Diseases mortality patterns in elderly patients: A Nigerian teaching hospital experience in Irrua, Nigeria.
Currently, in developing countries, there is a paradigm shift in the mortality patterns from communicable to non-communicable diseases. This study is aimed at providing a broad spectrum on the mortality patterns in elderly within a 5-year-period in a tertiary healthcare provider in Nigeria. This study is a retrospective review of mortality patterns of elderly patients from January 2007 to December 2011 occurring in Irrua specialist teaching hospital, (ISTH), Irrua and its environs. Information derived from the request cards include age, sex, clinical history, diagnosis, duration and cause of death. During this period a total of 3,002 elderly (>65 years) admissions were seen. Of this, 561 patients were confirmed dead. Among this, 317 and 244 cases were elderly male and female patients, respectively. Hence the ratio of male to female was 1.3:1.0. The peak age group was 65-70 years accounting for 147 patients (26.2%). The age range of patients was 65-104 years while the modal and mean ages were 69 years and 74 years ΁ 4.2 standard deviation (SD), respectively. The most commonly encountered cause of mortality was cerebrovascular accident constituting 141 (25.1%) cases. The 2(nd) and 3(rd) majority of mortality cases were malignancies and diabetes mellitus (metabolic disorder) accounting for 85 (15.2%) and 45 (8%) cases, respectively. Others include congestive cardiac failure 35 (6.2%), Septicaemia 29 (5.2%), trauma 26 (4.6%) while chronic renal failure and chronic obstructive pulmonary disease consist of 22 cases (3.9%) each. Non-communicable diseases particularly cerebrovascular diseases and malignancies were the most commonly encountered cause of elderly mortality in our environment. Notwithstanding a large percentage of mortality patterns also results from communicable diseases with sepsis as the leading cause of mortality.


The Yield of Routine Post-Operative Doppler Ultrasound to Detect Early Post-Liver Transplantation Vascular Complications.
Early detection of liver transplantation (LT) vascular complications enables timely management. Our aim was to assess if routine Doppler ultrasound (rDUS) improves the detection of hepatic artery thrombosis (HAT), portal vein thrombosis (PVT) and hepatic venous outflow obstruction (HVOO). We retrospectively analysed timing and outcomes, number needed to diagnose one complication (NND) and positive predictive value (PPV) of rDUS on post-operative day (POD) 0,1 and 7 in 708 adult patients who underwent primary LT between 2010-2022. We showed that HAT developed in 7.1%, PVT in 8.2% and HVOO in 3.1% of patients. Most early complications were diagnosed on POD 0 (26.9%), 1 (17.3%) and 5 (17.3%). rDUS correctly detected 21 out of 26 vascular events during the protocol days. PPV of rDUS was 53.8%, detection rate 1.1% and NND was 90.5. Median time to diagnosis was 4 days for HAT and 47 days for PVT and 21 days for HVOO. After intervention, liver grafts were preserved in 57.1%. In conclusion, rDUS protocol helps to detect first week's vascular events, but with low PPV and a high number of ultrasounds needed.


Structural analysis of HIV-1 maturation using cryo-electron tomography.
HIV-1 buds form infected cells in an immature, non-infectious form. Maturation into an infectious virion requires proteolytic cleavage of the Gag polyprotein at five positions, leading to a dramatic change in virus morphology. Immature virions contain an incomplete spherical shell where Gag is arranged with the N-terminal MA domain adjacent to the membrane, the CA domain adopting a hexameric lattice below the membrane, and beneath this, the NC domain and viral RNA forming a disordered layer. After maturation, NC and RNA are condensed within the particle surrounded by a conical CA core. Little is known about the sequence of structural changes that take place during maturation, however. Here we have used cryo-electron tomography and subtomogram averaging to resolve the structure of the Gag lattice in a panel of viruses containing point mutations abolishing cleavage at individual or multiple Gag cleavage sites. These studies describe the structural intermediates correlating with the ordered processing events that occur during the HIV-1 maturation process. After the first cleavage between SP1 and NC, the condensed NC-RNA may retain a link to the remaining Gag lattice. Initiation of disassembly of the immature Gag lattice requires cleavage to occur on both sides of CA-SP1, while assembly of the mature core also requires cleavage of SP1 from CA.


Surviving the Loss of a Child: A Mexican-American's Story.
This paper tells the story of a mother's loss of her 10-year-old daughter from cancer. It is in part a pain and suffering narrative and a story of remarkable post-loss growth and transformation. It is a story told for busy parents and multitasking nurses, to all of us who need to relearn how to be attentive to others, particularly our children. The woman who tells the story is one of the authors (M.V.-W.); she is a Mexican-American. The paper is based on two interviews of M.V.-W., using questions similar to those used by one of the authors (S.L.B.) with his study of fathers and sibling. Following the interviews is a brief discussion on the loss of a child from a humanbecoming perspective, with a few comments on the immigration of nurses.


Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.
Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.


Controlling for unmeasured confounding and spatial misalignment in long-term air pollution and health studies.
The health impact of long-term exposure to air pollution is now routinely estimated using spatial ecological studies, owing to the recent widespread availability of spatial referenced pollution and disease data. However, this areal unit study design presents a number of statistical challenges, which if ignored have the potential to bias the estimated pollution-health relationship. One such challenge is how to control for the spatial autocorrelation present in the data after accounting for the known covariates, which is caused by unmeasured confounding. A second challenge is how to adjust the functional form of the model to account for the spatial misalignment between the pollution and disease data, which causes within-area variation in the pollution data. These challenges have largely been ignored in existing long-term spatial air pollution and health studies, so here we propose a novel Bayesian hierarchical model that addresses both challenges and provide software to allow others to apply our model to their own data. The effectiveness of the proposed model is compared by simulation against a number of state-of-the-art alternatives proposed in the literature and is then used to estimate the impact of nitrogen dioxide and particulate matter concentrations on respiratory hospital admissions in a new epidemiological study in England in 2010 at the local authority level. © 2015 The Authors. Environmetrics published by John Wiley & Sons Ltd.


