was validated for cattle follicles and was used to test whether follicular fluid (from dominant or non-dominant follicles) modulates aromatase activity. Fluid from dominant follicles at a concentration of 24 or 12% (obtained during the luteal and follicular phases, respectively) significantly inhibited aromatase activity. Inhibitory activity was low or absent in fluid from non-dominant follicles. FSH-stimulated aromatase activity was also reduced by fluid from dominant follicles, but not to a greater extent than in basal conditions. Finally, charcoal-treated fluid from dominant follicles retained its inhibitory activity. In contrast, ovarian venous serum draining a dominant follicle had no activity at the three concentrations tested (6, 12 and 24%). In the second part of the study, identification of the compounds involved in this modulatory activity was attempted using SDS-PAGE. Comparison of the fluorographs from de novo synthesized proteins stored in follicular fluid (inhibitory medium) with those secreted in incubation medium (inactive medium) demonstrated that one protein (90 kDa, pI 5.8) was significantly (P < 0.05) more abundant in fluid from dominant follicles (2.0 +/- 0.09%) than in the culture medium (1.3 +/- 0.1% of the total proteins). This protein had characteristics similar to those of heat shock protein 90 (hsp 90). Therefore, in the final part of the study, the presence of hsp 90 in ovarian cells and follicular fluid was investigated using immunohistochemistry and western blot analysis. After immunohistochemistry, a positive signal was detected mainly in the granulosa cells of larger follicles and to a smaller extent in thecal cells and oocytes. Western blot analysis also demonstrated the presence of hsp 90 in follicular wall fragments and fluid. When blotting was achieved on a sample of follicular fluid resolved by two-dimensional PAGE, the spot detected had a similar location to that at 90 kDa and pI 5.8. Addition of purified hsp 90 to bovine follicles in vitro depressed aromatase activity by altering the K(m) value (and possibly the Vmax value) of the enzyme. It is proposed that hsp 90 is a functional regulator of follicular maturation through its action on aromatase.


Age at cancer onset in germline TP53 mutation carriers: association with polymorphisms in predicted G-quadruplex structures.
Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3' flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3' flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers.


Effect of thrombolysis on the evolution of late potentials within 10 days of infarction.
Patients with late potentials in the signal averaged electrocardiogram are more at risk of lethal arrhythmias in the period after acute myocardial infarction. To test the effects of thrombolysis on the incidence and evolution of late potentials, 158 consecutive patients were prospectively studied during the first 10 days after acute myocardial infarction. The study population consisted of two groups: 93 control patients treated conservatively and 65 patients treated with intravenous thrombolysis. Recordings of signal averaged electrocardiogram were obtained within two days and 7-10 days after infarction. The incidence of late potentials in the first two days after infarction was not significantly different in the thrombolytic and control groups (14% v 11.8%). By 7-10 days the incidence of late potentials among patients who underwent thrombolysis remained unchanged (14%); however, it increased significantly in the control group (11.8% to 22.5%). Thus thrombolysis seems to reduce the evolution of late potentials within 10 days of infarction. Because the risk of fatal arrhythmias is higher in patients with late potentials this study may partly explain the reduced mortality after thrombolysis.


Bidirectional prefrontal-hippocampal dynamics organize information transfer during sleep in humans.
How are memories transferred from short-term to long-term storage? Systems-level memory consolidation is thought to be dependent on the coordinated interplay of cortical slow waves, thalamo-cortical sleep spindles and hippocampal ripple oscillations. However, it is currently unclear how the selective interaction of these cardinal sleep oscillations is organized to support information reactivation and transfer. Here, using human intracranial recordings, we demonstrate that the prefrontal cortex plays a key role in organizing the ripple-mediated information transfer during non-rapid eye movement (NREM) sleep. We reveal a temporally precise form of coupling between prefrontal slow-wave and spindle oscillations, which actively dictates the hippocampal-neocortical dialogue and information transfer. Our results suggest a model of the human sleeping brain in which rapid bidirectional interactions, triggered by the prefrontal cortex, mediate hippocampal activation to optimally time subsequent information transfer to the neocortex during NREM sleep.


THE PROTECTION OF PANCREATIC LIPASE BY ACACIA GUM.
In this preliminary note we describe the results obtained by inoculation of the skin of the scrotum of four black rabbits with serous fluid expressed from an initial pinta lesion. The inoculation was made intradermally, as superficially as possible, with serous fluid rich in treponemata and diluted with normal salt solution. A papule appeared at the point of inoculation in one of the four rabbits on the 105th day. One hundred and fifteen days after inoculation the papule presented a circular erosion on an indurated base. The serous fluid expressed from this lesion contained numerous treponemata on dark-field examination, and these were easily impregnated by the Fontana-Tribondeau method. A volunteer inoculated with serous fluid expressed from the rabbit's lesion developed a typical initial pinta lesion at the point of inoculation, thus proving that the scrotal lesion of the rabbit was produced by Treponema carateum or Treponema herrejoni, the causal agent of pinta, mal del pinto or carate. Four rabbits inoculated with serous fluid from the scrotal lesion of the rabbit have not yet developed visible lesions.


Distance learning in discriminative vector quantization.
Discriminative vector quantization schemes such as learning vector quantization (LVQ) and extensions thereof offer efficient and intuitive classifiers based on the representation of classes by prototypes. The original methods, however, rely on the Euclidean distance corresponding to the assumption that the data can be represented by isotropic clusters. For this reason, extensions of the methods to more general metric structures have been proposed, such as relevance adaptation in generalized LVQ (GLVQ) and matrix learning in GLVQ. In these approaches, metric parameters are learned based on the given classification task such that a data-driven distance measure is found. In this letter, we consider full matrix adaptation in advanced LVQ schemes. In particular, we introduce matrix learning to a recent statistical formalization of LVQ, robust soft LVQ, and we compare the results on several artificial and real-life data sets to matrix learning in GLVQ, a derivation of LVQ-like learning based on a (heuristic) cost function. In all cases, matrix adaptation allows a significant improvement of the classification accuracy. Interestingly, however, the principled behavior of the models with respect to prototype locations and extracted matrix dimensions shows several characteristic differences depending on the data sets.


Pleomorphic adenoma of nasal septum: a rare case.
The most common benign tumour of the major salivary glands is the pleomorphic adenoma. They are seen rarely in the minor salivary glands, usually in hard palate, soft palate and nasopharynx. Pleomorphic adenomas in nasal cavity are unusual and may be misdiagnosed because they have predominant myoepithelial cellularity and fewer myxoid stromata compared with those elsewhere. We present a case of 38-year-old male with a 2-year history of left nasal obstruction and epistaxis since 6 months. Diagnostic nasal endoscopic examination showed a soft lobulated mass in left nasal cavity attached to anterior part of the septum. Radiological examination demonstrated soft tissue mass filling left nasal cavity with an eroded septum. The biopsy from the mass was suggestive of pleomorphic adenoma and was resected endoscopically. Histopathological examination was consistent with pleomorphic adenoma. These are rare tumours of the nasal cavity and can be managed effectively with the endoscopic approach.


