Densitometric and tomographic analyses of musculoskeletal interactions in humans.
Previous studies with standard densitometry (DXA) have suggested that the bone mass is strongly dependent on the muscle mass in the species, following a similar relationship at any age and sex hormones or related factors potentiate that relationship. Studies with pQCT indicated that the surplus bone mass per unit of muscle mass previously observed in premenopausal women would be stored in skeletal regions with relatively little mechanical relevance, thus avoiding remotion through mechanically oriented remodelling by the bone mechanostat. Scanning the distal radius with pQCT has also showed a highly significant, linear relationship between SSI of the distal radius and the dynamometric maximal bending moment of the forearm in normal men and women. In order to investigate similar relationships in regions that are inaccessible to pQCT, we used spinal radiographs and axial QCT. This study affords additional evidence to the previous references concerning the direct, significant impact of the regional muscle strength on the determination of the tomographic indicators of bone mechanical quality and their indirect repercussion of the skeletal condition (curvature of the spine).


About information systems.
Who should be involved when introducing a new information system? How will the budget be used? In this column, experts offer suggestions.


Influence of raphe nuclei on neuronal transmission from perforant pathway through dentate gyrus.
1. In chronically prepared, freely moving rats, electrical stimulation was applied to the perforant pathway and monosynaptic responses were recorded extracellularly in the ipsilateral dentate gyrus. In some tests a stimulus was also applied to the median raphe nucleus (mr) prior to activating the perforant pathway. Experiments were performed during two behavioral conditions: slow-wave sleep (SWS) and the still, alert state (SAL). Two varieties of evoked responses were recorded: those due to synchronous firing of neuronal action potentials (evoked action potentials or EAPs) and those produced by excitatory synaptic activity (evoked synaptic potentials or ESPs). 2. As reported previously (38), perforant path stimulation elicited EAPs of greater magnitude during SWS than during SAL. The application of a prior stimulus to mr (prestimulation) markedly increased the already elevated EAPs observed during SWS. The EAPs during SAL were unaffected by prestimulation. 3. The minimum delay time (time between mr and perforant path stimuli) at which the augmentation of the EAPs appeared during SWS was approximately 5 ms. The augmentation reached a maximum at delay times of 25-40 ms and was present up to a delay time of 150 ms. 4. As in former experiments (38), ESPs recorded in the molecular layer of the dentate gyrus after perforant path stimulation were found to be greater during SAL than during SWS. Prestimulation of mr had no significant effect on the ESPs at any level of the molecular layer during either SWS or SAL. 5. The perforant path afferent volley was recorded at high gain in the dentate gyrus. Its amplitude was found to be solely dependent on perforant path stimulus intensity and not on behavioral state or the prestimulation of mr. 6. In preparations anesthetized with Chloropent (82% chloral hydrate, 18% pentobarbital; Fort Dodge Laboratories, Fort Dodge, IA), prestimulation was applied at each of a number of loci within the pons and medulla, including mr, As in SWS, prestimulating mr resulted in augmented EAPs with a minimum delay time of 5 ms. Similar augmented responses were observed when stimulation was applied at other raphe nuclei (dorsal raphe, pontis, magnus, and pallidus), but there was no augmentation when stimulation was applied at other brain stem sites. Threshold stimulus intensities for producing augmented EAPs in the raphe nuclei were less than 30 microA. 7. In freely moving animals it was first established that the EAP responses during SWS were markedly greater than during SAL. Midline lesions were then made at the rostrocaudal level of mr. Following the lesions, there was no longer any significant difference in the magnitude of the EAPs recorded during the two behaviors. 8. These findings suggest that tonic influences arising from raphe nuclei during SWS may be involved in the facilitation of neuronal transmission through the dentate gyrus observed during this behavioral state.


Randomized controlled study to evaluate the effectiveness of dexamethasone oral minipulse therapy versus oral minocycline in patients with active vitiligo vulgaris.
Oral minocycline has been recently shown to halt disease progression in active vitiligo. The present study was planned to compare the efficacy and tolerability of oral minocycline with oral mini pulse (OMP) corticosteroids in active vitiligo. A total of 50 patients with actively spreading vitiligo were randomized to receive either minocycline 100 mg/day (Group I-25 patients) or OMP 2.5 mg dexamethasone on 2 consecutive days in a week (Group II-25 patients) for 6 months. These were followed-up at every 2 weeks interval. Mean vitiligo disease activity score (VIDA) and mean Vitiligo Area Scoring Index (VASI) were assessed in all patients in addition to the photographic comparison before and after treatment. Both groups showed a significant decrease in VIDA from 4.0 to 1.64±0.86 (P<0.001) in Group I and from 4.0 to 1.68±0.69 (P<0.001) in Group II. However, the difference between the mean VIDA scores in the two groups was not statistically significant (P=0.60) at the end of treatment period. The mean VASI declined from 1.71±1.45 to 1.52±1.43 Group I (P=0.06) and from 1.39±1.31 to 1.17±1.34 in Group II (P=0.05). The difference between VASI in Group I and II was not significant at the end of 24 weeks of treatment (P=0.11). Both dexamethasone OMP and oral minocycline are effective drugs for managing the arrest of disease activity in vitiligo.


Cell Therapy in the Treatment of Coronary Heart Disease.
Heart failure is a leading cause of death in patients who have suffered a myocardial infarction. Despite the timely use of modern reperfusion therapies such as thrombolysis, surgical revascularization and balloon angioplasty, they are sometimes unable to prevent the development of significant areas of myocardial damage and subsequent heart failure. Research efforts have focused on developing strategies to improve the functional status of myocardial injury areas. Consequently, the restoration of cardiac function using cell therapy is an exciting prospect. This review describes the characteristics of various cell types relevant to cellular cardiomyoplasty and presents findings from experimental and clinical studies investigating cell therapy for coronary heart disease. Cell delivery methods, optimal dosage and potential treatment mechanisms are discussed.


Design, Synthesis, and Targeted Delivery of an Immune Stimulant that Selectively Reactivates Exhausted CAR T Cells.
Although chimeric antigen receptor (CAR) T cells have demonstrated significant promise in suppressing hematopoietic cancers, their applications in treating solid tumors have been limited by onset of CAR T cell exhaustion that accompanies continuous CAR T cell exposure to tumor antigen. To address this limitation, we have exploited the abilities of recently designed universal CARs to bind fluorescein and internalize a fluorescein-TLR7 agonist conjugate by CAR-mediated endocytosis. We demonstrate here that anti-fluorescein CAR-mediated uptake of a fluorescein-TLR7-3 conjugate can reactivate exhausted CAR T cells, leading to dramatic reduction in T cell exhaustion markers (PD-1+ Tim-3+ ) and shrinkage of otherwise resistant tumors without inducing systemic activation of the immune system. We conclude that CAR T cell exhaustion can be reversed by administration of a CAR-targeted TLR7 agonist, thereby enabling the CAR T cells to successfully treat solid tumors without incurring the systemic toxicity that commonly accompanies administration of nontargeted TLR7 agonists.


Baicalin Weakens Staphylococcus aureus Pathogenicity by Targeting Sortase B.
Staphylococcus aureus (S. aureus) is a human and other animal pathogen that contributes to the primary etiology of nosocomial pneumonia, a disease with high mortality rates and costs. Treatment of multidrug-resistant S. aureus infection is extremely challenging, and new therapeutic strategies beyond antibiotic treatment are needed. Anti-virulence agents that specifically target the molecular determinants of virulence may be a novel method for treating drug-resistant nosocomial infections. Sortase B (SrtB) is a crucial virulence factor in S. aureus and plays an important role during infection. In this study, we find that baicalin suppresses the activity of SrtB. Minimum inhibitory concentration and growth curve assays confirmed that baicalin has no anti-S. aureus properties. We performed live/dead, lactate dehydrogenase (LDH), adherence, and enzyme-linked immunosorbent assays to confirm that baicalin reduced human alveolar epithelial A549 cell injury caused by S. aureus, reduced the adherence of S. aureus to A549 cells, and significantly attenuated the inflammatory response of mouse macrophage J774 cells to S. aureus. Additionally, we were able to elucidate the binding mechanics and identify the interacting sites of baicalin and SrtB via a molecular dynamics simulation, site-directed mutagenesis, and fluorescence spectroscopy quenching. Finally, we confirmed that baicalin directly binds to the active center of SrtB, and the residues Asn92 and Tyr128 perform an important function in the interaction of SrtB and baicalin. Taken together, these data indicate that baicalin is a promising candidate to combat S. aureus infections.


[Properties of 6-phosphogluconate dehydrogenase from livers of healthy and neoplastic rats].
The steady state kinetics of 6-phosphogluconate dehydrogenase from the liver of healthy and neoplastic rats (sarcoma S-45) were studied. The kinetic measurements were carried out at 18 degrees in a glycyl-glycine buffer, pH 7.6. The kinetic analysis of the purified enzyme preparations included determination of initial rates of the reaction and calculation of the kinetic plots of the reaction according to Cleland and Eisenthal and Kornish-Bouden. A comparison of the kinetic data for all experimental series allowed to postulate the absence of damages in the total mechanism of the reaction in case of neoplastic rats; however, the rate constants for individual steps of this process are changed as can be evidenced from the Km values for the substrates. The normalizing effect of hydroxythiamine injected parenterally into neoplastic animals on the kinetic parameters of 6-phosphogluconate dehydrogenase was observed.


Aortoiliac reconstructive surgery based upon the results of duplex scanning.
To evaluate whether duplex scanning can replace angiography in patients operated for aortoiliac obstructive disease. Retrospective. Between January 1995 and October 1996, 44 patients underwent vascular surgery of the aortoiliac tract. The study population was divided into two groups; patients operated upon the results of duplex scanning only and patients who also underwent angiography prior to surgery. The additional value of angiography and the differences between both groups concerning unexpected peroperative findings, early postoperative failures and the need for additional radiological or surgical interventions in the first three postoperative months were studied. Duplex scan group: 22 patients were operated upon the results of duplex scanning only. In two patients surgical strategy had to be changed. Early postoperative graft occlusion occurred in one case. A haemodynamically significant graft stenosis within 3 months of surgery occurred in one patient. Duplex/angiography group: 22 patients underwent both duplex scanning and angiography. Six patients underwent diagnostic angiography after failed duplex scanning. In 10 patients angiography was part of percutaneous transluminal angioplasty prior to surgery. In six patients angiograms were performed after successful duplex scanning. Angiography failed in two patients and added information in four of 16 patients. Unexpected findings at operation occurred in four patients. Graft stenosis within 3 months was detected in three patients. After successful duplex scanning information obtained by angiography has only a limited impact on therapeutic decision-making. In the majority of patients vascular reconstructive surgery of aortoiliac arteries can be planned based on duplex scanning only.