Polyethylene oxidation in total hip arthroplasty: evolution and new advances.
Ultra-high molecular weight polyethylene (UHMWPE) remains the gold standard acetabular bearing material for hip arthroplasty. Its successful performance has shown consistent results and survivorship in total hip replacement (THR) above 85% after 15 years, with different patients, surgeons, or designs. As THR results have been challenged by wear, oxidation, and liner fracture, relevant research on the material properties in the past decade has led to the development and clinical introduction of highly crosslinked polyethylenes (HXLPE). More stress on the bearing (more active, overweighted, younger patients), and more variability in the implantation technique in different small and large Hospitals may further compromise the clinical performance for many patients. The long-term in vivo performance of these materials remains to be proven. Clinical and retrieval studies after more than 5 years of in vivo use with HXLPE in THR are reviewed and consistently show a substantial decrease in wear rate. Moreover, a second generation of improved polyethylenes is backed by in vitro data and awaits more clinical experience to confirm the experimental improvements. Also, new antioxidant, free radical scavengers, candidates and the reinforcement of polyethylene through composites are currently under basic research.Oxidation of polyethylene is today significantly reduced by present formulations, and this forgiving, affordable, and wellknown material is still reliable to meet today's higher requirements in total hip replacement.


The impact and cost of the HIV/AIDS investment framework for adolescents.
In 2005, the resources needed to support orphans and vulnerable children in sub-Saharan Africa were estimated at US$ 1.1-4.1 billion. Approaches to support vulnerable children have changed considerably since then. This study updates previous estimates by including new types of support and information on support costs. We considered 16 types of support categorized as economic strengthening, education support, social care and community outreach, and program support. The estimates combine the number of children in need of each intervention with unit costs derived from the literature and coverage goals based on current coverage and feasible future improvements. The number of children affected by AIDS in low- and middle-income countries varies from 58 million to 315 million depending on the definition of need. The resources required to provide support to children living in poor households will grow from US$ 4.2 billion in 2012 to US$ 5-8 billion by 2020. Almost two-thirds of these resources will be needed for Sub-Saharan Africa. The largest needs are for cash transfers, community care workers, early childhood development, block grants for education, M&E monitoring and evaluation, and direct material support. The results show that we can significantly improve the coverage of services for vulnerable children with only modest increases in resources. This results from stable or declining numbers of orphans and children living with HIV plus economic growth that is moving more households out of poverty. The results also reflect an important shift toward providing support to strengthen families and communities that care for children rather than direct material support. More resources are required to support children affected by AIDS, but new approaches to provide that support will be cost effective and have broad social and economic benefits.


Slow oscillation amplitudes and up-state lengths relate to memory improvement.
There is growing evidence of the active involvement of sleep in memory consolidation. Besides hippocampal sharp wave-ripple complexes and sleep spindles, slow oscillations appear to play a key role in the process of sleep-associated memory consolidation. Furthermore, slow oscillation amplitude and spectral power increase during the night after learning declarative and procedural memory tasks. However, it is unresolved whether learning-induced changes specifically alter characteristics of individual slow oscillations, such as the slow oscillation up-state length and amplitude, which are believed to be important for neuronal replay. 24 subjects (12 men) aged between 20 and 30 years participated in a randomized, within-subject, multicenter study. Subjects slept on three occasions for a whole night in the sleep laboratory with full polysomnography. Whereas the first night only served for adaptation purposes, the two remaining nights were preceded by a declarative word-pair task or by a non-learning control task. Slow oscillations were detected in non-rapid eye movement sleep over electrode Fz. Results indicate positive correlations between the length of the up-state as well as the amplitude of both slow oscillation phases and changes in memory performance from pre to post sleep. We speculate that the prolonged slow oscillation up-state length might extend the timeframe for the transfer of initial hippocampal to long-term cortical memory representations, whereas the increase in slow oscillation amplitudes possibly reflects changes in the net synaptic strength of cortical networks.


Global and Specific Profiles of Executive Functioning in Prodromal and Early Psychosis.
Objective: Numerous reports on neurocognitive functioning deficits in individuals at clinical high risk (CHR) and first-episode psychosis (FEP) patients suggest particular deficits in executive functioning (EF). However, to date, most of the studies have administered a single or a few EF tests to participants, and few investigations have examined the different components of EF to identify specific subdomains of relative strength and weakness. Method: Forty CHR subjects, 85 FEP patients, and 85 healthy controls (HCs) were assessed with a neuropsychological battery to elucidate the profiles of EF in the subdomains of shift, attention, fluency, and planning. Results: In the subdomains of shift, attention, and fluency, CHR individuals and FEP patients showed deficits compared to HC. The post hoc analysis revealed that CHR individuals had comparable attention shifting and phonemic fluency compared to FEP. CHR showed intermediate deficits between FEP and HCs in spatial working memory and semantic fluency, and the largest effect size was observed in semantic fluency both for CHR and FEP. Conclusion: Overall, the findings of this study, in addition to providing detailed profiles of EF in prodromal and early psychosis patients, highlight the informative value of the specific subdomains of semantic fluency and spatial working memory.