Mechanistic insights into RNA transphosphorylation from kinetic isotope effects and linear free energy relationships of model reactions.
Phosphoryl transfer reactions are ubiquitous in biology and the understanding of the mechanisms whereby these reactions are catalyzed by protein and RNA enzymes is central to reveal design principles for new therapeutics. Two of the most powerful experimental probes of chemical mechanism involve the analysis of linear free energy relations (LFERs) and the measurement of kinetic isotope effects (KIEs). These experimental data report directly on differences in bonding between the ground state and the rate-controlling transition state, which is the most critical point along the reaction free energy pathway. However, interpretation of LFER and KIE data in terms of transition-state structure and bonding optimally requires the use of theoretical models. In this work, we apply density-functional calculations to determine KIEs for a series of phosphoryl transfer reactions of direct relevance to the 2'-O-transphosphorylation that leads to cleavage of the phosphodiester backbone of RNA. We first examine a well-studied series of phosphate and phosphorothioate mono-, di- and triesters that are useful as mechanistic probes and for which KIEs have been measured. Close agreement is demonstrated between the calculated and measured KIEs, establishing the reliability of our quantum model calculations. Next, we examine a series of RNA transesterification model reactions with a wide range of leaving groups in order to provide a direct connection between observed Brønsted coefficients and KIEs with the structure and bonding in the transition state. These relations can be used for prediction or to aid in the interpretation of experimental data for similar non-enzymatic and enzymatic reactions. Finally, we apply these relations to RNA phosphoryl transfer catalyzed by ribonuclease A, and demonstrate the reaction coordinate-KIE correlation is reasonably preserved. A prediction of the secondary deuterium KIE in this reaction is also provided. These results demonstrate the utility of building up knowledge of mechanism through the systematic study of model systems to provide insight into more complex biological systems such as phosphoryl transfer enzymes and ribozymes.


Understanding How Charged Nanoparticles Electrostatically Assemble and Distribute in 1-D.
The effects of increasing the driving forces for a 1-D assembly of nanoparticles onto a surface are investigated with experimental results and models. Modifications, which take into account not only the particle-particle interactions but also particle-surface interactions, to previously established extended random sequential adsorption simulations are tested and verified. Both data and model are compared against the heterogeneous random sequential adsorption simulations, and finally, a connection between the two models is suggested. The experiments and models show that increasing the particle-surface interaction leads to narrower particle distribution; this narrowing is attributed to the surface interactions compensating against the particle-particle interactions. The long-term advantage of this work is that the assembly of nanoparticles in solution is now understood as controlled not only by particle-particle interactions but also by particle-surface interactions. Both particle-particle and particle-surface interactions can be used to tune how nanoparticles distribute themselves on a surface.


Challenges, coping responses and supportive interventions for international and migrant students in academic nursing programs in major host countries: a scoping review with a gender lens.
International and migrant students face specific challenges which may impact their mental health, well-being and academic outcomes, and these may be gendered experiences. The purpose of this scoping review was to map the literature on the challenges, coping responses and supportive interventions for international and migrant students in academic nursing programs in major host countries, with a gender lens. We searched 10 databases to identify literature reporting on the challenges, coping responses and/or supportive interventions for international and migrant nursing students in college or university programs in Canada, the United-States, Australia, New Zealand or a European country. We included peer-reviewed research (any design), discussion papers and literature reviews. English, French and Spanish publications were considered and no time restrictions were applied. Drawing from existing frameworks, we critically assessed each paper and extracted information with a gender lens. One hundred fourteen publications were included. Overall the literature mostly focused on international students, and among migrants, migration history/status and length of time in country were not considered with regards to challenges, coping or interventions. Females and males, respectively, were included in 69 and 59% of studies with student participants, while those students who identify as other genders/sexual orientations were not named or identified in any of the research. Several papers suggest that foreign-born nursing students face challenges associated with different cultural roles, norms and expectations for men and women. Other challenges included perceived discrimination due to wearing a hijab and being a 'foreign-born male nurse', and in general nursing being viewed as a feminine, low-status profession. Only two strategies, accessing support from family and other student mothers, used by women to cope with challenges, were identified. Supportive interventions considering gender were limited; these included matching students with support services' personnel by sex, involving male family members in admission and orientation processes, and using patient simulation as a method to prepare students for care-provision of patients of the opposite-sex. Future work in nursing higher education, especially regarding supportive interventions, needs to address the intersections of gender, gender identity/sexual orientation and foreign-born status, and also consider the complexity of migrant students' contexts.


Injectional anthrax at a Scottish district general hospital.
This retrospective, descriptive case-series reviews the clinical presentations and significant laboratory findings of patients diagnosed with and treated for injectional anthrax (IA) since December 2009 at Monklands Hospital in Central Scotland and represents the largest series of IA cases to be described from a single location. Twenty-one patients who fulfilled National Anthrax Control Team standardized case definitions of confirmed, probable or possible IA are reported. All cases survived and none required limb amputation in contrast to an overall mortality of 28% being experienced for this condition in Scotland. We document the spectrum of presentations of soft tissue infection ranging from mild cases which were managed predominantly with oral antibiotics to severe cases with significant oedema, organ failure and coagulopathy. We describe the surgical management, intensive care management and antibiotic management including the first description of daptomycin being used to treat human anthrax. It is noted that some people who had injected heroin infected with Bacillus anthracis did not develop evidence of IA. Also highlighted are biochemical and haematological parameters which proved useful in identifying deteriorating patients who required greater levels of support and surgical debridement.


Oscillatory activity in the medial prefrontal cortex and nucleus accumbens correlates with impulsivity and reward outcome.
Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50-60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7-9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.


Developing the advanced nurse practitioner role in a memory service.
This article describes how one NHS trust in northern England developed the advanced nurse practitioner (ANP) role within its memory services. It discusses how ANP roles were developed and implemented across four localities of a large NHS trust that provides a number of locally based memory services to improve the diagnostic pathway for people referred to the service and their carers. Advanced practice is considered more broadly followed by a review of the literature related to the role of the ANP and non-medical prescriber in mental health and, more specifically, memory assessment and diagnostic services. Challenges to gaining the requisite competency to work as an ANP are discussed. The need for a clear agreed strategy to ensure practitioner competence and effective governance for the introduction of these roles is described. It is argued that using this model allowed for mental health nurses within memory services to make a major contribution to the transformation of such services and receive recognition for the expansion of their role and appropriate remuneration linked to national NHS employment role profiles. The potential benefit of the ANP role more broadly in mental health services is discussed, together with factors that may have previously hindered their contribution to the transformation of services. The strategic development and planning process that led to implementing the ANP role within memory services is presented, together with a description of how the relevant higher level clinical skills required for the roles were achieved and formally accredited.


Shugoshin forms a specialized chromatin domain at subtelomeres that regulates transcription and replication timing.
A chromosome is composed of structurally and functionally distinct domains. However, the molecular mechanisms underlying the formation of chromatin structure and the function of subtelomeres, the telomere-adjacent regions, remain obscure. Here we report the roles of the conserved centromeric protein Shugoshin 2 (Sgo2) in defining chromatin structure and functions of the subtelomeres in the fission yeast Schizosaccharomyces pombe. We show that Sgo2 localizes at the subtelomeres preferentially during G2 phase and is essential for the formation of a highly condensed subtelomeric chromatin body 'knob'. Furthermore, the absence of Sgo2 leads to the derepression of the subtelomeric genes and premature DNA replication at the subtelomeric late origins. Thus, the subtelomeric specialized chromatin domain organized by Sgo2 represses both transcription and replication to ensure proper gene expression and replication timing.