Strongyluris panamaensis n. sp. (Nematoda: Heterakidae) and other helminths from the lizard, Anolis biporcatus (Sauria: Polychrotidae), from Panama.
Strongyluris panamaensis n. sp. from the intestine of Anolis biporcatus collected in Panama is described and illustrated. Strongyluris panamaensis represents the 30th species assigned to this genus and the fourth from the neotropical region. Strongyluris panamaensis can be easily distinguished from all other neotropical species because it has the shortest spicule. In addition to S. panamaensis, 3 species of Trematoda, Mesocoelium monas, Parallellopharynx arctus, and Urotrema scabridum, and 3 species of Nematoda, Crytosomum penneri, Oswaldocruzia bainae, and Piratuba digiticauda, were identified.


Adaptation via symbiosis: recent spread of a Drosophila defensive symbiont.
Recent studies have shown that some plants and animals harbor microbial symbionts that protect them against natural enemies. Here we demonstrate that a maternally transmitted bacterium, Spiroplasma, protects Drosophila neotestacea against the sterilizing effects of a parasitic nematode, both in the laboratory and the field. This nematode parasitizes D. neotestacea at high frequencies in natural populations, and, until recently, almost all infections resulted in complete sterility. Several lines of evidence suggest that Spiroplasma is spreading in North American populations of D. neotestacea and that a major adaptive change to a symbiont-based mode of defense is under way. These findings demonstrate the profound and potentially rapid effects of defensive symbionts, which are increasingly recognized as major players in the ecology of species interactions.


Deacetylation of Histone H4 Accompanying Cardiomyogenesis is Weakened in HDAC1-Depleted ES Cells.
Cell differentiation into cardiomyocytes requires activation of differentiation-specific genes and epigenetic factors that contribute to these physiological processes. This study is focused on the in vitro differentiation of mouse embryonic stem cells (mESCs) induced into cardiomyocytes. The effects of clinically promising inhibitors of histone deacetylases (HDACi) on mESC cardiomyogenesis and on explanted embryonic hearts were also analyzed. HDAC1 depletion caused early beating of cardiomyocytes compared with those of the wild-type (wt) counterpart. Moreover, the adherence of embryonic bodies (EBs) was reduced in HDAC1 double knockout (dn) mESCs. The most important finding was differentiation-specific H4 deacetylation observed during cardiomyocyte differentiation of wt mESCs, while H4 deacetylation was weakened in HDAC1-depleted cells induced to the cardiac pathway. Analysis of the effect of HDACi showed that Trichostatin A (TSA) is a strong hyperacetylating agent, especially in wt mESCs, but only SAHA reduced the size of the beating areas in EBs that originated from HDAC1 dn mESCs. Additionally, explanted embryonic hearts (e15) responded to treatment with HDACi: all of the tested HDACi (TSA, SAHA, VPA) increased the levels of H3K9ac, H4ac, H4K20ac, and pan-acetylated lysines in embryonic hearts. This observation shows that explanted tissue can be maintained in a hyperacetylation state several hours after excision, which appears to be useful information from the view of transplantation strategy and the maintenance of gene upregulation via acetylation in tissue intended for transplantation.


Experimental radiative cooling rates of a polycyclic aromatic hydrocarbon cation.
Several small Polycyclic Aromatic Hydrocarbons (PAHs) have been identified recently in the Taurus Molecular Cloud (TMC-1) using radio telescope observations. Reproducing the observed abundances of these molecules has been a challenge for astrochemical models. Rapid radiative cooling of PAHs by Recurrent Fluorescence (RF), the emission of optical photons from thermally populated electronically excited states, has been shown to efficiently stabilize small PAHs following ionization, augmenting their resilience in astronomical environments and helping to rationalize their observed high abundances. Here, we use a novel method to experimentally determine the radiative cooling rate of the cation of 1-cyanonaphthalene (C10H7CN, 1-CNN), the neutral species of which has been identified in TMC-1. Laser-induced dissociation rates and kinetic energy release distributions of 1-CNN cations isolated in a cryogenic electrostatic ion-beam storage ring are analysed to track the time evolution of the vibrational energy distribution of the initially hot ion ensemble as it cools. The measured cooling rate is in good agreement with the previously calculated RF rate coefficient. Improved measurements and models of the RF mechanism are needed to interpret astronomical observations and refine predictions of the stabilities of interstellar PAHs.


Ultrastructural characterization of arterivirus replication structures: reshaping the endoplasmic reticulum to accommodate viral RNA synthesis.
Virus-induced membrane structures support the assembly and function of positive-strand RNA virus replication complexes. The replicase proteins of arteriviruses are associated with double-membrane vesicles (DMVs), which were previously proposed to derive from the endoplasmic reticulum (ER). Using electron tomography, we performed an in-depth ultrastructural analysis of cells infected with the prototypic arterivirus equine arteritis virus (EAV). We established that the outer membranes of EAV-induced DMVs are interconnected with each other and with the ER, thus forming a reticulovesicular network (RVN) resembling that previously described for the distantly related severe acute respiratory syndrome (SARS) coronavirus. Despite significant morphological differences, a striking parallel between the two virus groups, and possibly all members of the order Nidovirales, is the accumulation in the DMV interior of double-stranded RNA, the presumed intermediate of viral RNA synthesis. In our electron tomograms, connections between the DMV interior and cytosol could not be unambiguously identified, suggesting that the double-stranded RNA is compartmentalized by the DMV membranes. As a novel approach to visualize and quantify the RNA content of viral replication structures, we explored electron spectroscopic imaging of DMVs, which revealed the presence of phosphorus in amounts equaling on average a few dozen copies of the EAV RNA genome. Finally, our electron tomograms revealed a network of nucleocapsid protein-containing protein tubules that appears to be intertwined with the RVN. This potential intermediate in nucleocapsid formation, which was not observed in coronavirus-infected cells, suggests that arterivirus RNA synthesis and assembly are coordinated in intracellular space.


Changing the global obesity narrative to recognize and reduce weight stigma: A position statement from the World Obesity Federation.
Weight stigma, defined as pervasive misconceptions and stereotypes associated with higher body weight, is both a social determinant of health and a human rights issue. It is imperative to consider how weight stigma may be impeding health promotion efforts on a global scale. The World Obesity Federation (WOF) convened a global working group of practitioners, researchers, policymakers, youth advocates, and individuals with lived experience of obesity to consider the ways that global obesity narratives may contribute to weight stigma. Specifically, the working group focused on how overall obesity narratives, food and physical activity narratives, and scientific and public-facing language may contribute to weight stigma. The impact of weight stigma across the lifespan was also considered. Taking a global perspective, nine recommendations resulted from this work for global health research and health promotion efforts that can help to reduce harmful obesity narratives, both inside and outside health contexts.


[Pollution Properties and Ecological Risk Assessment of Heavy Metals in Farmland Soils and Crops Around a Typical Manganese Mining Area].
In order to assess the ecological risks of heavy metals and explore the pattern of heavy metal migration between farmland and corresponding crops in a typical and closed manganese mining area in Hunan province, farmland soils and crops surrounding the mining area (pollution area) and away from the mining area (control area) were collected, and then the contents of Cr, Mn, Ni, Cu, Zn, As, Cd, and Pb were analyzed. The sources and distribution of heavy metals in farmland soils were analyzed using Kriging spatial interpolation and principal component analysis, and the ecological risk was evaluated using the single factor index, comprehensive pollution index, and potential ecological risk index. The results showed that the surrounding farmland soils in the closed Manganese mining area presented serious pollution of Cd, Zn, As, and Mn, in which the average contents of the above heavy metals in the dry land soil in the polluted area were 6.22, 612.28, 37.72, and 1506.2 mg·kg-1, respectively. Compared with the soil risk screening value of agricultural land, the over-standard rates of Cd, Zn, and As were 88.41%, 94.20%, and 84.06%, respectively, and the average content of Mn in the farmland soil was three times that of the background value in the Hunan soil; however, the heavy metal pollution in the paddy field was relatively light. The principal component analysis showed that the sources of Cd, Mn, and Zn in the farmland soil were related to the manganese ore mining, whereas the source of As in the farmland soil might originate from agricultural activities. The pollution area was at a heavy pollution level, and the main pollution factors were Cd, Mn, and Zn. The Cd in the farmland soil could pose a strong potential ecological risk, but the rest of the heavy metals presented only a slight potential ecological risk. The content of Cr, Pb, and Cd in the crops in the study area exceeded the standard, and the exceeding standard rate was between 1.1% and 37.3%, where the average content of over-standard heavy metals in corn was higher than that in rice, and the average content of heavy metals in leafy vegetables was higher than that in root vegetables. The soil pollution degree of heavy metals could affect the accumulation ability of crops, and different crops had different accumulation abilities. For instance, leafy vegetables and root vegetables easily accumulated Cd and Zn; however, rice and corn separately enriched Cd and Cr, as well as Zn and Cu. The contents of heavy metals in dryland soils had a positive correlation with the content of heavy metals in corresponding crops. The contents of Cd and As in the paddy field and rice presented a positive correlation, but the remaining six heavy metal contents in rice (i.e., Cr, Mn, Ni, Cu, Zn, and Pb) did not correlate with the content of the paddy fields.