Growth fraction estimation of malignant lymphomas in formalin-fixed paraffin-embedded tissue using anti-PCNA/Cyclin 19A2. Correlation with Ki-67 labeling.
The immunohistochemical detection of PCNA/Cyclin, a nuclear protein associated with cell proliferation, represents a potentially useful tool for the study of tumor proliferative activity. Previous studies investigating the reactivity of anti-PCNA/Cyclin monoclonal antibody 19A2 have not clearly defined the population of proliferating cells with which 19A2 reacts in tissue sections. The authors describe a method for detection of PCNA/Cyclin in formalin-fixed, paraffin-embedded tissue using a routine biotin-streptavidin immunohistochemical system that employs an anti-IgM, mu-chain-specific second-stage antibody. The authors used this method to study the proliferative activity of 24 malignant lymphomas, consisting of 12 low-grade lymphomas (LGLs) and 12 intermediate-grade lymphomas (IGLs), and five reactive tonsils. 19A2 data was compared with Ki-67 labeling in frozen sections in the same group of cases. 19A2 provided easily detectable nuclear staining of proliferating cells with reactive cells demonstrating varying intensity of staining, this latter finding most likely due to the varying nuclear concentration of PCNA/Cyclin protein during the cell cycle. In tonsils, 19A2 reacted with germinal center cells and basal keratinocytes. In the malignant lymphomas, there was good correlation between 19A2 and Ki-67 data (r = 0.90, P less than 0.001). The subgroup of LGLs showed a mean PCNA/Cyclin of 26% and a mean Ki-67 of 28%. In the subgroup of IGLs, mean PCNA/Cyclin = 54% and mean Ki-67 = 59%. These results indicate that 19A2 detects a fraction of proliferating cells that is similar to that detected by Ki-67, ie, the growth fraction, and that 19A2 is a reliable marker of proliferative activity in uniformly handled, formalin-fixed, paraffin-embedded tissue.


Membranoproliferative glomerulonephritis and persistent hypocomplementaemia.
The clinical, laboratory, and histological findings of 50 patients with membranoproliferative glomerulonephritis are described. Three-quarters of the patients, who were mostly older children and young adults, presented clinically with a mixture of "nephritic" and "nephrotic" symptoms; the remaining quarter had no symptoms and were diagnosed after the discovery of proteinuria and microscopic haematuria.Though this clinical picture may occur in other forms of glomerulonephritis, the patients described here were unified as a group by their glomerular morphological appearance-namely, a combination of mesangial proliferation and capillary wall thickening, mainly due to subendothelial accumulations of mesangial matrix.In 68% serum C3 (beta10-globulin) levels were reduced initially, while a further 16% subsequently showed a fall to abnormally low levels. All patients had substantial proteinuria, usually of moderately impaired selectivity, and all but one had haematuria in addition. Children frequently presented with an illness resembling acute nephritis, whereas adults usually had a nephrotic syndrome from the start.In 31 patients, followed for periods of one to eight and a half years, serial measurements of glomerular filtration rate were made. Sixteen have experienced no deterioration of renal function, though their proteinuria continues unchanged. Fifteen have shown progressive deterioration; six of them are still well, six are on regular dialysis treatment, and three have died. Treatment with corticosteroids, azathioprine, or cyclophosphamide, alone or in combination, did not seem to influence the course of the disease, and another two patients died from complications of steroid therapy. The disease usually runs a chronic course and appears to be progressive.


Effect of pyridines on phenotypic properties of Bordetella pertussis.
Several conditions of growth of Bordetella pertussis cause a reversible phenotypic alteration in properties termed modulation. Growth in medium containing nicotinic acid induces normal (X-mode) cells to change to modulated (C-mode) cells. We examined several pyridines and compounds resembling pyridines for their ability to affect modulation, using envelope protein patterns and serological reactivity as indicators of modulation. We found that 6-chloronicotinic acid and quinaldic acid were more effective modulating stimuli than was nicotinic acid on a molar basis. Both 2-chloronicotinamide and isoniazid interfered with nicotinic acid-induced modulation, and can be called antimodulators. Picolinic acid inhibited growth.


Further studies of the role of cyclic beta-glucans in symbiosis. An NdvC mutant of Bradyrhizobium japonicum synthesizes cyclodecakis-(1-->3)-beta-glucosyl.
The cyclic beta-(1-->3),beta-(1-->6)-D-glucan synthesis locus of Bradyrhizobium japonicum is composed of at least two genes, ndvB and ndvC. Mutation in either gene affects glucan synthesis, as well as the ability of the bacterium to establish a successful symbiotic interaction with the legume host soybean (Glycine max). B. japonicum strain AB-14 (ndvB::Tn5) does not synthesize beta-glucans, and strain AB-1 (ndvC::Tn5) synthesizes a cyclic beta-glucan lacking beta-(1-->6)-glycosidic bonds. We determined that the structure of the glucan synthesized by strain AB-1 is cyclodecakis-(1-->3)-beta-D-glucosyl, a cyclic beta-(1-->3)-linked decasaccharide in which one of the residues is substituted in the 6 position with beta-laminaribiose. Cyclodecakis-(1-->3)-beta-D-glucosyl did not suppress the fungal beta-glucan-induced plant defense response in soybean cotyledons and had much lower affinity for the putative membrane receptor protein than cyclic beta-(1-->3),beta-(1-->6)-glucans produced by wild-type B. japonicum. This is consistent with the hypothesis presented previously that the wild-type cyclic beta-glucans may function as suppressors of a host defense response.