Levodopa-Reduced Mucuna pruriens Seed Extract Shows Neuroprotective Effects against Parkinson's Disease in Murine Microglia and Human Neuroblastoma Cells, Caenorhabditis elegans, and Drosophila melanogaster.
Mucuna pruriens (Mucuna) has been prescribed in Ayurveda for various brain ailments including 'kampavata' (tremors) or Parkinson's disease (PD). While Mucuna is a well-known natural source of levodopa (L-dopa), published studies suggest that other bioactive compounds may also be responsible for its anti-PD effects. To investigate this hypothesis, an L-dopa reduced (<0.1%) M. pruriens seeds extract (MPE) was prepared and evaluated for its anti-PD effects in cellular (murine BV-2 microglia and human SH-SY5Y neuroblastoma cells), Caenorhabditis elegans, and Drosophila melanogaster models. In BV-2 cells, MPE (12.5⁻50 μg/mL) reduced hydrogen peroxide-induced cytotoxicity (15.7-18.6%), decreased reactive oxygen species production (29.1-61.6%), and lowered lipopolysaccharide (LPS)-induced nitric oxide species release by 8.9⁻60%. MPE (12.5-50 μg/mL) mitigated SH-SY5Y cell apoptosis by 6.9-40.0% in a non-contact co-culture assay with cell-free supernatants from LPS-treated BV-2 cells. MPE (12.5-50 μg/mL) reduced 6-hydroxydopamine (6-OHDA)-induced cell death of SH-SY5Y cells by 11.85⁻38.5%. Furthermore, MPE (12.5-50 μg/mL) increased median (25%) and maximum survival (47.8%) of C. elegans exposed to the dopaminergic neurotoxin, methyl-4-phenylpyridinium. MPE (40 μg/mL) ameliorated dopaminergic neurotoxin (6-OHDA and rotenone) induced precipitation of innate negative geotaxis behavior of D. melanogaster by 35.3 and 32.8%, respectively. Therefore, MPE contains bioactive compounds, beyond L-dopa, which may impart neuroprotective effects against PD.


Selective Targeting of TNF Receptors as a Novel Therapeutic Approach.
Tumor necrosis factor (TNF) is a central regulator of immunity. Due to its dominant pro-inflammatory effects, drugs that neutralize TNF were developed and are clinically used to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, despite their clinical success the use of anti-TNF drugs is limited, in part due to unwanted, severe side effects and in some diseases its use even is contraindicative. With gaining knowledge about the signaling mechanisms of TNF and the differential role of the two TNF receptors (TNFR), alternative therapeutic concepts based on receptor selective intervention have led to the development of novel protein therapeutics targeting TNFR1 with antagonists and TNFR2 with agonists. These antibodies and bio-engineered ligands are currently in preclinical and early clinical stages of development. Preclinical data obtained in different disease models show that selective targeting of TNFRs has therapeutic potential and may be superior to global TNF blockade in several disease indications.


Utilization Study of Antihypertensives in a South Indian Tertiary Care Teaching Hospital and Adherence to Standard Treatment Guidelines.
Hypertension represents a major health problem primarily because of its role in contributing to the initiation and progression of major cardiovascular diseases. Concerns pertaining to hypertension and its sequelae can be substantially addressed and consequent burden of disease reduced by early detection and appropriate therapy of elevated blood pressure. This cross-sectional observational study aims at analyzing the utilization pattern of antihypertensives used for the treatment of hypertension at a tertiary care hospital in perspective of standard treatment guidelines. Prescriptions were screened for antihypertensives at the medicine outpatient department of a tertiary care teaching hospital. Medical records of the patients were scrutinized after which 286 prescriptions of patients suffering from hypertension were included. The collected data were sorted and analyzed on the basis of demographic characteristics and comorbidities. The calcium channel blockers were the most frequently used antihypertensive class of drugs (72.3%). Amlodipine (55.6%) was the single most frequently prescribed antihypertensive agent. The utilization of thiazide diuretics was 9%. Adherence to the National List of Essential Medicines (NLEMs) was 65%. The combination therapy was used more frequently (51.5%) than monotherapy (48.8%). The use of angiotensin-converting enzyme inhibitors/angiotensin 2 receptor blockers (ACE-I/ARB) was 41.4% in diabetes. The treatment pattern, in general, conformed to standard treatment guidelines. Few areas, however, need to be addressed such as the underutilization of thiazide diuretics, need for more awareness of drugs from the NLEMs and enhanced use of ACE-I/ARB in diabetic hypertensives.


"Standard Care" in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials.
Background: For trials to validly evaluate new treatments, comparison against the best existing alternative treatment is essential. We reviewed the care provided to women in control arms of breast cancer clinical trials to estimate the proportion consistent with the standard of care as defined in clinical guidelines. Methods: We analyzed phase III randomized controlled breast cancer trials comparing drug treatments with "standard care," enrolling between 2004 and 2014, and registered on ClinicalTrials.gov Our primary outcome was the proportion of trials in which treatment in the control arm was consistent with concurrent NCCN Guidelines. A secondary analysis assessed trials recruiting outside the United States that provided control group therapy not consistent with NCCN Guidelines, comparing them with the German Gynecological Oncology Group (AGO) guidelines. We assessed associations between the primary outcome and a priori selected trial characteristics. Results: This study included 210 trials that recruited 229,182 women worldwide; 29% of trials (60/210) did not provide control group treatment that was consistent with NCCN Guidelines. For trials not recruiting in the United States, results were similar; in 21% of trials, control arm treatment was inconsistent with both AGO and NCCN Guidelines. Factors significantly associated with offering control arm treatment that were inconsistent with guidelines were time period (later trials were less likely to be consistent), breast cancer stage and type (trials in early-stage breast cancer and estrogen receptor-negative disease were less likely consistent), and recruitment in ≥4 countries and recruitment outside the United States. Conclusions: To ensure that clinical trials achieve their goal of obtaining the best information to guide patient treatment, the question of how investigators chose and describe "standard care" for control arm participants warrants further investigation.


The Prevalence of Prison-based Physical and Sexual Victimization in Males and Females: A Systematic Review and Meta-Analysis.
This systematic review investigated the prevalence of prison-based interpersonal harm by type of victimization (physical and sexual) and sex, along with the heterogeneity among studies using meta-regression. Using Preferred Reporting Items for Systematic Reviews and the Meta-Analysis guidelines, 24 articles met the selection criteria. Study quality was assessed using the Joana Briggs Institute (20.8% deemed low quality, 33.3% moderate, and 45.9% high). Searches were conducted in Criminal Justice Abstracts, PsycINFO, PubMed, and Web of Science. The 24 articles comprised 36 separate samples inclusive of 23,967 incarcerated individuals. The random-effects pooled prevalence estimate of prison-based physical victimization was 18.8%, with slightly higher rates for females (20.3%) than males (18.1%). For sexual victimization, the pooled prevalence estimate was 12.4%, with higher rates among females (15.3%) than males (9.7%). For females, younger individuals reported higher rates of physical and sexual victimization and studies using smaller samples had higher rates of physical victimization. Rates of physical and sexual victimization for men were higher if perpetrators included residents and staff, the recall period was since admission, data was collected using self-administered surveys, and in low-quality studies (sexual victimization only). Rates of prison-based interpersonal harm, while high, varied significantly by type of victimization, sex, and study methodology. High heterogeneity will be reduced only if future studies adhere to best methodological practices in defining and collecting data on interpersonal harm and consistently test risk and prevention factors instrumental to prevention efforts. Study limitations include the exclusion of unpublished and non-English-language studies, small sample sizes for female studies, and methodological "noise" within the literature that reduce predictive precision.