Increased Habit Frequency in the Daily Lives of Patients with Acute Anorexia Nervosa.
Strict eating routines and frequent rigid behavior patterns are commonly observed in patients with anorexia nervosa (AN). A recent theory proposes that while these behaviors may have been reinforced initially, they later become habitual. To date, however, research has been overly focused on eating-disorder (ED)-related habits. Over the course of seven days, we applied an ecological momentary assessment (EMA) to investigate the habit frequency and strength of ED-specific (food intake) and ED-unspecific (hygiene) habits in the daily lives of a sample of n = 57 AN and n = 57 healthy controls (HC). The results of the hierarchical models revealed that habits were significantly more likely in patients compared with HC for both categories, independently. Furthermore, a lower body mass index (BMI) was associated with increased habit frequency in AN. Our study strengthens the habit theory of AN by showing the relevance of habits beyond ED-specific behavioral domains. This also supports the development of innovative therapeutic interventions targeting habitual behavior in EDs.


Tiger Swallowtail Genome Reveals Mechanisms for Speciation and Caterpillar Chemical Defense.
Predicting phenotype from genotype represents the epitome of biological questions. Comparative genomics of appropriate model organisms holds the promise of making it possible. However, the high heterozygosity of many Eukaryotes currently prohibits assembling their genomes. Here, we report the 376 Mb genome sequence of Papilio glaucus (Pgl), the first sequenced genome from the Papilionidae family. We obtained the genome from a wild-caught specimen using a cost-effective strategy that overcomes the high (2%) heterozygosity problem. Comparative analyses suggest the molecular bases of various phenotypic traits, including terpene production in the Papilionidae-specific organ, osmeterium. Comparison of Pgl and Papilio canadensis transcriptomes reveals mutation hotspots (4% genes) associated with their divergence: four key circadian clock proteins are enriched in inter-species mutations and likely responsible for the difference in pupal diapause. Finally, the Pgl genome confirms Papilio appalachiensis as a hybrid of Pgl and Pca, but suggests it inherited 3/4 of its genes from Pca.


Poor sleep is associated with small hippocampal subfields in cognitively normal elderly individuals.
Recent studies demonstrated reduced hippocampal volumes in elderly healthy individuals who are cognitively normal but poor sleepers. The association between sleep quality and the pattern of volume loss across hippocampal subfields (HSs) is not well known. Thus, it is the focus of the present study. Sleep quality was self-assessed using the Pittsburgh Sleep Quality Index (PSQI). The HS volumes were measured using sub-millimetre in-plane resolution T2-weighted magnetic resonance imaging data. A total of 67 cognitively normal elderly individuals aged 60-83 years were classified into 30 normal sleepers with a PSQI <5 and 37 poor sleepers with a PSQI ≥5. The two groups were equivalent in age, gender distribution, ethnicity, education attainment, handedness and cognitive performance. Compared to normal sleepers, poor sleepers exhibited significantly lower normalised volumes in the left cornu ammonis field 1 (CA1), dentate gyrus (DG) and subiculum. In contrast, there were no significant differences in normalised grey and white matter volumes between the two groups. The global PSQI was negatively associated with the normalised volumes of the left CA1, DG and subiculum. Sleep duration was associated with the normalised volumes of the bilateral CA1, DG, left CA2 and subiculum. Verbal memory scores were associated with the left CA1 volume. In conclusion, poor sleep quality, especially insufficient sleep duration, was associated with volume loss in several HSs that are involved in specific learning and memory tasks. As the hippocampus does not regulate sleep, it is more likely that poor sleep leads to small hippocampi. Thus, based on this assumption, improving sleep quality of poor sleeper elderly individuals could benefit hippocampal health.


Observations on the accidental poisoning of birds by organophosphate insecticides and other toxic substances.
Details of cases involving the inadvertent exposure of birds to eight toxic substances are recorded. The organophosphate insecticides dichlorvos, diazinon and malathion produced respiratory symptoms which in the former and latter cases were initially thought to be caused by infectious disease. Birds which consumed feed containing fenitrothion showed nervous signs before death. On three separate occasions feral starlings (Sternus vulgaris) were found dead and their gizzard contents contained mevinphos. The rodenticide warfarin was associated with petechial haemorrhages in the skeletal muscles and on the serosal surfaces of one hen. Cyanogenic glycosides from Eucalyptus cladocalyx were responsible for the sudden deaths of ducks and guinea fowl. 'Ornamental dough' containing sodium chloride was fed to birds which were deprived of water and they showed diarrhoea and nervous disorders before death.


Integrated genomic profiling, therapy response, and survival in adult acute myelogenous leukemia.
Recurrent gene mutations, chromosomal translocations, and acquired genomic copy number aberrations (aCNA) have been variously associated with acute myelogenous leukemia (AML) patient outcome. However, knowledge of the co-occurrence of such lesions and the relative influence of different types of genomic alterations on clinical outcomes in AML is still evolving. We performed SNP 6.0 array-based genomic profiling of aCNA/copy neutral loss-of-heterozygosity (cnLOH) along with sequence analysis of 13 commonly mutated genes on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo, secondary, and therapy-related AML. TP53 and RUNX1 mutations are strongly associated with the presence of SNP-A-based aCNA/cnLOH, while FLT3 and NPM1 mutations are strongly associated with the absence of aCNA/cnLOH. The presence of mutations in RUNX1, ASXL1, and TP53, elevated SNP-A-based genomic complexity, and specific recurrent aCNAs predicted failure to achieve a complete response to induction chemotherapy. The presence of ≥1 aCNA/cnLOH and higher thresholds predicted for poor long-term survival irrespective of TP53 status, and the presence of ≥1 aCNA/cnLOH added negative prognostic information to knowledge of mutations in TET2, IDH1, NPM1, DNMT3A, and RUNX1. Results of multivariate analyses support a dominant role for TP53 mutations and a role for elevated genomic complexity as predictors of short survival in AML. Integrated genomic profiling of a clinically relevant adult AML cohort identified genomic aberrations most associated with SNP-A-based genomic complexity, resistance to intensive induction therapies, and shortened overall survival. Identifying SNP-A-based lesions adds prognostic value to the status of several recurrently mutated genes.


Will mothers use free household safety devices?
This study was intended to determine if mothers of small children would use free safety devices to help safety-proof their homes. The study population consisted of an experimental group of 101 families receiving general health education on home safety proofing and a control group of 104 families. Each of the 205 families received two types of safety devices: Kindergards (which are plastic locking devices for cabinets and so forth) and covers for electric outlets. The families were given identical instructions on their use. There was significant increase in the use of the outlet covers in both subgroups, with experimental group using them more (P less than .05) than the control group. There was no significantly increased use of the Kindergards.


Characterization of the replication cycle of the Lymantria dispar nuclear polyhedrosis virus.
The life cycle of the Lymantria dispar nuclear polyhedrosis virus (LdMNPV) was characterized through analysis of budded virus (BV) release, the temporal formation of polyhedra, the temporal transcription pattern of representative early, late, and hyper-expressed late genes, and the onset of DNA replication in the Ld652Y cell line. Transcripts from the LdMNPV immediate early gene G22 were detected 4 h post infection (h p.i.). The late and hyper-expressed late p39 capsid and polyhedrin genes were initially transcribed at approximately 20 and 24 h p.i., respectively. Viral DNA replication initiated at approximately 18-20 h p.i. Budded virus was released from infected cells between 24 and 36 h p.i., and polyhedra were first detected at approximately 48 h p.i.


Polyphyllin VII induces mitochondrial apoptosis by regulating the PP2A/AKT/DRP1 signaling axis in human ovarian cancer.
Ovarian cancer is a gynecological malignancy with high mortality. Adjuvant therapy such as chemoradiotherapy inevitably leads to side effects and drug resistance. In recent years, traditional Chinese medicine has been widely studied for its safety, effectiveness, and unique pharmacological effects. Polyphyllin VII is an important component of Rhizoma paridis saponins, and has cytotoxic effects on many types of cancer cells. The aim of the present study was to evaluate the anti‑tumor activity of polyphyllin VII in human ovarian cancer cells. Recent studies found that polyphyllin VII induces mitochondrial pathway apoptosis by increasing mitochondrial division, but the specific mechanism was unclear. The results of this study revealed that polyphyllin VII could effectively induce mitochondrial dysfunction, including increased mitochondrial division and reactive oxygen species (ROS) production. Notably, the mitochondrial location of dynamin‑related protein 1 (DRP1) plays an important role in its function. In addition, polyphyllin VII enhanced the mitochondrial localization of DRP1 which is mediated by increased protein phosphatase 2A (PP2A) activity, and decreased AKT activity. A specific PP2A inhibitor, LB100, attenuated mitochondrial division and apoptosis in cells caused by polyphyllin VII, confirming the function of the PP2A/AKT pathway in polyphyllin VII treatment. Additionally, xenotransplantation experiments have also confirmed the anti‑tumor effect of polyphyllin VII in vivo. Therefore, interference of the mitochondrial translocation of DRP1 through PP2A/AKT pathway may be an attractive and effective therapeutic approach by polyphyllin VII in ovarian cancer. This may provide new strategies for polyphyllin VII in the clinical treatment of ovarian cancer.


Hematopoiesis from human embryonic stem cells.
Human embryonic stem cells (hESCs) have the capacity to differentiate into multiple lineages, such as neural and hepatic, and include the ability to form hematopoietic cells. Efforts to develop efficient methods to induce hematopoietic differentiation effectively from hESCs, and generate primitive blood stem cells with multilineage hematopoietic repopulating function, are ongoing in several laboratories. Here, we will discuss the past and current progress of our laboratory in this area, and share our ideas to further this use of hESCs in both experimental and clinical hematology.


The variation in frequency with which markers are transduced by phage P1 is primarily a result of discrimination during recombination.
The efficiency of recovery of P1 transductants is marker dependent and normally varies over a 25-fold range. UV irradiation of either transducing lysates for recipient cells results in a selective stimulation of the transduction of markers which are normally transduced poorly. As a result the range in frequency of transduction is reduced to about 3-fold and resembles the gene frequency distribution expected in the donor cells. We conclude that P1 transducing lysates are likely to contain a random sample of donor DNA but that the recombination system of the recipient cell exhibits a preference for the DNA of some regions over that of others. Damage to DNA presumably overrides this specificity.