Objectively Measured Physical Activity in European Adults: Cross-Sectional Findings from the Food4Me Study.
Comparisons of objectively measured physical activity (PA) between residents of European countries measured concurrently with the same protocol are lacking. We aimed to compare PA between the seven European countries involved in the Food4Me Study, using accelerometer data collected remotely via the Internet. Of the 1607 participants recruited, 1287 (539 men and 748 women) provided at least 3 weekdays and 2 weekend days of valid accelerometer data (TracmorD) at baseline and were included in the present analyses. Men were significantly more active than women (physical activity level = 1.74 vs. 1.70, p < 0.001). Time spent in light PA and moderate PA differed significantly between countries but only for women. Adherence to the World Health Organization recommendation to accumulate at least 150 min of moderate-equivalent PA weekly was similar between countries for men (range: 54-65%) but differed significantly between countries for women (range: 26-49%). Prevalence estimates decreased substantially for men and women in all seven countries when PA guidelines were defined as achieving 30 min of moderate and vigorous PA per day. We were able to obtain valid accelerometer data in real time via the Internet from 80% of participants. Although our estimates are higher compared with data from Sweden, Norway, Portugal and the US, there is room for improvement in PA for all countries involved in the Food4Me Study.


Sporobacterium olearium gen. nov., sp. nov., a new methanethiol-producing bacterium that degrades aromatic compounds, isolated from an olive mill wastewater treatment digester.
A strictly chemo-organotrophic, anaerobic bacterium was isolated from an olive mill wastewater treatment digester on syringate and designated strain SR1T. The cells were slightly curved rods, stained Gram-positive and possessed terminal spores. Strain SR1T utilized crotonate, methanol and a wide range of aromatic compounds including 3,4,5-trimethoxybenzoate (TMB), 3,4,5-trimethoxycinnamate (TMC), syringate, 3,4,5-trimethoxyphenylacetate (TMPA), 3,4,5-trimethoxyphenylpropionate (TMPP), ferulate, sinapate, vanillate, 3,4-dimethoxybenzoate, 2,3-dimethoxybenzoate, gallate, 2,4,6-trihydroxybenzoate (THB), pyrogallol, phloroglucinol and quercetin as carbon and energy sources. Acetate and butyrate were produced from aromatic compounds, methanol and crotonate whereas methanethiol (MT) was produced from methoxylated aromatic compounds and methanol. Strain SR1T had a G + C content of 38 mol% and grew optimally between 37 and 40 degrees C at pH 7.2 on a crotonate-containing medium. Phylogenetically, strain SR1T was a member of cluster XIVa of the Clostridiales group and shared a sequence similarity of 90% with Clostridum aminovalericum and Eubacterium fissicatena. Consequently, its precise neighbourliness to any one of them depended on the selection of strains of the cluster. On the basis of the phylogenetic and phenotypic evidence presented in this paper, the designation of strain SR1T as Sporobacterium olearium gen. nov., sp. nov. is proposed. The type strain is SR1T (= DSM 12504T).


Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2.
We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at P<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the United States/Australia, Germany, China, Japan, Israel and Sweden (n=5142 cases/6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), P=0.0009). The SNP maps 85 kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia.


Effects of Tau and MAP2 on the interaction of maytansine with tubulin: inhibitory effect of maytansine on vinblastine-induced aggregation of tubulin.
Maytansine, a potent inhibitor of mitosis and in vitro microtubule assembly, was used to demonstrate a striking difference in the mechanism by which two of the main groups of brain microtubule-associated proteins, Tau and MAP2, interact with tubulin. At the low concentrations of 0.5 to 2 microM, maytansine inhibited Tau-catalyzed tubulin assembly more effectively than it did MAP2-catalyzed assembly. This effect differed markedly from that of vinblastine, although both drugs bind competitively to tubulin. At the same low concentrations, vinblastine almost completely inhibited Tau- and MAP2-mediated tubulin assembly. At higher concentrations of 10 to 40 microM, a more striking difference was observed between the actions of the two drugs. Maytansine very effectively inhibited tubulin assembly promoted by either Tau or MAP2. Vinblastine also had this effect on MAP2-mediated tubulin assembly but in the presence of Tau induced extensive tubulin aggregation into spirals. In addition maytansine strongly inhibited vinblastine-induced Tau-dependent tubulin aggregation into spiral polymers. Even at very low concentrations, maytansine completely inhibited the effect of very high concentrations of vinblastine. These results very strongly suggest that the binding sites of maytansine and vinblastine on the tubulin molecule overlap and that the changes that they probably induce in the conformation of this molecule are markedly different, at least in the presence of microtubule-associated proteins.


Development of Biofortified Maize Hybrids through Marker-Assisted Stacking of β-Carotene Hydroxylase, Lycopene-ε-Cyclase and Opaque2 Genes.
Traditional yellow maize though contains high kernel carotenoids, the concentration of provitamin A (proA) is quite low (<2 μg/g), compared to recommended level (15 μg/g). It also possesses poor endosperm protein quality due to low concentration of lysine and tryptophan. Natural variant of crtRB1 (β-carotene hydroxylase) and lcyE (lycopene-ε-cyclase) cause significant enhancement of proA concentration, while recessive allele, opaque2 (o2) enhances the level of these amino acids. Development of biofortified maize enriched in proA, lysine and tryptophan thus holds significance in alleviation of micronutrient malnutrition. In the present study, marker-assisted stacking of crtRB1, lcyE and o2 was undertaken in the genetic background of four maize hybrids (HQPM1, HQPM4, HQPM5, and HQPM7) popularly grown in India. HP704-22 and HP704-23 were used as donors, while four elite QPM parents viz., HKI161, HKI163, HKI193-1, and HKI193-2 were used as recipients. CrtRB1 showed severe segregation distortion, while lcyE segregated as per the expectation. Recovery of recurrent parent genome (RPG) among selected backcross progenies ranged from 89 to 93%. Introgressed progenies possessed high concentration of proA (7.38-13.59 μg/g), compared to 1.65-2.04 μg/g in the recurrent parents. The reconstituted hybrids showed an average of 4.5-fold increase in proA with a range of 9.25-12.88 μg/g, compared to original hybrids (2.14-2.48 μg/g). Similar plant-, ear-, and grain- characteristics of improved versions of both inbreds and hybrids were observed when evaluated with their respective original versions. Mean lysine (0.334%) and tryptophan (0.080%) of the improved hybrids were at par with the original versions (lysine: 0.340%, tryptophan: 0.083%). Improved hybrids also possessed similar grain yield potential (6,301-8,545 kg/ha) with their original versions (6,135-8,479 kg/ha) evaluated at two locations. This is the first study of staking crtRB1-, lcyE-, and o2-, favorable alleles in single genetic background. The improved inbreds can be effectively used as potential donor for independent and/or simultaneous introgression of crtRB1, lcyE, and o2 in the future breeding programme. These biofortified maize hybrids, rich in proA, lysine and tryptophan will hold great promise for nutritional security.