Typing of Amerindian Kichwas and Mestizos from Ecuador with the SNPforID multiplex.
A total of 119 unrelated individuals from two of the major ethnic groups in Ecuador were typed for 49 of the autosomal single nucleotide polymorphisms (SNPs) in the SNPforID 52plex using the SNapShot(®) assay. Of the above, 42 samples originated from Mestizos (an admixed population) and the remaining 77 were from Native Amerindian Kichwas. We obtained full SNP profiles in all individuals and concordance of duplicated analyses. No deviation from Hardy-Weinberg equilibrium (HWE) was observed for any SNP in the Mestizo and Kichwa populations and only one and four pairs of loci, respectively showed significant linkage disequilibrium. A relatively low genetic diversity and global positive F(IS) value was observed in Kichwas. A statistically significant global F(ST) value was obtained when the two Ecuadorian populations were compared with populations in Spain, Portugal, Argentina, Denmark, Greenland, China, Somalia and Mozambique. All pairwise F(ST) values were statistically significant. A multi-dimensional scaling based on pairwise F(ST) values showed that the Kichwa population differed from all other populations investigated and that the Mestizos had an intermediate position between Kichwas and Europeans. An admixture analysis indicated that the greater contributor to the Mestizo population was the Kichwas (71.2%) compared to the European contribution. The combined mean match probability and mean paternity exclusion probability were 3.3 × 10(-17) and 0.998, respectively, for the Mestizo population and 3.3 × 10(-14) and 0.993, respectively, for the Kichwa population.


Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review.
Ipilimumab (Yervoy; Medarex and Bristol-Myers Squibb) is a human MAB against cytotoxic T-lymphocyte antigen 4, which enhances co-stimulation of cytotoxic T-lymphocytes, resulting in their proliferation and an anti-tumour response. It is licensed for the treatment of unresectable or metastatic malignant melanoma, while multiple clinical trials using this medication in the treatment of other malignancies are ongoing. As a clinical response to ipilimumab results from immunostimulation, predictably it generates autoimmunity as well, causing immune-related adverse events in the majority of patients. Of those, endocrinopathies are frequently seen, and in particular, autoimmune lymphocytic hypophysitis with anterior panhypopituitarism has been reported a number of times in North America. We present a case of a male referred to our department with manifestations of anterior panhypopituitarism after his third dose of ipilimumab for metastatic malignant melanoma, and we discuss the management of his case in the light of previous reports. We also review the published literature on the presenting symptoms, time to presentation, investigations, imaging, treatment and follow-up of ipilimumab-induced autoimmune lymphocytic hypophysitis.


Abnormal renal glucose handling in X-linked hypophosphataemic mice.
1. The renal handling of glucose was determined in male X-linked hypophosphataemic (Hyp/Y) mice and in control littermates (+/Y) aged 4 months. Plasma glucose concentration and urinary glucose excretion were measured before and during stepwise increase in glycaemia induced by an acute infusion of glucose. The relationship between plasma glucose concentration and urinary glucose excretion was monitored per ml of glomerular filtrate in mice fed high and low phosphate diets. 2. Hyp/Y mice fed the high phosphate diet showed a significantly higher glucosuria compared with +/Y littermates. When glycaemia was increased, Hyp/Y mice developed frank glucosuria earlier than +/Y animals. In Hyp/Y mice we could not find a threshold below which virtually no glucose was excreted in the urine, whereas this was clearly visible in +/Y mice. These differences persisted in animals fed the low phosphate diet. 3. Using the acute response to the glucoregulatory hormones, glucagon and insulin, administered exogenously, we found that the regulation of plasma glucose concentration did not differ between Hyp/Y and +/Y mice. 4. The significantly lower plasma glucose concentration observed in Hyp/Y as compared with +/Y mice decreased further during fasting. 5. We conclude that the renal reabsorptive capacity for glucose is defective in Hyp/Y mice and their low plasma glucose concentration may be explained by the renal leak. Therefore the X-linked phosphataemic mouse appears not only to be characterized by a defect in renal phosphate and calcium reabsorption but also by an altered glucose reabsorption.


Proteinuria in rheumatoid arthritis--drug-induced or amyloid?
Over a 5-year period 325 patients with rheumatoid arthritis received treatment with gold (162) or D-penicillamine (163). Thirty-eight (11.7%) developed proteinuria, which persisted in 10 patients; renal biopsies in these 10 patients revealed 6 cases of amyloid disease. These 6 cases illustrate the importance of investigation of rheumatoid patients developing proteinuria even when they are receiving potentially nephrotoxic drugs.


Living Under the Constant Threat of Ebola: A Phenomenological Study of Survivors and Family Caregivers During an Ebola Outbreak.
Ebola is a highly infectious disease that is caused by viruses of the family Filoviridae and transmitted to humans by direct contact with animals infected from unknown natural reservoirs. Ebola virus infection induces acute fever and death within a few days in up to 90% of symptomatic individuals, causing widespread fear, panic, and antisocial behavior. Uganda is vulnerable to future Ebola outbreaks. Therefore, the survivors of Ebola and their family caregivers are likely to continue experiencing related antisocial overtones, leading to negative health outcomes. This study articulated the lived experiences of survivors and their family caregivers after an Ebola outbreak in Kibale District, Western Uganda. Eliciting a deeper understanding of these devastating lifetime experiences provides opportunities for developing and implementing more compassionate and competent nursing care for affected persons. Ebola survivors and their family caregivers were recruited using a purposive sampling method. Twelve (12) adult survivors and their family caregivers were recruited and were interviewed individually between May and July 2013 in Kibale, a rural district in Western Uganda close to the border of the Democratic Republic of the Congo, where Ebola virus was first discovered in 1976. Oral and written informed consent was obtained before all in-depth interviews, and the researchers adhered to principles of anonymity and confidentiality. The interviews were recorded digitally, and data analysis employed Wertz's Empirical Psychological Reflection method, which is grounded in descriptive phenomenology. Living under the constant threat of Ebola is experienced through two main categories: (a) defining features of the experience and (b) responding to the traumatizing experience. Five themes emerged in the first category: (a) fear, ostracism, and stigmatization; (b) annihilation of sufferer's actualities and possibilities; (c) the lingering nature of the traumatic experience; (d) psychosomatic manifestations; and (e) the inescapable nature of the experience. The second category was composed of two themes: (a) seeking self-preservation and protection and (b) transcending victimhood and becoming empowered. Living under the constant threat of Ebola is experienced as distressing in the physical, social, and psychological realms. In the future, prompt treatment and nursing care are recommended to minimize deaths and to reduce the widespread terror, anxiety, ostracism, and stigmatization that affected individuals and families face. Furthermore, it is recommended that the resilience of survivors and caregivers be increased to facilitate their better coping with the rampant antisocial overtones that they are likely to experience because of their association with Ebola.