A deep breath bronchoconstricts obese asthmatics.
Asthma is characterized by the loss of a deep breath (DB)-induced bronchodilation and bronchoprotection. Obesity causes lung restriction and increases airway resistance, which may further worsen the capacity of a DB to induce bronchodilation; however, whether increasing BMI impairs the bronchodilatory response to a DB in asthmatics is unknown. The population consisted of 99 subjects, 87 with moderate to severe persistent asthma and 12 obese control subjects. Using transfer impedance we derived airway resistance (Raw). Participants breathed for 1 minute and took a slow DB followed by passive exhalation to functional residual capacity (FRC) and tidal breathing for another minute. After a DB, obese asthmatics had the largest percent increase in Raw (median 9.8% interquartile range [IQR] 3.1-15.1), compared with overweight (6.5% IQR -1.3, 12.1) and lean (0.7% IQR -3, 7.9) asthmatics and obese controls (2.5% IQR -.6, 11) (p for trend = 0.008). The association between the percent increase in Raw after a DB and BMI as a continuous variable was significant (p = 0.02). In obese, moderate to severe and poorly controlled asthmatics, a DB results in increased Raw. This phenomenon was not observed in leaner asthmatics of similar severity or in obese control subjects.


Pair bonding prevents reinforcing effects of testosterone in male California mice in an unfamiliar environment.
Testosterone (T) can be released by stimuli such as social interactions, and thereby influence future social behaviours. Because the reinforcing effects of T can induce preferences for specific environmental locations, T has the potential to alter behaviour through space use. In a monogamous species, this T pulse may contribute differently to space use in sexually naive (SN) and pair-bonded (PB) males: SN males may be more likely to explore new areas to set up a territory than PB males, which are more likely to defend an existing, established territory. In this study, we test for variation in T-driven space use by examining variation in the formation of conditioned place preferences (CPPs) in SN and PB male California mice. In the three-chambered CPP apparatus, subcutaneous administrations of physiological levels of T were used to repeatedly condition SN and PB males to a side chamber, which is an unfamiliar/neutral environment. The final tests revealed that T-induced CPPs in the side chamber are developed in SN, but not PB males. This study fills a gap in our knowledge about plasticity in the rewarding nature of T pulses, based on past social experience.


Decoquinate liposomes: highly effective clearance of Plasmodium parasites causing severe malaria.
Severe malaria caused by Plasmodium falciparum leads to most malaria-related deaths globally. Decoquinate (DQ) displays strong activity against multistage infection by Plasmodium parasites. However, the development of DQ as an oral dosage form for the treatment of malaria at the blood stage has not been successful. In this study, liposome formulations of DQ were created for intravenous (IV) injection to suppress Plasmodium berghei, a parasite that causes severe malaria in mice. DQ liposomes were prepared by conventional ethanol injection method with slight modifications and encapsulation efficiency evaluated by the well-established centrifugation method. Potency of the DQ liposomes against P. falciparum was assessed in vitro using freshly isolated human red blood cells. The efficacy of the DQ liposomes was examined in the mouse model of severe malaria. The DQ liposomes were around 150 nm in size and had the encapsulation efficiency rates > 95%. The freshly prepared and lyophilized liposomes were stable after storage at - 20 °C for 6 months. The liposomes were shown to have excellent activity against P. falciparum in vitro with DQ IC50 0.91 ± 0.05 nM for 3D7 (chloroquine sensitive strain) and DQ IC50 1.33 ± 0.14 nM for Dd2 (multidrug resistant strain), which were 18- and 14-fold more potent than artemisinin, respectively. Mice did not have any signs of toxicity after receiving high dose of the liposomes (DQ 500 mg/kg per mouse) by IV injection. In the mouse model of severe malaria, the liposomes had impressive efficacy against P. berghei with DQ ED50 of 0.720 mg/kg. The DQ liposomes prepared in this study were stable for long term storage and safe for IV injection in mammalian animals. The newly created liposome formulations had excellent activity against Plasmodium infection at the blood-stage, which encourages their application in the treatment of severe malaria.


Insulin-stimulated translocation of glucose transporters in the isolated rat adipose cells: characterization of subcellular fractions.
Insulin stimulates glucose transport in rat adipose cells through the translocation of glucose transporters from an intracellular pool to the plasma membrane. A detailed characterization of the morphology, protein composition and marker enzyme content of subcellular fractions of these cells, prepared by differential ultracentrifugation, and of the distribution of glucose transporters among these fractions is now described. Glucose transporters were measured using specific D-glucose-inhibitable [3H]cytochalasin B binding. In the basal state, roughly 90% of the cells' glucose transporters are associated with a low-density microsomal, Golgi marker enzyme-enriched membrane fraction. However, the distributions of glucose transporters and Golgi marker enzyme activities over all fractions are clearly distinct. Incubation of intact cells with insulin increases the number of glucose transporters in the plasma membrane fraction 4-5 fold and correspondingly decreases the intracellular pool, without influencing any other characteristics of the subcellular fractions examined or the estimated total number of glucose transporters (3.7 X 10(6)/cell). Insulin does not influence the Kd of the glucose transporters in the plasma membrane fraction for cytochalasin B binding (98 nM), but lowers that in the intracellular pool (from 141 to 93 nM). The calculated turnover numbers of the glucose transporters in the plasma membrane vesicles from basal and insulin-stimulated cells are similar (15 X 10(3) mol of glucose/min per mol of transporters at 37 degrees C), whereas insulin appears to increase the turnover number in the plasma membrane of intact cells roughly 4-fold. These results suggest that (1) the intracellular pool of glucose transporters may comprise a specialized membrane species, (2) intracellular glucose transporters may undergo conformational changes during their cycling to the plasma membrane in response to insulin, and (3) the translocation of glucose transporters may represent only one component in the mechanism through which insulin regulates glucose transport in the intact cell.


Sugar content of commonly eaten snack foods of school children in relation to their dental health status.
Sugar is the principal substrate for micro-organisms causing dental caries. Yet it is impossible to eliminate sugar in the diet as almost all available foods particularly snack foods contain sugar. WHO recommended 10 kg. sugar or 27.40 gms. per person per year in non-fluoridated area and 15 kg. sugar/person year in non-flouridated areas for low caries prevalence. The FFQ and 24-Hour Food recall of 824 rural and urban schoolchildren showed that all their snacks foods are high in sugar except gelatine. Their sugar intake was three times more than the WHO recommendation with a mean daily intake of 90 gms. for urban and 88 grams of sugar for the rural. White sugar, hard candies, raisins, coco jam, and milk choco were the five most commonly eaten snack foods with high sugar content. Oral examination of the schoolchildren showed that dental caries was higher in the urban than in the rural. As a whole, the urban schoolchildren consumed more sugar and had higher dental caries compared to the rural schoolchildren. No significant correlation was found between sugar intake and dental caries.


Stress Erythropoiesis is a Key Inflammatory Response.
Bone marrow medullary erythropoiesis is primarily homeostatic. It produces new erythrocytes at a constant rate, which is balanced by the turnover of senescent erythrocytes by macrophages in the spleen. Despite the enormous capacity of the bone marrow to produce erythrocytes, there are times when it is unable to keep pace with erythroid demand. At these times stress erythropoiesis predominates. Stress erythropoiesis generates a large bolus of new erythrocytes to maintain homeostasis until steady state erythropoiesis can resume. In this review, we outline the mechanistic differences between stress erythropoiesis and steady state erythropoiesis and show that their responses to inflammation are complementary. We propose a new hypothesis that stress erythropoiesis is induced by inflammation and plays a key role in maintaining erythroid homeostasis during inflammatory responses.


Anterior cruciate ligament reconstruction: socioeconomic issues and cost effectiveness.
Anterior cruciate ligament ruptures continue to occur in increasing numbers. These injuries and their treatment create significant social and economic problems for patients, their physicians, and for society. By critically evaluating the trade-off between the costs and benefits of various treatment options, one can define a cost-effective approach to the management of this problem. Limited available data suggest that anterior cruciate ligament reconstruction is a highly cost-effective method of treatment for active young adults. The cost per additional quality-adjusted life year provided by surgery compares favorably with figures associated with other highly utilized health care interventions. Such data may prove invaluable within the context of health care reform.


Speech watermarking: an approach for the forensic analysis of digital telephonic recordings.
In this article, the authors discuss the problem of forensic authentication of digital audio recordings. Although forensic audio has been addressed in several articles, the existing approaches are focused on analog magnetic recordings, which are less prevalent because of the large amount of digital recorders available on the market (optical, solid state, hard disks, etc.). An approach based on digital signal processing that consists of spread spectrum techniques for speech watermarking is presented. This approach presents the advantage that the authentication is based on the signal itself rather than the recording format. Thus, it is valid for usual recording devices in police-controlled telephone intercepts. In addition, our proposal allows for the introduction of relevant information such as the recording date and time and all the relevant data (this is not always possible with classical systems). Our experimental results reveal that the speech watermarking procedure does not interfere in a significant way with the posterior forensic speaker identification.


The novel mouse Polo-like kinase 5 responds to DNA damage and localizes in the nucleolus.
Polo-like kinases (Plk1-4) are emerging as an important class of proteins involved in many aspects of cell cycle regulation and response to DNA damage. Here, we report the cloning of a fifth member of the polo-like kinase family named Plk5. DNA and protein sequence analyses show that Plk5 shares more similarities with Plk2 and Plk3 than with Plk1 and Plk4. Consistent with this observation, we show that mouse Plk5 is a DNA damage inducible gene. Mouse Plk5 protein localizes predominantly to the nucleolus, and deletion of a putative nucleolus localization signal (NoLS) within its N-terminal moiety disrupts its nucleolar localization. Ectopic expression of Plk5 leads to cell cycle arrest in G1, decreased DNA synthesis, and to apoptosis, a characteristic it shares with Plk3. Interestingly, in contrast to mouse Plk5 gene, the sequence of human Plk5 contains a stop codon that produces a truncated protein lacking part of the kinase domain.