A mixed-methods approach to conceptualizing friendships in anorexia nervosa.
Individuals with anorexia nervosa have reported feelings of loneliness, social anhedonia, and interpersonal difficulties. This study sought to clarify the nature of interpersonal relationships in adults with anorexia, which may help improve existing interventions while also facilitating the attainment of something that might compete with the drive for thinness: friendships. The present study used a mixed-methods approach to investigate friendship experiences in three groups: anorexia (n = 27), participants with a history of anorexia who are weight restored (n = 20), and healthy controls (n = 24). Thematic analysis was used to isolate the most prevalent themes that emerged from an open-ended interview of experiencing friendships in a subset of participants. Three self-report questionnaires investigating friendship valuation and attachment styles were also administered. 11 unique themes emerged in the data: social comparison, reciprocity, trust, fear of negative evaluation, perceived skills deficit, logistical barriers, reliability, identity issue, low interest, similarity, and conflict avoidance. Only 17% of those with anorexia reported experiencing friendships as positive, relative to 82% of healthy controls and 52% of weight restored participants. Lastly, on self-report measures, participants with anorexia reported greater reliance on themselves versus others, greater use of care-seeking behaviors, and more fear/anger at the thought of losing an attachment figure (p < .05 in all cases). Results suggest that individuals with anorexia have particular challenges which interfere with the formation and maintenance of friendships, such as viewing friendships negatively and struggling with social comparisons in friendships. Assessing and addressing barriers to intimacy may motivate those with anorexia to relinquish dangerous symptoms that maintain the illness.


Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.
A group of 256 newly diagnosed myeloma patients were enrolled in a phase III study that included 4 monthly cycles of induction chemotherapy and tandem transplant. All patients were randomized to either receive or not receive thalidomide. A total of 221 patients (86%) received no prophylactic anticoagulation (cohort I); 35 patients received low dose coumadin (cohort II). The incidence of deep vein thrombosis (DVT) was significantly higher in the thalidomide arm hazard ratio: 4.5; P < 0.0001). As low dose coumadin (1 mg/d) failed to decrease thrombotic complications in 35 patients (cohort II), low molecular weight heparin (LMWH, enoxaparin 40 mg s.c. q.d.) was instituted as DVT prophylaxis in the thalidomide-treated patients (n = 68) of the subsequent cohort (n = 130, cohort III). This intervention eliminated the difference in DVT incidence between the two arms (thalidomide and no thalidomide). Within cohorts I and II, 36 patients, in whom thalidomide was discontinued after experiencing a thrombotic episode during chemotherapy, subsequently resumed the drug on full anticoagulation; with a median follow-up of 22 months, DVT recurred in four patients (11%). After completing induction and tandem transplantation, 55 patients were re-exposed to thalidomide and chemotherapy during consolidation treatment. Thrombotic complications were observed in 4%. Our experience, although not based on a randomized study, suggests that the excess frequency of thrombosis in patients treated with chemotherapy and thalidomide can be safely reduced by the prophylactic use of LMWH. The rate of DVT recurrence observed in our study upon thalidomide resumption was sufficiently low to allow its continuation in patients who may benefit from this therapeutic intervention.


From prolonging life to prolonging working life: Tackling unemployment among liver-transplant recipients.
Return to active and productive life is a key goal of modern liver transplantation (LT). Despite marked improvements in quality of life and functional status, a substantial proportion of LT recipients are unable to resume gainful employment. Unemployment forms a threat to physical and psychosocial health, and impairs LT cost-utility through lost productivity. In studies published after year 2000, the average post-LT employment rate is 37%, ranging from 22% to 55% by study. Significant heterogeneity exists among studies. Nonetheless, these employment rates are lower than in the general population and kidney-transplant population. Most consistent employment predictors include pre-LT employment status, male gender, functional/health status, and subjective work ability. Work ability is impaired by physical fatigue and depression, but affected also by working conditions and society. Promotion of post-LT employment is hampered by a lack of interventional studies. Prevention of pre-LT disability by effective treatment of (minimal) hepatic encephalopathy, maintaining mobility, and planning work adjustments early in the course of chronic liver disease, as well as timely post-LT physical rehabilitation, continuous encouragement, self-efficacy improvements, and depression management are key elements of successful employment-promoting strategies. Prolonging LT recipients' working life would further strengthen the success of transplantation, and this is likely best achieved through multidisciplinary efforts ideally starting even before LT candidacy.