Effect of cardiovascular comorbidities and concomitant aspirin use on selection of cyclooxygenase inhibitor among rheumatologists.
To evaluate the effects of cardiovascular comorbidities and aspirin coprescription on cyclooxygenase (COX)-2 inhibitor (coxib) prescribing patterns among rheumatologists. A prospective cohort study was carried out with rheumatoid arthritis and osteoarthritis patients in the Consortium of Rheumatology Researchers of North America registry. Medication and comorbidity data were obtained prospectively from physician and patient questionnaires between March 2002 and September 2003. Multivariate adjusted associations between coxib use and specific cardiovascular variables, including aspirin use, were examined. A total of 3,522 arthritis patients were included. COX inhibitors, including coxibs, nonselective nonsteroidal antiinflammatory drugs (NSAIDs), and meloxicam, were prescribed to a larger proportion of osteoarthritis patients (68.4%) than rheumatoid arthritis patients (47.1%) in our study (P < 0.001). COX inhibitors were prescribed to the majority of aspirin users (51.5%) and a similar proportion of nonusers (49.8%). In multivariate analyses, independent predictors of coxib use versus nonselective NSAID use included diagnoses of osteoarthritis (odds ratio [OR] 2.52, 95% confidence interval [95% CI] 1.81-3.52) and diabetes (OR 1.63, 95% CI 1.06-2.51). Conversely, aspirin use independently predicted selection of a nonselective NSAID rather than a coxib (OR 0.73, 95% CI 0.55-0.98). Neither a history of myocardial infarction nor stroke predicted utilization of a coxib. Similarly, cardiovascular variables did not predict the use of rofecoxib versus celecoxib. Our data indicate that COX inhibitor coprescription among aspirin users is frequent. Despite cardiovascular concerns regarding the coxibs, our data suggest that aspirin use, but not cardiovascular comorbidities, predicted the selection of nonselective NSAIDs over coxibs.


Evaluation of the National Comprehensive Cancer Network and American Urological Association renal cell carcinoma surveillance guidelines.
The National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) provide guidelines for surveillance after surgery for renal cell carcinoma (RCC). Herein, we assess the ability of the guidelines to capture RCC recurrences and determine the duration of surveillance required to capture 90%, 95%, and 100% of recurrences. We evaluated 3,651 patients who underwent surgery for M0 RCC between 1970 and 2008. Patients were stratified as AUA low risk (pT1Nx-0) after partial (LR-partial) or radical nephrectomy (LR-radical) or as moderate/high risk (M/HR; pT2-4Nx-0/pTanyN1). Guidelines were assessed by calculating the percentage of recurrences detected when following the 2013 and 2014 NCCN and AUA recommendations, and associated Medicare costs were compared. At a median follow-up of 9.0 years (interquartile range, 5.7 to 14.4 years), a total of 1,088 patients (29.8%) experienced a recurrence. Of these, 390 recurrences (35.9%) were detected using 2013 NCCN recommendations, 742 recurrences (68.2%) were detected using 2014 NCCN recommendations, and 728 recurrences (66.9%) were detected using AUA recommendations. All protocols missed the greatest amount of recurrences in the abdomen and among pT1Nx-0 patients. To capture 95% of recurrences, surveillance was required for 15 years for LR-partial, 21 years for LR-radical, and 14 years for M/HR patients. Medicare surveillance costs for one LR-partial patient were $1,228.79 using 2013 NCCN, $2,131.52 using 2014 NCCN, and $1,738.31 using AUA guidelines. However, if 95% of LR-partial recurrences were captured, costs would total $9,856.82. If strictly followed, the 2014 NCCN and AUA guidelines will miss approximately one third of RCC recurrences. Improved surveillance algorithms, which balance patient benefits and health care costs, are needed.


Synergistic effects of seasonal rainfall, parasites and demography on fluctuations in springbok body condition.
1. Seasonality of rainfall can exert a strong influence on animal condition and on host-parasite interactions. The body condition of ruminants fluctuates seasonally in response to changes in energy requirements, foraging patterns and resource availability, and seasonal variation in parasite infections may further alter ruminant body condition. 2. This study disentangles the effects of rainfall and gastrointestinal parasite infections on springbok (Antidorcas marsupialis) body condition and determines how these factors vary among demographic groups. 3. Using data from four years and three study areas, we investigated (i) the influence of rainfall variation, demographic factors and parasite interactions on parasite prevalence or infection intensity, (ii) whether parasitism or rainfall is a more important predictor of springbok body condition and (iii) how parasitism and condition vary among study areas along a rainfall gradient. 4. We found that increased parasite intensity is associated with reduced body condition only for adult females. For all other demographic groups, body condition was significantly related to prior rainfall and not to parasitism. Rainfall lagged by two months had a positive effect on body condition. 5. Adult females showed evidence of a 'periparturient rise' in parasite intensity and had higher parasite intensity and lower body condition than adult males after parturition and during early lactation. After juveniles were weaned, adult females had lower parasite intensity than adult males. Sex differences in parasitism and condition may be due to differences between adult females and males in the seasonal timing of reproductive effort and its effects on host immunity, as well as documented sex differences in vulnerability to predation. 6. Our results highlight that parasites and the environment can synergistically affect host populations, but that these interactions might be masked by their interwoven relationships, their differential impacts on demographic groups, and the different time-scales at which they operate.


Dnmt3a-mediated inhibition of Wnt in cardiac progenitor cells improves differentiation and remote remodeling after infarction.
Adult cardiac progenitor cells (CPCs) display a low capacity to differentiate into cardiomyocytes in injured hearts, strongly limiting the regenerative capacity of the mammalian myocardium. To identify new mechanisms regulating CPC differentiation, we used primary and clonally expanded Sca-1+ CPCs from murine adult hearts in homotypic culture or coculture with cardiomyocytes. Expression kinetics analysis during homotypic culture differentiation showed downregulation of Wnt target genes concomitant with increased expression of the Wnt antagonist, Wnt inhibitory factor 1 (Wif1), which is necessary to stimulate CPC differentiation. We show that the expression of the Wif1 gene is repressed by DNA methylation and regulated by the de novo DNA methyltransferase Dnmt3a. In addition, miR-29a is upregulated early during CPC differentiation and downregulates Dnmt3a expression, thereby decreasing Wif1 gene methylation and increasing the efficiency of differentiation of Sca-1+ CPCs in vitro. Extending these findings in vivo, transient silencing of Dnmt3a in CPCs subsequently injected in the border zone of infarcted mouse hearts improved CPC differentiation in situ and remote cardiac remodeling. In conclusion, miR-29a and Dnmt3a epigenetically regulate CPC differentiation through Wnt inhibition. Remote effects on cardiac remodeling support paracrine signaling beyond the local injection site, with potential therapeutic interest for cardiac repair.


Incidence and risk factors for healthcare utilisation among patients discharged on outpatient parenteral antimicrobial therapy.
Outpatient parenteral antimicrobial therapy (OPAT) programmes facilitate hospital discharge, but patients remain at risk of complications and consequent healthcare utilisation (HCU). Here we elucidated the incidence of and risk factors associated with HCU in OPAT patients. This was a retrospective, single-centre, case-control study of adult patients discharged on OPAT. Cases (n = 63) and controls (n = 126) were patients that did or did not utilise the healthcare system within 60 days. Characteristics associated with HCU in bivariate analysis (P ≤ 0.2) were included in a multivariable logistic regression model. Variables were retained in the final model if they were independently (P < 0.05) associated with 60-day HCU. Among all study patients, the mean age was 55 ± 16, 65% were men, and wound infection (22%) and cellulitis (14%) were common diagnoses. The cumulative incidence of 60-day unplanned HCU was 27% with a disproportionately higher incidence in the first 30 days (21%). A statin at discharge (adjusted odds ratios (aOR) 0.23, 95% confidence intervals (CIs) 0.09-0.57), number of prior admissions in past 12 months (aOR 1.48, 95% CIs 1.05-2.10), and a sepsis diagnosis (aOR 4.62, 95% CIs 1.23-17.3) were independently associated with HCU. HCU was most commonly due to non-infection related complications (44%) and worsening primary infection (31%). There are multiple risk factors for HCU in OPAT patients, and formal OPAT clinics may help to risk stratify and target the highest risk groups.


Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons.
We recently discovered that ICI 182,780 (1), an antagonist of estrogen receptor (ER)-dependent proliferation in reproductive tissues, functions as an estrogenic agonist in primary neurons. The present study investigated whether the agonist properties of 1 in neurons could be translated into structural analogs. 7alpha-[(4R,8R)-4,8,12-trimethyltridecyl]estra-1,3,5-trien-3,17beta-diol (2), a hybrid structure of 17beta-estradiol and vitamin E, was synthesized and found to bind to both ERalpha and ERbeta. In vitro analyses demonstrated that 2 was neuroprotective and effective in activating molecular mechanisms associated with estrogenic agonist activity in rat primary hippocampal neurons. Collectively, the data support an estrogenic agonist profile of 2 action comparable to 1 in primary neurons, confirming that estrogenic activity of 1 in neurons is not a unique phenomenon. These results provide support for the development of a brain-selective ER modulator, with potential as an efficacious and safe estrogen alternative to prevent Alzheimer's disease and cognitive decline in postmenopausal women.


Updates to the zoonotic niche map of Ebola virus disease in Africa.
As the outbreak of Ebola virus disease (EVD) in West Africa is now contained, attention is turning from control to future outbreak prediction and prevention. Building on a previously published zoonotic niche map (Pigott et al., 2014), this study incorporates new human and animal occurrence data and expands upon the way in which potential bat EVD reservoir species are incorporated. This update demonstrates the potential for incorporating and updating data used to generate the predicted suitability map. A new data portal for sharing such maps is discussed. This output represents the most up-to-date estimate of the extent of EVD zoonotic risk in Africa. These maps can assist in strengthening surveillance and response capacity to contain viral haemorrhagic fevers.


Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice.
Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8+/N2373K) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.


Seasonal exposure to drought and air warming affects soil Collembola and mites.
Global environmental changes affect not only the aboveground but also the belowground components of ecosystems. The effects of seasonal drought and air warming on the genus level richness of Collembola, and on the abundance and biomass of the community of Collembola and mites were studied in an acidic and a calcareous forest soil in a model oak-ecosystem experiment (the Querco experiment) at the Swiss Federal Research Institute WSL in Birmensdorf. The experiment included four climate treatments: control, drought with a 60% reduction in rainfall, air warming with a seasonal temperature increase of 1.4 °C, and air warming + drought. Soil water content was greatly reduced by drought. Soil surface temperature was slightly increased by both the air warming and the drought treatment. Soil mesofauna samples were taken at the end of the first experimental year. Drought was found to increase the abundance of the microarthropod fauna, but reduce the biomass of the community. The percentage of small mites (body length ≤ 0.20 mm) increased, but the percentage of large mites (body length >0.40 mm) decreased under drought. Air warming had only minor effects on the fauna. All climate treatments significantly reduced the richness of Collembola and the biomass of Collembola and mites in acidic soil, but not in calcareous soil. Drought appeared to have a negative impact on soil microarthropod fauna, but the effects of climate change on soil fauna may vary with the soil type.


Modelling the transmission and control strategies of varicella among school children in Shenzhen, China.
Varicella (chickenpox) is a highly transmissible childhood disease. Between 2010 and 2015, it displayed two epidemic waves annually among school populations in Shenzhen, China. However, their transmission dynamics remain unclear and there is no school-based vaccination programme in Shenzhen to-date. In this study, we developed a mathematical model to compare a school-based vaccination intervention scenario with a baseline (i.e. no intervention) scenario. Data on varicella reported cases were downloaded from the Infectious Disease Reporting Information Management System. We obtained the population size, age structure of children aged 15 or under, the class and school distribution from Shenzhen Education Bureau. We developed an Agent-Based Susceptible-Exposed-Infectious-Recovered (ABM-SEIR) Model that considered within-class, class-to-class and out-of-school transmission modes. The intervention scenario was that school-wide vaccination intervention occurred when an outbreak threshold was reached within a school. We varied this threshold level from five to ten cases. We compared the reduction of disease outbreak size and estimated the key epidemiological parameters under the intervention strategy. Our ABM-SEIR model provided a good model fit to the two annual varicella epidemic waves from 2013 to 2015. The transmission dynamics displayed strong seasonality. Our results suggested that a school-based vaccination strategy could effectively prevent large outbreaks at different thresholds. There was a considerable increase in reported varicella cases from 2013 to 2015 in Shenzhen. Our modelling study provided important theoretical support for disease control decision making during school outbreaks and the development of a school-based vaccination programme.


A Cretaceous scleractinian coral with a calcitic skeleton.
It has been generally thought that scleractinian corals form purely aragonitic skeletons. We show that a well-preserved fossil coral, Coelosmilia sp. from the Upper Cretaceous (about 70 million years ago), has preserved skeletal structural features identical to those observed in present-day scleractinians. However, the skeleton of Coelosmilia sp. is entirely calcitic. Its fine-scale structure and chemistry indicate that the calcite is primary and did not form from the diagenetic alteration of aragonite. This result implies that corals, like other groups of marine, calcium carbonate-producing organisms, can form skeletons of different carbonate polymorphs.


Resistance mechanisms and population structure of highly drug resistant Klebsiella in Pakistan during the introduction of the carbapenemase NDM-1.
Klebsiella pneumoniae is a major threat to public health with the emergence of isolates resistant to most, if not all, useful antibiotics. We present an in-depth analysis of 178 extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae collected from patients resident in a region of Pakistan, during the period 2010-2012, when the now globally-distributed carbapenemase bla-NDM-1 was being acquired by Klebsiella. We observed two dominant lineages, but neither the overall resistance profile nor virulence-associated factors, explain their evolutionary success. Phenotypic analysis of resistance shows few differences between the acquisition of resistance genes and the phenotypic resistance profile, including beta-lactam antibiotics that were used to treat ESBL-positive strains. Resistance against these drugs could be explained by inhibitor-resistant beta-lactamase enzymes, carbapenemases or ampC type beta-lactamases, at least one of which was detected in most, but not all relevant strains analysed. Complete genomes for six selected strains are reported, these provide detailed insights into the mobile elements present in these isolates during the initial spread of NDM-1. The unexplained success of some lineages within this pool of highly resistant strains, and the discontinuity between phenotypic resistance and genotype at the macro level, indicate that intrinsic mechanisms contribute to competitive advantage and/or resistance.