How much bilateral and multilateral climate adaptation finance is targeting the health sector? A scoping review of official development assistance data between 2009-2019.
Climate change is adversely affecting human health. Rapid and wide-scale adaptation is urgently needed given the negative impact climate change has across the socio-environmental determinants of health. The mobilisation of climate finance is critical to accelerate adaptation towards a climate resilient health sector. However, a comprehensive understanding of how much bilateral and multilateral climate adaptation financing has been channelled to the health sector is currently missing. Here, we provide a baseline estimate of a decade's worth of international climate adaptation finance for the health sector. We systematically searched international financial reporting databases to analyse 1) the volumes, and geographic targeting, of adaptation finance for the health sector globally between 2009-2019 and 2) the focus of health adaptation projects based on a content analysis of publicly available project documentation. We found that health was largely a co-benefit, not the principal objective, within the projects. We estimate that USD 1,431 million (4.9%) of total multilateral and bilateral adaptation has been committed to health activities across the decade. However, this is likely an overestimate of the true figure. Most health adaptation projects were in Sub-Saharan Africa, with average project funding comparable to East Asia and the Pacific and the MENA region. Fragile and conflict affected countries received 25.7% of total health adaptation financing. The paucity of health indicators as part of project monitoring and evaluation criteria and the lack of emphasis on local adaptation were particularly significant. This study contributes to the wider evidence base on global health adaptation and climate financing by quantifying adaptation funds directed towards the health sector and revealing specific gaps in financing health adaptation. We anticipate these results will support researchers in developing actionable research on health and climate finance and decision-makers in mobilizing funds to low-resource settings with high health sector adaptation needs.


Factors associated with injuries occurring aboard vessels in Alaska: differences between residents and nonresidents.
Over the past decade, visitors to Alaska have spent increasing amounts of time engaged in water-based recreational activities aboard vessels of various sizes. Serious vessel-related injuries to travelers in Alaska involve not only medical care from unfamiliar health care providers and facilities but also entail the loss of vacation time and the need for injured travelers to return to their homes under less than optimal traveling conditions. This study employed a retrospective, case-comparison analysis to identify differences in factors associated with recreational injuries acquired aboard watercraft that resulted in hospitalizations of residents and nonresidents of Alaska during 1991 to 2000. Tests of proportions were conducted to elucidate differences in demographic characteristics and injury precursors between the two subgroups. Specific injury outcomes were then tested for significance using odds ratios. Alaska residents and nonresidents demonstrated significant differences for both demographic factors and factors describing events leading to injuries, and for injury outcomes. Nonresidents were more likely to be 65 years or older, female, and aboard cruise ships when injuries occurred. Nonresidents were more likely to suffer fracture injuries, to suffer injuries with Abbreviated Injury Scores greater than 2, to experience posthospital discharges to sites other than their homes, and to experience postinjury disabilities. Alaska residents and nonresidents in this study showed significant differences in demographics, precipitating events, and injury outcomes. The findings lend support for targeted safety promotion programs.


Genome-wide linkage analysis for identifying quantitative trait loci involved in the regulation of lipoprotein a (Lpa) levels.
Lipoprotein Lp(a) levels are highly heritable and are associated with cardiovascular risk. We performed a genome-wide linkage analysis to delineate the genomic regions that influence the concentration of Lp(a) in families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. Lp(a) levels were measured in 387 individuals belonging to 21 extended Spanish families. A total of 485 DNA microsatellite markers were genotyped to provide a 7.1 cM genetic map. The variance component linkage method was used to evaluate linkage and to detect quantitative trait loci (QTLs). The main QTL that showed strong evidence of linkage with Lp(a) levels was located at the structural gene for apo(a) on chromosome 6 (LOD score=13.8). Interestingly, another QTL influencing Lp(a) concentration was located on chromosome 2 with an LOD score of 2.01. This region contains several candidate genes. One of them is the tissue factor pathway inhibitor (TFPI), which has antithrombotic action and also has the ability to bind lipoproteins. However, quantitative trait association analyses performed with 12 SNPs in TFPI gene revealed no association with Lp(a) levels. Our study confirms previous results on the genetic basis of Lp(a) levels. In addition, we report a new QTL on chromosome 2 involved in the quantitative variation of Lp(a). These data should serve as the basis for further detection of candidate genes and to elucidate the relationship between the concentration of Lp(a) and cardiovascular risk.


The Hedgehog signal transducer Smoothened and microRNA-326: pathogenesis and regulation of drug resistance in pediatric B-cell acute lymphoblastic leukemia.
Multidrug resistance (MDR) and the subsequent disease relapse are the major causes of childhood acute lymphoblastic leukemia (ALL) related death. The Hedgehog (Hh) signaling pathway can contribute to cancer MDR. In the current study, Smoothened (Smo) was selected as the experimental target due to its importance in the Hh pathway in order to evaluate its probable role in pediatric B-ALL drug resistance. The study included 27 pediatric B-ALL and 16 control bone marrow samples. Quantitative RT-PCR was used to investigate the expression levels of Smo and miR-326 as the key players of the Hh pathway. Western blot analysis was performed. The presence of minimal residual disease was studied using PCR-SSCP. The association between Smo expression and drug resistance was analyzed statistically. Results showed a significant increase in the Smo expression levels in drug-resistant patients in comparison with drug-sensitive children with B-ALL (P=0.0128, AUC=0.82). A considerable negative association between miR-326 and Smo expression levels was identified (r=-0.624, P=0.002). A binomial test confirmed the regulatory role of miR-326 on the translational repression of Smo (P=0.031). Statistics showed no association between Smo and ABCA2 expression levels. However, a significant positive correlation was observed between the Smo and ABCA3 transcripts in the resistant ALL children (r=0.607, P=0.016). Data revealed the possible oncogenic impact of Smo on leukemogenesis and drug resistance in pediatric B-ALL. Upregulation of Smo was introduced, for the first time, as a prognostic factor for drug resistance in childhood B-ALL. To the best of our knowledge, this is the first study that shows a positive correlation between Smo and ABCA3 expression levels in pediatric B-ALL, explaining a possible mechanism for the development of drug resistance in this cancer. Moreover, the current project revealed a negative modulatory effect of miR-326 on the expression levels of Smo.


Candida glabrata oropharyngeal candidiasis in patients receiving radiation treatment for head and neck cancer.
Candida glabrata colonization is common in patients receiving radiation treatment for head and neck cancer, but to our knowledge has never been described as the infecting organism with oropharyngeal candidiasis (OPC). This study presents the first three patients described with C. glabrata OPC in this patient population. Patient 1 developed C. glabrata OPC and required fluconazole, 800 mg/day, for clinical resolution. Antifungal susceptibility testing revealed a MIC of fluconazole of >64 microg/ml. Elapsed time from initial culturing to treatment decision was 7 days. Patients 2 and 3 developed C. glabrata OPC. They were patients in a study evaluating OPC infections, and cultures were taken immediately. CHROMagar Candida plates with 0, 8, and 16 microg of fluconazole/ml were employed for these cultures. Lavender colonies, consistent with C. glabrata, grew on the 0- and 8-microg plates but not on the 16-microg plate from patient 2 and grew on all three plates from patient 3. Based on these data, a fluconazole dose of 200 mg/day was chosen for patient 2 and a dose of 400 mg/day was chosen for patient 3, with clinical resolution in both. Elapsed time from initial culturing to treatment decision was 2 days. C. glabrata does cause OPC in head and neck radiation treatment patients, and the use of fluconazole-impregnated chromogenic agar may significantly reduce treatment decision time compared to that with conventional culturing and antifungal susceptibility testing.


Thoracic adaptations for ventilation during locomotion in humans and other mammals.
Bipedal humans, like canids and some other cursorial mammals, are thought to have been selected for endurance running, which requires the ability to sustain aerobic metabolism over long distances by inspiring large volumes of air for prolonged periods of time. Here, we tested the general hypothesis that humans and other mammals selected for vigorous endurance activities evolved derived thoracic features to increase ventilatory capacity. To do so, we investigated whether humans and dogs rely on thoracic motion to increase tidal volume during running to a greater extent than goats, a species that was not selected for endurance locomotion. We found that while all three species use diaphragmatic breathing to increase tidal volume with increasing oxygen demand, humans also use both dorsoventral and mediolateral expansion of the thorax. Dogs use increased dorsoventral expansion of the thorax, representing an intermediate between humans and goats. 3D analyses of joint morphology of 10 species across four mammalian orders also showed that endurance-adapted cursorial species independently evolved more concavo-convex costovertebral joint morphologies that allow for increased rib mobility for thoracic expansion. Evidence for similarly derived concavo-convex costovertebral joints in Homo erectus corresponds with other evidence for the evolution of endurance running in the genus Homo.


Silicon nanotubes from sacrificial silicon nanowires: fabrication and manipulation via embedding in flexible polymers.
In the present work we report a simple method to fabricate Si nanotubes (NTs) starting from the growth of self-assembled sacrificial Si nanowires that, at the same time, embeds them into a polyimide matrix, allowing a very easy manipulation of these nano-objects, including removal, transfer and positioning. Our all-silicon fabrication method is completely compatible with the Si technology platform and is therefore implementable using the existing technology. Transferred NTs show good electrical contact with underlying electrodes, and relatively low resistance values have been measured. All these features demonstrate the effectiveness of the transfer method and the potentiality of the NTs in electronics. Finally, optical reflectivity of the NTs has been measured in the near UV-near IR spectral range.


Couriers of asthma: antigenic proteins in natural rubber latex.
Natural rubber latex (NRL) is a milky, white liquid containing the polymer cis-1,4-polyisoprene, derived from the laticifer cells of the rubber tree, Hevea brasiliensis. Reports of allergic reactions to NRL, ranging in severity from skin rashes to anaphylaxis and death, have been increasing. High rates of latex allergy are seen in children with spina bifida. Healthcare workers, especially those who frequently use powdered latex medical gloves, can develop NRL allergy and asthma, often resulting in considerable disability. Atopy and, possibly, pre-existing dermatitis predispose to sensitization and allergic symptoms. NRL protein antigens are found in many NRL products and also have been shown to bind to cornstarch glove-donning powders. Of the approximately 240 polypeptides in NRL, nearly 60 are antigenic, and nine have been identified and registered (Hev b 1&ndash9). Many natural latex antigens share epitopes with structural proteins and enzymes from other plant species. Current knowledge indicates that proposed reductions in total glove protein and limitations on the use of powder on NRL gloves are likely to result in a decline in the prevalence and severity of NRL allergies among healthcare workers.