Targeted Genomic Profiling Reveals Recurrent KRAS Mutations in Mesonephric-like Adenocarcinomas of the Female Genital Tract.
Mesonephric adenocarcinoma most commonly arises in the cervix and is presumed to be derived from normal or hyperplastic mesonephric remnants. It is characterized by recurrent KRAS mutations and lack of PIK3CA/PTEN alterations. Adenocarcinomas of the uterine corpus and ovary characterized by morphologic and immunophenotypic similarities to mesonephric adenocarcinoma have been reported. The pathogenesis of these tumors, which have been designated "mesonephric-like adenocarcinomas" is unknown, and it has been debated whether these represent mesonephric adenocarcinomas that arise in the endometrium/ovary or endometrioid adenocarcinomas that closely mimic mesonephric adenocarcinoma. The relationship at the molecular level between mesonephric adenocarcinomas and mesonephric-like adenocarcinomas is unknown. The aim of this study was to examine the molecular alterations in mesonephric-like adenocarcinomas to identify driver mutations and potential therapeutically targetable mutations, and to determine the relationship between mesonephric-like adenocarcinomas and mesonephric adenocarcinomas using targeted next-generation sequencing. Seven mesonephric-like adenocarcinomas (4 ovarian, 3 uterine corpus) underwent targeted next-generation sequencing to detect mutations, copy number variations and structural variants in exonic regions of 300 cancer genes, and 113 selected intronic regions across 35 genes. All 7 tumors (100%) harbored canonical activating KRAS mutations (4 G12D, 3 G12V). PIK3CA activating mutations were identified in 3 of 7 (43%) cases. There were no alterations in PTEN, ARID1A, or TP53 in any of the tumors. In copy number analysis, 5 of 7 (71%) tumors exhibited 1q gain, which was accompanied by 1p loss in 2 cases. In addition, 4 of 7 (57%) tumors had chromosome 10 gain, which was accompanied by gain of chromosome 12 in 3 cases. Mesonephric-like adenocarcinomas, similar to mesonephric adenocarcinomas, are characterized by recurrent KRAS mutations, gain of 1q, lack of PTEN mutations, and gains of chromosomes 10 and 12. PIK3CA mutations, which have not previously been identified in mesonephric adenocarcinoma, were found in 3 of 7 (43%) mesonephric-like adenocarcinomas in our study. Mesonephric-like adenocarcinomas exhibit strikingly similar molecular aberrations to mesonephric adenocarcinomas, but also frequently harbor PIK3CA mutations, demonstrating biological overlap with carcinomas of both mesonephric and Mullerian (endometrioid) differentiation. Given the previously documented association with endometriosis (ovarian neoplasms) and the prominent endometrial involvement (uterine corpus neoplasms), we believe these are best regarded as of Mullerian origin and representing adenocarcinomas which differentiate along mesonephric lines; as such, we propose the term mesonephric-like Mullerian adenocarcinoma.


Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target.
Four members of two glucose transporter families, SGLT1, SGLT2, GLUT1, and GLUT2, are differentially expressed in the kidney, and three of them have been shown to be necessary for normal glucose resorption from the glomerular filtrate. Mutations in SGLT1 are associated with glucose-galactose malabsorption, SGLT2 with familial renal glucosuria (FRG), and GLUT2 with Fanconi-Bickel syndrome. Patients with FRG have decreased renal tubular resorption of glucose from the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from <1 to >150 g/1.73 m(2) per d. The majority of patients do not seem to develop significant clinical problems over time, and further description of specific disease sequelae in these individuals is reviewed. SGLT2, a critical transporter in tubular glucose resorption, is located in the S1 segment of the proximal tubule, and, as such, recent attention has been given to SGLT2 inhibitors and their utility in patients with type 2 diabetes, who might benefit from the glucose-lowering effect of such compounds. A natural analogy is made of SGLT2 inhibition to observations with inactivating mutations of SGLT2 in patients with FRG, the hereditary condition that results in benign glucosuria. This review provides an overview of renal glucose transport physiology, FRG and its clinical course, and the potential of SGLT2 inhibition as a therapeutic target in type 2 diabetes.


Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened airway HGF.
The hepatocyte growth factor (HGF)/c-Met pathway is often dysregulated in non-small-cell lung cancer (NSCLC). HGF activation of c-Met induces cyclooxygenase-2 (COX-2), resulting in downstream stimulation by prostaglandin E2 of additional pathways. Targeting both c-Met and COX-2 might lead to enhanced antitumor effects by blocking signaling upstream and downstream of c-Met. Effects of crizotinib or celecoxib alone or in combination were tested in NSCLC cells in vitro and in mice transgenic for airway expression of human HGF. Proliferation and invasion of NSCLC cells treated with a combination of crizotinib and celecoxib were significantly lower compared with single treatments. Transgenic mice showed enhanced COX-2 expression localized to preneoplastic areas following exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, which was not present without carcinogen exposure. This shows that COX-2 activity is present during lung tumor development in a high HGF environment. After 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment, a significant decrease in the number of lung tumors per animal was observed after 13-week treatments of crizotinib, celecoxib, or the combination compared with placebo (p < 0.001). With combination treatment, the number of tumors was also significantly lower than single agent treatment (p < 0.001). In the resulting lung tumors, P-c-Met, COX-2, prostaglandin E2, and P-MAPK were significantly downmodulated by combination treatment compared with single treatment. Expression of the epithelial-mesenchymal transition markers E-cadherin and snail was also modulated by combination treatment. In the presence of high HGF, dual inhibition of c-Met and COX-2 may enhance antitumor effects. This combination may have clinical potential in NSCLCs with high HGF/c-Met expression or epithelial-mesenchymal transition phenotype.


Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance.
A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy-induced tumorigenesis and drug resistance including Beclin-1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF-2, MEG3, LAPTM4B, mTOR, BRAF and c-MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance.