Super-resolution spectral estimation of optical micro-angiography for quantifying blood flow within microcirculatory tissue beds in vivo.
In this paper, we propose a super-resolution spectral estimation technique to quantify microvascular hemodynamics using optical microangiography (OMAG) based on optical coherence tomography (OCT). The proposed OMAG technique uses both amplitude and phase information of the OCT signals which makes it sensitive to the axial and transverse flows. The scanning protocol for the proposed method is identical to three-dimensional ultrahigh sensitive OMAG, and is applicable for in vivo measurements. In contrast to the existing capillary flow quantification methods, the proposed method is less sensitive to tissue motion and does not have aliasing problems due fast flow within large blood vessels. This method is analogous to power Doppler in ultrasonography and estimates the number of red blood cells passing through the beam as opposed to the velocity of the particles. The technique is tested both qualitatively and quantitatively by using OMAG to image microcirculation within mouse ear flap in vivo.


Radionuclide imaging in the diagnosis of osteoid osteoma.
Oseteoid osteoma is a well-known type of benign bone-forming tumor, which has previously been diagnosed using plain radiograph imaging. However, diagnosis of osteoid osteoma may be delayed due to ambiguities on plain radiograph images; despite the increasing use of magnetic resonance imaging (MRI), this type of misdiagnosis is not uncommon. The aim of the present study was to evaluate the effectiveness of radionuclide imaging scans for the diagnosis of osteoid osteoma, as this form of imaging was proposed to be a more sensitive test. The characteristics of 18 cases of osteoid osteoma were analyzed based on diagnostic imaging and the time from initial recognition of symptoms by the patient to diagnosis. Diagnostic modalities included plain radiograph, computed tomography (CT), MRI and radionuclide imaging. Among the 18 patients, 14 patients had unique positive findings in plain radiographs. The mean duration between initial cognition of symptoms to the diagnosis for these patients was 5.2 months (range, 3.8-9.3 months). A total of 4 patients exhibited no radiographic abnormalities in the initial plain radiographs and were diagnosed a mean of 18.5 months (range, 17-20 months) following the onset of symptoms. Overall, radionuclide imaging was performed on 16 patients and all of the cases demonstrated positive findings. In these cases, 28.6% of osteoid osteoma patients with clinical indications revealed no abnormal findings in plain radiographs. Therefore, in situations such as these, radionuclide imaging may be a useful indicator for diagnosis, as these results have demonstrated that it positively identified all cases of osteoid osteoma. In addition, the results of the present study indicated that if the radionuclide imaging was positive, CT scan was a more valuable diagnostic tool, whereas if the radionuclide imaging was negative, MRI should be recommended for the diagnosis of other undiscovered disease entities.


Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor β-1 Activation Mechanism.
PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2) hydroxylates lysine residues in collagen telopeptides and is essential for collagen pyridinoline cross-link formation. PLOD2 expression and subsequent pyridinoline cross-links are increased in fibrotic pathologies by transforming growth factor β-1 (TGFβ1). In this report we examined the molecular processes underlying TGFβ1-induced PLOD2 expression. We found that binding of the TGFβ1 pathway related transcription factors SMAD3 and SP1-mediated TGFβ1 enhanced PLOD2 expression and could be correlated to an increase of acetylated histone H3 and H4 at the PLOD2 promoter. Interestingly, the classical co-activators of SMAD3 complexes, p300 and CBP, were not responsible for the enhanced H3 and H4 acetylation. Depletion of SMAD3 reduced PLOD2 acetylated H3 and H4, indicating that another as of yet unidentified histone acetyltransferase binds to SMAD3 at PLOD2. Assessing histone methylation marks at the PLOD2 promoter depicted an increase of the active histone mark H3K79me2, a decrease of the repressive H4K20me3 mark, but no role for the generally strong transcription-related modifications: H3K4me3, H3K9me3 and H3K27me3. Collectively, our findings reveal that TGFβ1 induces a SP1- and SMAD3-dependent recruitment of histone modifying enzymes to the PLOD2 promoter other than the currently known TGFβ1 downstream co-activators and epigenetic modifications. This also suggests that additional activation strategies are used downstream of the TGFβ1 pathway, and hence their unraveling could be of great importance to fully understand TGFβ1 activation of genes.


Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.
We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.


Prospective study of telomere length and LINE-1 methylation in peripheral blood cells: the role of B vitamins supplementation.
Deficiencies of folate, vitamins B12 and D are common age-related conditions. Vitamin B12 and folate are necessary for DNA methylation. Telomeres appear to be regulated by DNA methylation. Here, we study the effect of B vitamins supplementation on telomere length and global DNA methylation in a prospective study. In total, 60 elderly subjects were supplemented for 1 year with either vitamin B12, B6, folate, vitamin D and calcium (group A n = 31) or only vitamin D and calcium (group B n = 29). LINE-1 methylation, relative telomere length (T/S), vitamin B12, folate, homocysteine (tHcy) , 5-methyltetrahydrofolate (5-methylTHF), S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), cystathionine and vitamin D were quantified before and after supplementation. At baseline, tHcy was high, vitamin D was low, and T/S did not differ between groups A and B. Vitamin supplementation increased LINE-1 methylation in group A at site 317 but reduced LINE-1 methylation in group B at site 327. There was no correlation between T/S and LINE-1 methylation at baseline. Multiple backward regression analysis revealed baseline tHcy and 5-methylTHF are significant predictors of T/S. After supplementation in group B but not in group A, LINE-1 methylation correlated inversely with T/S, and LINE-1 methylation variation was an independent predictor of T/S variation. B vitamins decreased tHcy significantly in group A. Multiple backward regression analysis showed 5-methylTHF in group A and tHcy in group B were significant predictors for LINE-1 methylation. At baseline, the lower LINE-1 methylation observed in subjects with 5-methylTHF >10 nmol/l was in agreement with a reduced methyl group transfer due to a lower SAM formation. In group B, an increase in telomere length was correlated with lower LINE-1 methylation. Subjects with hyperhomocysteinemia >12 µmol/L had compared to those with normal tHcy a reduced LINE-1 methylation accompanied by a higher SAM and SAH (that inhibits demethylation of SAM) as well as lower 5-methylTHF. Additionally, subjects with tHcy > 12 µmol/L had longer telomeres when compared with subjects having tHcy < 12 µmol/L. The results suggest a possible effect of B vitamins for telomere biology in blood cells. Suboptimal B vitamins status and hyperhomocysteinemia are associated with altered DNA methylation and telomere length. These data have to be confirmed in future studies.


WNT secretion and signalling in human disease.
Wnt signalling, a key pathway involved in various aspects of embryonic development, also underlies many human diseases, in particular, cancer. Research focused on signal transduction within signal-receiving cells led to the discovery of many Wnt pathway components, but study of the secretion of Wnt ligands themselves was neglected until recently. Attention was drawn to this highly regulated process by the association of aberrant Wnt levels with an increasing number of diseases. Studying the biogenesis and processing of active Wnt ligands will open new avenues for generating therapeutics to specifically target aberrant Wnt signalling. Here we review the proteins required for Wnt secretion and signalling at the plasma membrane, ending with a discussion on potential therapeutic approaches to treat Wnt-induced diseases.