Moral lessons from the jury box.
A decade ago a North Carolina jury awarded millions of dollars in damages because of a healthcare institution's failure to provide appropriate pain relief to a dying patient. In 2001, a California jury found a physician guilty of elder abuse for his failure to properly manage the pain of a cancer patient. In both instances, state licensing boards had failed to take any disciplinary action against those involved. These cases dramatically illustrate a significant and persistent gulf between the lay public and the health professions with regard to the moral significance they attach to the duty to relieve suffering. Measures to insure that all patients receive effective assessment and management of their pain must take into account this disparity, and endeavor to achieve congruence by reconnecting the health professions to their ancient and core value--the relief of suffering.


Design and Mechanical Sensitivity Analysis of a MEMS Tuning Fork Gyroscope with an Anchored Leverage Mechanism.
This paper presents the design and analysis of a new micro-electro-mechanical system (MEMS) tuning fork gyroscope (TFG), which can effectively improve the mechanical sensitivity of the gyroscope sense-mode by the designed leverage mechanism. A micromachined TFG with an anchored leverage mechanism is designed. The dynamics and mechanical sensitivity of the design are theoretically analyzed. The improvement rate of mechanical sensitivity (IRMS) is introduced to represent the optimization effect of the new structure compared with the conventional one. The analytical solutions illustrate that the IRMS monotonically increases with increased stiffness ratio of the power arm (SRPA) but decreases with increased stiffness ratio of the resistance arm (SRRA). Therefore, three types of gyro structures with different stiffness ratios are designed. The mechanical sensitivities increased by 79.10%, 81.33% and 68.06% by theoretical calculation. Additionally, FEM simulation demonstrates that the mechanical sensitivity of the design is in accord with theoretical results. The linearity of design is analyzed, too. Consequently, the proposed new anchored leverage mechanism TFG offers a higher displacement output of sense mode to improve the mechanical sensitivity.


[Rhinoplasty--functional and esthetic surgery on the nose].
With the aid of rhinoplasty, functional or cosmetic defects affecting the nose can be surgically corrected. In cases of disturbed nasal breathing due to septum deviations, hypertrophy of the conchae or a crooked nose which, for example, has led to deformation of the inside of the nose and thus to a functional disturbance, there is no question that the insurance will cover the costs. In the case of mild deformities, however, an expertise is first required. Purely cosmetic corrections are not covered by the health insurance and must be paid for by the patient him/herself. At the end of the operation, the nose is supported with splints and tamponades. Any subsequent surgery should be done at the earliest after one year.


Serum neuregulin 1 in relation to ventricular function and subclinical atherosclerosis in type 2 diabetes patients.
Neuregulin 1 (NRG-1) is one of the members of the epidermal growth factors proteins. The present study provides novel insights into the relationship between serum levels of NRG-1 and insulin resistance, subclinical atherosclerosis and cardiac dysfunction that occur in type 2 diabetes (T2D). The study included 50 patients with T2D and 40 healthy age- and gender-matched controls. Serum NRG-1 was measured using ELISA. Glycemic parameters, lipid profile and insulin resistance were assessed. Trans-thoracic echocardiography and carotid intima media thickness (CIMT) were studied for all study subjects. T2D patients had significantly lower serum NRG-1 levels than controls. Serum NRG-1 was negatively correlated with age, fasting blood glucose, HbA1c, insulin resistance, blood urea, serum creatinine and LDL-C, and positively correlated with HDL-C, eGFR and CIMT. Regarding echocardiographic variables, serum NRG-1 was found to correlate positively with left ventricular global longitudinal strain and negatively with E/Ea ratio. NRG-1 was found to predict subclinical atherosclerosis in type 2 diabetes patients at a cut-off value<108.5pg/ml with 78% sensitivity and 80% specificity. A robust relationship was found between serum NRG-1 levels and hyperglycemia, insulin resistance, subclinical atherosclerosis, and cardiac dysfunction in patients with type 2 diabetes. These results shed light on a possible role of NRG-1 as a potential noninvasive biomarker for detection of cardiometabolic risk in T2D.


Visualisation of direct interaction of MDA5 and the dsRNA replicative intermediate form of positive strand RNA viruses.
The innate immune system is a vital part of the body's defences against viral pathogens. The proteins retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) function as cytoplasmic pattern recognition receptors that are involved in the elimination of actively replicating RNA viruses. Their location and their differential responses to RNA viruses emphasises the complexity of the innate detection system. Despite the wealth of information on the types of RNA that trigger RIG-I, much less is known about the nature of the RNAs that act as agonists for MDA5. In order to identify which RNA species triggers MDA5 activation during infection, we isolated viral ssRNA and replicative intermediates of RNA from positive sense ssRNA viruses. We reveal that MDA5 recognises not the genomic ssRNA but the dsRNA generated by the replication of these viruses. Furthermore, using fluorescent imaging we present the first report of the visualisation of dsRNA and MDA5, which provides unique evidence of the relationship between viral dsRNA and MDA5 and proves without a doubt that MDA5 is the key sensor for the dsRNA replicative intermediate form of positive sense ssRNA viruses.


The polar side of polyphenylene dendrimers.
Polyphenylene dendrimers (PPDs) represent a unique class of dendrimers based on their rigid, shape persistent chemical structure. These macromolecules are typically looked at as nonpolar precursors for conjugated systems. Yet over the years there have been synthetic achievements that have produced PPDs with a range of polarities that break the hydrophobic stereotype, and provide dendrimers that can be synthetically tuned to be used in applications such as stable transition metal catalysts, nanocarriers for biological drug delivery, and sensors for volatile organic compounds (VOCs), among many others. This is based on strategies that allow for the modification of PPDs at the core, scaffold, and surface to introduce numerous different groups, such as electrolytes, ions, or other polar species. This review is aimed to demonstrate the versatility of PPDs through their site-specific chemical functionalization to produce robust materials with various polarities.


The disability profile of patients with schizophrenia in psychiatric hospital and community settings in Singapore.
The disability profile of persons with schizophrenia in Singapore and how disability levels vary in patients cared for in the community and in the long-stay wards of a state mental hospital were studied using the Life Skills Profile (LSP). The inter-rater reliability of the LSP assessed by the intraclass correlation coefficient (ICC), was lower than in the Australian studies. The test-retest ICCs for the total LSP score and the five subscale scores were satisfactory for the hospitalised subjects and for the community psychiatric nurse subjects, but generally poor for the community care facility subjects. The average ICCs were lower compared to the Australian study. Female hospitalised subjects but not male hospitalised subjects returned higher disability scores on all LSP scales compared to community subjects. This study provided some preliminary data on the usefulness and validity of the LSP in a multi-ethnic Asian setting like Singapore. If the LSP is used as a measure of disability in schizophrenia, it would appear that ratings should only be made by those who know the subject well, and that raters should be formally trained mental health professionals.


Approximation of normalized point source sensitivity using power spectral density and slopes of wavefront aberration.
We have investigated two approximation methods for estimating the normalized point source sensitivity (PSSN), which is a recently developed optical performance metric for telescopes. One is an approximation based on the power spectral density (PSD) of the wavefront error. The other is the root-square-sum of the wavefront slope. We call these approximations β approximation and SlopeRMS approximation, respectively. Our analysis shows that for the Thirty Meter Telescope (TMT), the uncertainty of the β approximation is less than 1×10(-3) if the PSSN is better than 0.95, assuming the input PSD estimation is accurate. In addition, we find that the SlopeRMS approximation is a simple method for estimating the worst-case PSSN value in the specific situation when the PSSN is dominated by low-frequency aberrations. Therefore, the SlopeRMS approximation is expected to be useful for specifying a mirror surface for mirror vendors. Accordingly, TMT has a plan to adopt the SlopeRMS approximation for its M2 and M3 polishing specification.


Clinical and microbial evaluation of treatment regimens to reduce denture stomatitis.
This study evaluated the effect of an antimicrobial mouthrinse, denture soft relines, and a placebo rinse on the clinical findings and microbial flora of 78 patients with denture stomatitis. For 28 days the study and control groups performed oral rinses and denture soaks. Reline group patients had maxillary denture soft relines that were changed every 7 days. At the end of the study, the mean severity of denture stomatitis was significantly less in the groups that used the study rinse (P less than 0.01) and received denture relines (P less than 0.05) compared to the control. Analysis of variance revealed significant differences in ranked adjusted percentage counts in two out of 13 denture plaque organisms investigated (Fusobacterium nucleatum [P less than 0.05] and total Bacteroides [P less than 0.05]), with the antiseptic rinse producing the lowest count. Yeast populations were reduced, but not significantly (P = 0.07). In the absence of other mechanical denture hygiene procedures, the antiseptic rinse and relines were equally effective in reducing denture stomatitis and potential pathogens of denture plaque flora.


Role of cardiac imaging in acute chest pain.
Chest pain is the second most common complaint in the emergency department. The need to diagnose the cause of chest pain in a timely manner and appropriately direct care is crucial. This article discusses the role of imaging in acute chest pain, after first differentiating chest pain into cardiac and non-cardiac causes with upfront clinical and biochemical assessment. The role of non-invasive imaging including point-of-care ultrasound, echocardiography, myocardial perfusion imaging, cardiac MRI, coronary computed tomography angiography and novel cardiac CT applications are discussed. Updates in the literature regarding the role of coronary plaque imaging in acute chest pain are reviewed, as are ongoing challenges and future directions. This includes a discussion on the yield of diagnostic testing in low-risk acute chest pain cohorts vs intermediate-high risk cohorts. The incremental value of further testing in the former is low, which is reflected in contemporary guidelines that discourage the use of costly diagnostic tests in these cohorts. In the latter cohort, emerging evidence has shown specifically the role coronary computed tomography angiography could play in reducing the need for invasive coronary angiography in selective patients where the true probability of acute coronary syndrome is thought to be low. Real-world considerations such as accessibility and affordability are also discussed in the paper because while guidelines offer clinicians the flexibility of evidence-based choice, physician decision must necessarily be made in consideration of real-world constraints.