[Kinetics of the immobilization of trypsin on activated silichrome].
Trypsin is studied for kinetics of its immobilization on the surface of a porous spheric inorganic carrier with the grafted aldehyde groups in the surface layer. This process is found to be controlled by the enzyme diffusion. It is shown possible to use a body of mathematics known for kinetics of physical adsorption on the porous adsorbents to describe kinetics of protein chemosorption on the analogous carriers. A simple method is suggested for plotting a kinetic curve of the enzyme immobilization on the matrix with any sizes of particles from the experimentally obtained kinetic curve of its binding on the carrier with a definite diameter of particles.


Microenvironmental influences that drive progression from benign breast disease to invasive breast cancer.
Invasive breast cancer represents the endpoint of a developmental process that originates in the terminal duct lobular units and is believed to progress through stages of increasing proliferation, atypical hyperplasia, and carcinoma in situ before the cancer acquires invasive and metastatic capabilities. By comparison with invasive breast cancer, which has been studied extensively, the preceding stages of benign breast disease are more poorly understood. Much less is known about the molecular changes underlying benign breast disease development and progression, as well as the transition from in situ into invasive disease. Even less focus has been given to the specific role of stroma in this progression. The reasons for lack of knowledge about these lesions often come from their small size and limited sample availability. More challenges are posed by limitations of the models used to investigate the lesions preceding invasive breast cancer. However, recent studies have identified alterations in stromal cell function that may be critical for disease progression from benign disease to invasive cancer: key functions of myoepithelial cells that maintain tissue structure are lost, while tissue fibroblasts become activated to produce proteases that degrade the extracellular matrix and trigger the invasive cellular phenotype. Gene expression profiling of stromal alterations associated with disease progression has also identified key transcriptional changes that occur early in disease development. In this review, we will summarize recent studies showing how stromal factors can facilitate progression of ductal carcinoma in situ to invasive disease. We also suggest approaches to identify processes that control earlier stages of disease progression.


Transient failure of opening of the lower oesophageal sphincter on upright oesophagrams: radiographic and clinical findings.
The purpose of our study was to determine the frequency, radiographic features, and clinical importance of transient failure of opening of the lower oesophageal sphincter (LOS) on upright double-contrast views of the oesophagus. A computerized search of radiology records identified 16 patients who had transient failure of opening of the LOS on upright views from biphasic oesophagrams or upper gastrointestinal tract examinations using high-density barium but normal opening of the LOS on prone views using low-density barium. The radiographic findings were reviewed and correlated with the clinical and manometric findings. In all cases, barium studies revealed tapered, beaklike narrowing of the distal oesophagus on upright double-contrast views, with a normal-appearing distal oesophagus, normal opening of the LOS, and intact peristalsis on prone single-contrast views. Only seven patients (44%) had dysphagia. Five of these patients had clinical follow-up, and the dysphagia improved or resolved without specific treatment for LOS dysfunction in four. The remaining patient had persistent dysphagia, but this individual had polymyositis as the likely cause for his dysphagia. Manometry revealed incomplete relaxation of the LOS in two patients and normal relaxation in one. Our experience suggests that failure of opening of the LOS may be observed as a transient finding of little clinical importance on upright double-contrast views of the oesophagus using high-density barium, with normal opening of the LOS on prone single-contrast views using low-density barium. It is important to be aware of this finding, so that it is not mistaken for achalasia or other abnormalities of the distal oesophagus.


Cognitive compensations for blindness in children: an investigation using odour naming.
Historically, blindness has been associated with compensation for the loss of vision by the other senses. However, research to date has focused on perceptual compensations, largely ignoring possible cognitive compensations. We explored the notion that cognitive skills of blind children may facilitate performance in apparently perceptual tasks, by investigating the cognitive factors related to naming a familiar odour. Eighty-three children participated in olfactory and cognitive tasks (thirty-two early-blind, five late-blind, fourteen low-vision, and thirty-two sighted). In the olfactory tasks, the early-blind children performed significantly better than the sighted children on the odour-naming task but not on the odour-sensitivity task. From the cognitive tasks, scores on a nonvisualisable word-pairs task and a sound-word-pairs task were significantly higher for early-blind children and were highly correlated with odour-naming score. The early-blind children outperformed the sighted controls on a task of directed attention. The groups did not differ on memory for a story or for visualisable word pairs. The results suggest that blind children enjoy an advantage in tasks that assess nonvisual memory for paired associates and directed attention, and that superiority on these tasks facilitates performance in the odour-naming task. Other data suggest that sighted children rely on visualisation as a strategy to aid their performance on the cognitive tasks, and are disadvantaged when these strategies cannot be utilised.


Trends in Direct Breath Analysis by Secondary Electrospray Ionization Mass Spectrometry for Clinical Applications.
Exhaled breath can reveal insights about the metabolic state of the human body through the endo- and exogenous compounds it contains. The extent of detectable compounds, however, was revolutionized by the application of mass spectrometry. More specifically, secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS) enables the detection of a broad range of breath-derived compounds simultaneously and with high sensitivity. Together with its rapid and non-invasive nature, direct breath analysis by SESI-HRMS raised particular interest for clinical applications. Over the past years, various clinical trials successfully demonstrated the technology´s capability for biomarker discovery in exhaled breath in adults and more recently in children. Current challenges lie within the potential translation of SESI-HRMS into clinical settings and the requirements therein, such as biomarker identification and validation, which became a focus of more recent studies.