Evaluation of a tablet PC technology to screen and educate oncology patients.
The aim of the study was to evaluate The Patient Assessment, Care and Education (PACE) System-an electronic patient symptom screening and reporting system for oncology. Specifically, the study determined provider and patient opinions of The PACE System and documented evidence as to whether symptom assessment rates increased after this system was implemented. Ninety-two providers (i.e., physicians, nurse practitioners, and physician assistants) at 16 community oncology clinics were surveyed about their experiences with The PACE System. In addition, 100 patients at two community oncology clinics were surveyed about their perceptions of The PACE System. Finally, at two oncology clinics, 100 patient charts were abstracted in the year before implementation of The PACE System, and 100 patient charts were abstracted in the year after its implementation to evaluate changes in symptom assessment rates. Providers seemed to value the system. In particular, they reported that the screening and reporting system helped them to identify, track, and document the patients' most important symptoms. The patient survey indicated that the majority of patients at the two sites found the system easy to use and generally helpful and would recommend it to others. The chart review indicated that assessment rates for depression, fatigue, and pain increased after The PACE System was implemented. The PACE System appears to be a promising approach to addressing the widespread problem of under-identification and under-treatment of symptoms in patients receiving cancer treatment.


A novel two-step mild hyperthermia for advanced liposomal chemotherapy.
Liposomal chemotherapy brings the advantage of minimizing systemic toxicity towards healthy organs and tissues, while has the drawbacks of limited nanoparticle accumulation and low drug bioavailability at targeted tumors. The aim of our study is to apply a clinically available mild hyperthermia (HT) treatment with thermosensitive liposomes (TSL) to tackle both issues. A two-step HT approach was combined with systemic administration of doxorubicin (Dox) TSL, in a first step to maximize nanoparticle accumulation in tumors and second step to actively trigger Dox release. The therapeutic activity of the two-step approach was compared to a one-step HT triggering intravascular Dox release from circulating TSL. Whereas the intravascular drug release approach requires fast releasing Dox-TSL (Dox-fTSL), the TSL formulation used in the two-step approach is fine-tuned to prolong Dox retention at physiological temperature in circulation, while releasing their drug content at mild HT at a slower rate (Dox-sTSL). Cytotoxicity assays show that a first-step HT at 41°C for 1h causes no drug resistance on murine BFS-1 sarcoma, human BLM melanoma cell lines and Human Umbilical Vein Endothelial Cells (HUVEC) towards subsequent exposure to Dox. However, HT sensitizes HUVEC towards Dox at higher concentrations (10-100μM). After 2h of intratumoral Dox-TSL accumulation, HT at 42°C for 1h was applied to trigger Dox release from Dox-sTSL. Quantification of intratumoral Dox accumulation revealed that the two-step HT approach increased TSL accumulation and Dox bioavailability reaching levels comparable to the intravascular release approach. The two-step HT in combination with Dox-sTSL delayed tumor growth for 12days compared to PBS group, however, was less effective compared to intravascular Dox release from Dox-fTSL using one-step HT. The two-step approach focuses on interstitial drug release upon mild HT, instead of intravascular drug release. This novel two-step approach represents an attractive alternative for the treatment of large and deep seated tumors, which are difficult to heat precisely and require loco-regional HT of the tumor area and accumulated Dox-sTSL therein to obtain a precise intratumoral drug delivery.


Characteristics and response to treatment of posttraumatic temporomandibular disorder: a retrospective study.
Temporomandibular disorders (TMDs) are likely the most common cause of persistent pain in the head and neck. Treatment for TMDs can be quite varied although, in general, favorable treatment outcome is reported to be on the order of 75-80%, regardless of treatment approach. However, it has been reported that patients suffering from posttraumatic TMDs, and, in particular, patients who have been involved in motor vehicle accidents (MVAs), do not respond as well to therapy. Therefore, this study was undertaken to elucidate some of the historical and clinical features of posttraumatic TMDs and to compare this with the features of TMDs that developed independent of identifiable trauma. Furthermore, a comparison between recovery rates in the two populations was undertaken as well as a comparison of the treatment modalities used in the two groups. Fifty-two posttraumatic TMD patients were compared to an age- and sex-matched population of "routine" TMD patients whose conditions developed independent of trauma. Treatment, consisting of various accepted modalities, ranged from 3 to 5 years after the MVA, with progress assessed at each visit. The data indicate that 48% of posttraumatic TMD and 75% of TMD patients reported recovery with treatment (p less than 0.001). The posttraumatic TMD patients required significantly more treatment than the control TMD population. The findings suggest further that 60% of MVA TMD patients suffer from symptoms suggestive of affective disorder compared to only 14% of TMD patients. In view of the above, it appears that posttraumatic TMD patients do not respond to therapy as well as the control subjects. While the mechanisms underlying this finding are not clear, it could be related to a difference in underlying pathophysiology. The data showing that posttraumatic TMD patients develop significantly more symptoms suggestive of affective disorders than control TMD patients could imply that there is a relationship between these findings that requires further study.


Imiquimod reactivation of lichen planus.
A 44-year-old man who was previously diagnosed with actinic cheilitis was prescribed imiquimod cream 5%, which resulted in thick hemorrhagic crusting of the lower lip after 4 applications. He subsequently noted the development of lichen planus lesions on his arms and legs for the first time in 15 years following imiquimod use. On follow-up he also was noted to have characteristic Wickham striae on his lower lip. Lichen planus is an autoimmune inflammatory condition in which autoreactive T lymphocytes attack keratinocytes. The mechanism of action for imiquimod is upregulation of IFN-alpha and IFN-beta. Treatment with clobetasol cream 0.05% led to resolution of his lichen planus lesions.


Weight and plasma lipid control by decaffeinated green tea.
We investigated whether regular decaffeinated green tea intake could modulate body weight in an experimental model of obesity. Male leptin-deficient (ob/ob) mice and their C57BL/6J lean littermates (4 weeks of age; n 20/genotype) were assigned randomly to receive either decaffeinated green tea or vehicle, for 6 weeks. Body weights were recorded weekly and fluid intake was measured at each replacement. Blood was collected from the heart into collection tubes, with Li(+)-heparin as the anticoagulant. Administration of decaffeinated green tea to ob/ob mice significantly slowed their rate of weight gain, as compared with animals that were fed buffer alone. This effect is apparent after only 1 week of supplementation. No significant difference was recorded between C57BL/6J lean mice administrated decaffeinated green tea and those given buffer alone. Decaffeinated green tea consumption by ob/ob mice was also associated with significantly lower cholesterolemia, triglyceridemia, and adiponectin concentration. Fecal lipids did not change significantly throughout the experiment. In conclusion, administration of decaffeinated green tea might contribute to weight control and provides an opportunity for through-the-day consumption, without the excitatory effects of caffeine.


Surface modification of smooth poly(L-lactic acid) films for gelatin immobilization.
Poly(L-lactic acid) (PLLA) is widely used in drug delivery and medical implants. Surface modification of PLLA with functional groups to immobilize gelatin or other extracellular matrix proteins is commonly used to improve its cellular affinity. In this work, we use the oxygen plasma to treat PLLA film followed by modification with organosilanes with different functional groups, such as amine, epoxy, and aldehyde groups. Gelatin is then immobilized on the modified PLLA film, which is confirmed by water contact angle measurement, atomic force microscopy (AFM), and laser scanning confocal microscopy (LSCM). Among the used organosilanes, aminosilane is the best one for modification of PLLA used for immobilization of gelatin with the highest efficiency. Moreover, the cellular affinity of gelatin-immobilized PLLA is studied through the evaluation of cell proliferation and focal adhesion using the human umbilical vein endothelial cells (HUVECs). Our experimental results show that the gelatin immobilized on aminosilane- and aldehyde-silane-modified PLLA improves the cellular affinity of HUVECs, whereas that immobilized on epoxy-silane-modified PLLA does not show significant improvement on the cell proliferation.