NX4: a web-based visualization of large multiple sequence alignments.
Multiple Sequence Alignments (MSAs) are a fundamental operation in genome analysis. However, MSA visualizations such as sequence logos and matrix representations have changed little since the nineties and are not well suited for displaying large-scale alignments. We propose a novel, web-based MSA visualization tool called NX4, which can handle genome alignments comprising thousands of sequences. NX4 calculates the frequency of each nucleotide along the alignment and visually summarizes the results using a color-blind friendly palette that helps identifying regions of high genetic diversity. NX4 also provides the user with additional assistance in finding these regions with a 'focus + context' mechanism that uses a line chart of the Shannon entropy across the alignment. The tool offers geneticists an easy-to-use and scalable analysis for large MSA studies. NX4 is freely available at https://www.nx4.io, and its source code at https://github.com/NX4/nx4. Supplementary data are available at Bioinformatics online.


Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease.
Better identification of severe acute graft-versus-host disease (GvHD) may improve the outcome of this life-threatening complication of allogeneic hematopoietic stem cell transplantation. GvHD induces tissue damage and the release of damage-associated molecular pattern (DAMP) molecules. Here, we analyzed GvHD patients (n = 39) to show that serum heat shock protein glycoprotein 96 (Gp96) could be such a DAMP molecule. We demonstrate that serum Gp96 increases in gastrointestinal GvHD patients and its level correlates with disease severity. An increase in Gp96 serum level was also observed in a mouse model of acute GvHD. This model was used to identify complement C3 as a main partner of Gp96 in the serum. Our biolayer interferometry, yeast two-hybrid and in silico modeling data allowed us to determine that Gp96 binds to a complement C3 fragment encompassing amino acids 749-954, a functional complement C3 hot spot important for binding of different regulators. Accordingly, in vitro experiments with purified proteins demonstrate that Gp96 downregulates several complement C3 functions. Finally, experimental induction of GvHD in complement C3-deficient mice confirms the link between Gp96 and complement C3 in the serum and with the severity of the disease.


Peripheral areas of nonperfusion in treated central retinal vein occlusion as imaged by wide-field fluorescein angiography.
To develop a method of imaging the retina using wide-field fluorescein angiography and use this method to investigate the areas of perfusion abnormalities in patients treated with ranibizumab for central retinal vein occlusion. Cross-sectional analysis of patients recruited to a prospective study. Patients in a prospective study of ranibizumab for central retinal vein occlusion were imaged with wide-field angiography. Fluorescein angiograms taken with the Optos P200 Scanning Laser Ophthalmoscope were obtained of the posterior portion of the eye and of the periphery through ocular steering. Resultant images of the periphery were registered to the posterior image using thin-plate spline warping. A transformation was used to measure the retinal surface area. Perfusion characteristics were compared with injection frequencies and protocol refraction visual acuity measurements. Of 22 patients imaged, 7 would be classified as nonperfused by the Central Retinal Vein Occlusion Study (CVOS) angiographic criteria. However, all patients showed confluent areas of nonperfusion in the retinal periphery ranging in size from 16 disk areas to 242 disk areas. The areas of peripheral nonperfusion were not significantly different in the Central Retinal Vein Occlusion Study-perfused group versus nonperfused group. The area of peripheral nonperfusion was not correlated with the number of injections (r = -0.13, P = 0.58), but was inversely correlated with visual acuity (r = -0.52, P = 0.013). Blood vessels at the border of the peripheral nonperfusion did not show signs of neovascular growth or profuse leakage. Angiographic mapping of the retina is possible using image-processing techniques with wide-field images. Eyes with central retinal vein occlusion develop widespread peripheral vascular obliteration in regions that are difficult to image with conventional fundus cameras. These nonperfused areas may have important implications for visual function.


Trastuzumab infusion reactions in breast cancer. Should we routinely observe after the first dose?
Trastuzumab (Herceptin) is used in neoadjuvant, adjuvant and metastatic breast cancer. Infusion reactions are a common side effect most of which are mild and easily managed, anaphylaxis occurs rarely. The summary of product characteristics recommends observation for 6 hours after the commencement of the first administration; we wanted to evaluate this practice. We assessed first administrations of trastuzumab infusions retrospectively to determine both rate and timing of reactions. Medical and nursing notes of 94 patients who had been prescribed intravenous trastuzumab in 2012 were reviewed; 2 additional patients did not have records available. Fourteen patients received palliative, 73 adjuvant and 7 neoadjuvant trastuzumab.r. Two (2%) had a reaction to trastuzumab occurring at 70 and 80 min from infusion commencement. We did not observe a reaction in the 4.5 hours after the 90 min infusion was complete. We recommend discharge with verbal and written advice immediately after uncomplicated first administration.


Staphylococcus aureus α-Toxin Response Distinguishes Respiratory Virus-Methicillin-Resistant S. aureus Coinfection in Children.
Development of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia after a respiratory viral infection is frequently fatal in children. In mice, S. aureus α-toxin directly injures pneumocytes and increases mortality, whereas α-toxin blockade mitigates disease. The role of α-toxin in pediatric staphylococcal-viral coinfection is unclear. We enrolled children across 34 North American pediatric intensive care units with acute respiratory failure and suspected influenza virus infection. Serial serum anti-α-toxin antibody titers and functional α-toxin neutralization capacity were compared across children coinfected with MRSA or methicillin-susceptible S. aureus (MSSA) and control children infected with influenza virus only. MRSA isolates were tested for α-toxin production and lethality in a murine pneumonia model. Influenza virus was identified in 22 of 25 children with MRSA coinfection (9 died) and 22 patients with MSSA coinfection (all survived). Initial α-toxin-specific antibody titers were similar, compared with those in the 13 controls. In patients with serial samples, only MRSA-coinfected patients showed time-dependent increases in anti-α-toxin titer and functional neutralization capacity. MRSA α-toxin production from patient isolates correlated with initial serologic titers and with mortality in murine pneumonia. These data implicate α-toxin as a relevant antigen in severe pediatric MRSA pneumonia associated with respiratory viral infection, supporting a potential role for toxin-neutralizing therapy.


Growth of human hepatoma cells lines with differentiated functions in chemically defined medium.
A human hepatoma cell line, HuH-7, which was established from a hepatocellular carcinoma, was found to replicate continuously in a chemically defined medium when the medium was supplemented with Na2SeO3. The cells grew better in this medium than in serum-containing medium without any adaptation period. Other established human hepatoma and hepatoblastoma cell lines, HuH-6 cl-5, PLC/PRF/5, huH-1, and huH-4, also grew in the defined medium. Although HLEC-1 cells failed to proliferate continuously with Na2SeO3 alone, they grew if a cell-free conditioned medium from HuH-7 cells was added to the medium. These cell lines, except the HLEC-1 cell line, produced the following human plasma proteins among those examined: albumin, prealbumin, alpha 1-antitrypsin, ceruloplasmin, fibrinogen, fibronectin, haptoglobin, hemopexin, beta-lipoprotein, alpha 2-macroglobulin, beta 2-microglobulin, transferrin, lipoprotein, alpha 2-macroglobulin, beta 2-microglobulin, transferrin, Complement Components 3 and 4, and alpha 1-fetoprotein. Beside plasma proteins, the media from HuH-7, HuH-6 cl-5, PLC/PRF/5, and huH-1 contained anti-carcinoembryonic antigen-reactive proteins, and those from PLC/PRF/5, huH-1, and huH-4 medium contained hepatitis B surface antigen. These proteins were detected during periods of serial cultivation over 9 months under the above culture conditions. The hepatoma cell lines grown in the fully defined synthetic medium may provide a new approach for investigating the growth and metabolism of human hepatoma cells in vitro.


[Improvement of infusion-transfusion therapy in a multidisciplinary emergency care hospital].
The article deals with the analysis of works of S.S. Yudin's students and followers devoted to scientific practical and scientific-organizational research into optimization of infusion-transfusion therapy in emergency service hospitals in emergency states: multiple and combined trauma, the crush syndrome, burns, exogenous poisoning, and pyoseptic complications in surgical and traumatological practice. The principles of transfusion media rationing in an emergency service hospital, particularly in mass admission of patients and accident victims, are substantiated. The medico-economical efficacy of including infusion-transfusion therapy in complex treatment of emergency conditions is shown.


Thoracic Aortic Calcium Density and Area in Long-Term Atherosclerotic Cardiovascular Disease Risk Among Men Versus Women.
The development of thoracic aortic calcium (TAC) temporally precedes coronary artery calcium more often in women versus men. Whether TAC density and area confer sex-specific differences in atherosclerotic cardiovascular disease (ASCVD) risk is unknown. We studied 5317 primary prevention patients who underwent coronary artery calcium scoring on noncontrast cardiac gated computed tomography with TAC >0. The Agatston TAC score (Agatston units), density (Hounsfield units), and area (mm2) were compared between men and women. Cox proportional hazards regression calculated adjusted hazard ratios for TAC density-area groups with ASCVD mortality, adjusting for traditional risk factors, coronary artery calcium, and TAC. Multinomial logistic regression calculated adjusted odds ratios for the association between traditional risk factors and TAC density-area groups. The mean age was 60.7 years, 38% were women, and 163 ASCVD deaths occurred over a median of 11.7-year follow-up. Women had higher median TAC scores (97 versus 84 Agatston units; P=0.004), density (223 versus 210 Hounsfield units; P<0.001), and area (37 versus 32 mm2; P=0.006) compared with men. There was a stepwise higher incidence of ASCVD deaths across increasing TAC density-area groups in men though women with low TAC density relative to TAC area (3.6 per 1000 person-years) had survival probability commensurate with the high-density-high-area group (4.8 per 1000 person-years). Compared with low TAC density-area, low TAC density/high TAC area conferred a 3.75-fold higher risk of ASCVD mortality in women (adjusted hazard ratio, 3.75 [95% CI, 1.13-12.44]) but not in men (adjusted hazard ratio, 1.16 [95% CI, 0.48-2.84]). Risk factors most strongly associated with low TAC density/high TAC area differed in women (diabetes: adjusted odds ratio, 2.61 [95% CI, 1.34-5.07]) versus men (hypertension: adjusted odds ratio, 1.45 [95% CI, 1.11-1.90]). TAC density-area phenotypes do not consistently associate with ASCVD mortality though low TAC density relative to area may be a marker of increased ASCVD risk in women.


[Autism in children. Speech, behavior and motor activity point to diagnosis].
Austistic disorders characteristically involve specific impairments of social skills, of the language and of stereotyped body movements. L Kanner and H. Asperger were the first to describe these psychopathologic features, which still form the core of the diagnostic criteria of contemporary psychiatric classification systems, ICD-10 and DSM-IV, in the category pervasive developmental disorders. Useful diagnostic tools have been developed to establish the clinical diagnosis. The results of research point to a predominantly genetic pathogenesis involving a complex interaction of multiple genes. While no causal treatments are available for these heterogenic disorders, there are many therapeutic concepts. Although some treatments may achieve significant improvements, autistic disorders usually mean a lifelong individual impairment.


Acute and Chronic Molecular Signatures and Associated Symptoms of Blast Exposure in Military Breachers.
Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigations of blast-related neurotrauma and operational breaching. In this study, military "breachers" were exposed to controlled, low-level blast during a 10-day explosive breaching course. Using an omics approach, we assessed epigenetic, transcriptional, and inflammatory profile changes in blood from operational breaching trainees, with varying levels of lifetime blast exposure, along with daily self-reported symptoms (with tinnitus, headaches, and sleep disturbances as the most frequently reported). Although acute exposure to blast did not confer epigenetic changes, specifically in DNA methylation, differentially methylated regions (DMRs) with coordinated gene expression changes associated with lifetime cumulative blast exposures were identified. The accumulative effect of blast showed increased methylation of PAX8 antisense transcript with coordinated repression of gene expression, which has been associated with sleep disturbance. DNA methylation analyses conducted in conjunction with reported symptoms of tinnitus in the low versus high blast incidents groups identified DMRS in KCNE1 and CYP2E1 genes. KCNE1 and CYP2E1 showed the expected inverse correlation between DNA methylation and gene expression, which have been previously implicated in noise-related hearing loss. Although no significant transcriptional changes were observed in samples obtained at the onset of the training course relative to chronic cumulative blast, we identified a large number of transcriptional perturbations acutely pre- versus post-blast exposure. Acutely, 67 robustly differentially expressed genes (fold change ≥1.5), including UFC1 and YOD1 ubiquitin-related proteins, were identified. Inflammatory analyses of cytokines and chemokines revealed dysregulation of MCP-1, GCSF, HGF, MCSF, and RANTES acutely after blast exposure. These data show the importance of an omics approach, revealing that transcriptional and inflammatory biomarkers capture acute low-level blast overpressure exposure, whereas DNA methylation marks encapsulate chronic long-term symptoms.


Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease.
Reduced caveolin-1 levels in lung fibroblasts from patients with scleroderma and the lungs of bleomycin-treated mice promote collagen overexpression and lung fibrosis. This study was undertaken to determine whether caveolin-1 is deficient in leucocytes from bleomycin-treated mice and patients with scleroderma and to examine the consequences of this deficiency and its reversal. Mice or cells received the caveolin-1 scaffolding domain (CSD) peptide to reverse the pathological effects of reduced caveolin-1 expression. In bleomycin-treated mice, the levels of caveolin-1 in leucocytes and the effect of CSD peptide on leucocyte accumulation in lung tissue were examined. To validate the results in human disease and to identify caveolin-1-regulated molecular mechanisms, monocytes and neutrophils were isolated from patients with scleroderma and control subjects and caveolin-1, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase 9 (MMP-9) expression/activation were evaluated. These parameters were also studied in monocytes treated with cytokines or CSD peptide. Leucocyte caveolin-1 is important in lung fibrosis. In bleomycin-treated mice, caveolin-1 expression was diminished in monocytes and CSD peptide inhibited leucocyte recruitment into the lungs. These observations are relevant to human disease. Monocytes and neutrophils from patients with scleroderma contained less caveolin-1 and more activated ERK, JNK and p38 than those from control subjects. Treatment with CSD peptide reversed ERK, JNK and p38 hyperactivation. Scleroderma monocytes also overexpressed CXCR4 and MMP-9, which was inhibited by the CSD peptide. Cytokine treatment of normal monocytes caused adoption of the scleroderma phenotype (low caveolin-1, high CXCR4 and MMP-9 and signalling molecule hyperactivation). Caveolin-1 downregulation in leucocytes contributes to fibrotic lung disease, highlighting caveolin-1 as a promising therapeutic target in scleroderma.


KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer.
Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative, "triple-negative" breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.


Protein tyrosine phosphorylation mediates TNF-induced endothelial-neutrophil adhesion in vitro.
Proinflammatory cytokines initiate the vascular inflammatory response via the upregulation of adhesion molecules on the luminal endothelial surface. We investigated directly the role of protein tyrosine phosphorylation in the upregulation of the endothelial adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) and E-selectin, and the consequent adhesion of neutrophils, after tumor necrosis factor (TNF)-alpha-stimulation of human aortic endothelial cells in vitro. Time- and dose-dependent TNF-alpha-stimulated ICAM-1 and E-selectin upregulation and neutrophil adhesion each were suppressed by tyrosine kinase inhibitors, including genistein (200 microM), but not genistein, its isoflavone analog without tyrosine kinase inhibitory activity. Tyrphostin AG 126, a synthetic selective tyrosine kinase inhibitor, also suppressed ICAM-1 and E-selectin upregulation and neutrophil adhesion, each in a dose-dependent manner, whereas tyrphostin AG 1288 had no effect. Tyrosine phosphorylation of two proteins (85 and 145 kDa in the cytoskeleton fraction) found minutes after TNF-alpha-stimulation was also inhibited by genistein. These findings suggest that, in endothelial cells, TNF-alpha upregulates ICAM-1 and E-selectin expression and consequent neutrophil adhesion via protein tyrosine phosphorylation.


Evaluation of amastigote reactive cells in human cutaneous leishmaniasis caused by Leishmania aethiopica.
Lymphoproliferative responses to three affinity chromatography purified amastigote antigens of Leishmania pifanoi, P-2, P-4 and P-8, were evaluated in peripheral blood mononuclear cells (PBMC) from patients with Ethiopian cutaneous leishmaniasis. Antigen-stimulated cells were analysed for the percentage of CD4+, CD8+ and CD16/56+ cells and the expressed levels of gamma interferon (IFNgamma) and interleukin (IL)-10 were determined in culture supernatants. The amastigote antigens induced cellular responses in leishmaniasis patients with heterologous Leishmania parasite infection. These responses were compared to those of freeze-thawed L. aethiopica promastigote antigen stimulation. The membrane protein (P-8), and to a lesser extent the megasomal/cytoplasmic cysteine proteinase(P-2), induced proliferation with high levels of IFNgamma and IL-10 production in cells from patients with active L. aethiopica lesions. CD16/56+ NK cells were the main cell types induced to proliferate in response to P-8 and P-2 stimulation, followed by CD8+ cell populations. P-4 had no such effect. This contrasts from previous studies of New World human leishmaniasis where P-4 and P-8 were stimulatory. The success of a particular molecule in the induction of a response with a protective phenotype may be dependent on the infecting Leishmania spp. To our knowledge, there are no studies that directly compare the New versus Old World cutaneous leishmaniasis in respect of NK cell and IL-10 responses. Our studies indicate that some leishmanial molecules are recognized across the species, while others are apparently more species specific.


Sodium Hydrosulfide Attenuates Beta-Amyloid-Induced Cognitive Deficits and Neuroinflammation via Modulation of MAPK/NF-κB Pathway in Rats.
Beta-amyloid (Aβ), a neurotoxic peptide, accumulates in the brain of Alzheimer's disease (AD) subjects to initiate neuroinflammation eventually leading to memory impairment. Here, we demonstrated that Aβ-injected rats exhibited cognitive impairment and neuroinflammation with a remarkable reduction of hydrogen sulfide (H2S) levels in the hippocampus compared with that in shamoperated rats. Interestingly, the expression of cystathionine-β-synthase (CBS) and 3- mercaptopyruvate-sulfurtransferase (3MST), the major enzymes responsible for endogenous H2S generation, were also significantly decreased. However, intraperitoneal (i.p.) injection of sodium hydrosulfide (NaHS, a H2S donor) dramatically attenuated cognitive impairment and neuroinflammation induced by hippocampal injection of 10 μg of Aβ1-42 in rats. Subsequently, NaHS significantly suppressed the expression of tumor necrosis factor (TNF)-α, interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) in rat hippocampus following Aβ administration. Furthermore, NaHS exerted a beneficial effect on inhibition of IκB-α degradation and subsequent activation of transcription factor nuclear factor κB (NF-κB), as well as inhibition of extracellular signal-regulated kinase (ERK1/2) activity and p38 MAPK activity but not c-Jun N-terminal kinase (JNK) activity induced by Aβ. These results demonstrate that NaHS might be a potential agent for treatment of neuroinflammation-related AD.


Severity of reported childhood sexual abuse and its relationship to severity of borderline psychopathology and psychosocial impairment among borderline inpatients.
This study has two purposes. The first purpose is to describe the severity of sexual abuse reported by a well-defined sample of borderline inpatients. The second purpose is to determine the relationship between the severity of reported childhood sexual abuse, other forms of childhood abuse, and childhood neglect and the severity of borderline symptoms and psychosocial impairment. Two semistructured interviews of demonstrated reliability were used to assess the severity of adverse childhood experiences reported by 290 borderline inpatients. It was found that more than 50% of sexually abused borderline patients reported being abused both in childhood and in adolescence, on at least a weekly basis, for a minimum of 1 year, by a parent or other person well known to the patient, and by two or more perpetrators. More than 50% also reported that their abuse involved at least one form of penetration and the use of force or violence. Using multiple regression modeling and controlling for age, gender, and race, it was found that the severity of reported childhood sexual abuse was significantly related to the severity of symptoms in all four core sectors of borderline psychopathology (affect, cognition, impulsivity, and disturbed interpersonal relationships), the overall severity of borderline personality disorder, and the overall severity of psychosocial impairment. It was also found that the severity of childhood neglect was significantly related to five of the 10 factors studied, including the overall severity of borderline personality disorder, and that the severity of other forms of childhood abuse was significantly related to two of these factors, including the severity of psychosocial impairment. Taken together, the results of this study suggest that the majority of sexually abused borderline inpatients may have been severely abused. They also suggest that the severity of childhood sexual abuse, other forms of childhood abuse, and childhood neglect may all play a role in the symptomatic severity and psychosocial impairment characteristic of borderline personality disorder.