Accuracy estimation for projection-to-volume targeting during rotational therapy: a feasibility study.
Estimating motion and deformation parameters from a series of projection radiographs acquired during arc therapy using a reference CT volume has become a promising technique for targeting treatment. The purpose of this work is to investigate the influence of rotational arc length on maximum achievable accuracy of motion estimation. The projection-to-volume alignment procedure used a nonrigid model to describe motion in thorax area, a cost function consisting of a least-squared error metric and a simple regularizer that encourages local invertibility, and a four-level multiresolution scheme with a conjugate gradient method to optimize the cost function. The authors tested both small and large scale deformations typically found in the thorax of a radiotherapy patient at different breathing states and limited-angle scans of six angular widths (12 degrees, 18 degrees, 24 degrees, 36 degrees, 60 degrees, and 90 degrees) centered at three angles (0 degrees, 45 degrees, and 90 degrees). The experiments illustrate the potential accuracy of limited-angle projection-to-volume alignment. Registration accuracy can be sensitive to angular center, tends to be lower along direction of the projection set, and tends to decrease away from the rotation center. The studies of small as well as large but realistically scaled deformations show similar dependencies. These trends appear to have fairly low sensitivity to quantum noise effects. There is potentially sufficient information present in a small spread of projections to monitor the configuration of reasonably high contrast tumors without implanted markers.


Comparisons of physiological performance in sexual and asexual whiptail lizards (genus Cnemidophorus): implications for the role of heterozygosity.
Many asexual animal species are of hybrid origin, with consequent high levels of heterozygosity. Data from some studies suggest that increased heterozygosity may be functionally correlated with superior performance in a variety of fitness-related traits. Thus, hybrid asexual species could be expected to exhibit some degree of heterosis. This spontaneous heterosis hypothesis is tested in a comparative study of asexual and sexual species of the lizard genus Cnemidophorus. Asexual species of the genus are parthenogenetically reproducing hybrids of the sexual species and as a result have high levels of heterozygosity that have persisted since their origins. Five whole-organism physiological traits (burst speed, endurance, maximal exertion, standard metabolic rate, and evaporative water loss rate) were examined in five asexual species and the sexual species that gave rise to them. Trait values for sexual and asexual species were compared using a nonphylogenetic approach and two phylogenetically controlled approaches capable of dealing with reticulate phylogenies. In contrast to the predictions of the heterosis hypothesis, performance for four of the traits in asexual Cnemidophorus was not statistically different than that in their sexual parental species, and asexuals had significantly worse endurance. On the whole, the overall trend appeared to be toward worse performance in asexuals. An obvious interpretation of these results is that heterozygosity and "vigor" need not be functionally related. However, other factors may be counterbalancing possible beneficial effects of heterozygosity, including detrimental epistatic effects resulting from the karyotypically mixed genome of these hybrids, and the accumulation of deleterious mutations in the asexual lineages via Muller's ratchet.


Prevention and treatment of venous thromboembolism during pregnancy.
Women who are pregnant or have recently given birth are at significantly increased risk of venous thromboembolism (VTE) compared with the general population. Furthermore, the issues surrounding the appropriate prevention, diagnosis, and treatment of VTE are more complex in pregnancy, where not only the effects on the mother, but also the effects on the fetus need to be considered. Although guidelines provide recommendations for the optimal management of these patients, most of these guidelines are based on evidence from observational studies, or on data extrapolated from a nonpregnant population. Randomized clinical trials are needed to identify the optimal strategies for prevention and treatment of VTE in pregnancy.


[Indications for carotid endarterectomy and its outcomes].
The paper analyzes a correlation between the sonographic and morphological characteristics of the structure of atherosclerotic plaques and the severity of cerebrovascular insufficiency. This significantly expands indications for surgical treatment in patients with carotid atherosclerosis. In the authors' opinion, not only the degree of carotid stenosis, but also the structure of a plaque is an important criterion for assessing indications for surgical treatment. The outcomes of carotid endarterectomy are comparatively evaluated in relation to the mode of carotid plastic repair. A role of intraoperative cerebral oximetry is shown.


A method to estimate treatment efficacy among latent subgroups of a randomized clinical trial.
Subgroup analysis arises in clinical trials research when we wish to estimate a treatment effect on a specific subgroup of the population distinguished by baseline characteristics. Many trial designs induce latent subgroups such that subgroup membership is observable in one arm of the trial and unidentified in the other. This occurs, for example, in oncology trials when a biopsy or dissection is performed only on subjects randomized to active treatment. We discuss a general framework to estimate a biological treatment effect on the latent subgroup of interest when the survival outcome is right-censored and can be appropriately modelled as a parametric function of covariate effects. Our framework builds on the application of instrumental variables methods to all-or-none treatment noncompliance. We derive a computational method to estimate model parameters via the EM algorithm and provide guidance on its implementation in standard software packages. The research is illustrated through an analysis of a seminal melanoma trial that proposed a new standard of care for the disease and involved a biopsy that is available only on patients in the treatment arm.


Patients with cancer. Is there a role for chiropractic?
People who have a diagnosis of cancer may develop, or already have musculoskeletal conditions, just like any other person. However, discussion about potential benefits of chiropractic treatment to this group has generally been avoided related to the fear of misrepresentation. We aimed to derive a consensus from a group of experienced chiropractors regarding their perception of what chiropractic care offered to patients with cancer. An anonymous, two stage, online, Delphi process was performed using experienced chiropractors (n=23: >10 yrs practice experience, who had treated patients with cancer) purposively selected and recruited independently. One opted out of the study, 13 actively engaged in two rounds of questions and verification; agreeing such patients gained benefit from chiropractic care but use of spinal manipulation was not essential. There was no clear consensus regarding a protocol for interaction within any multidisciplinary team treating the patient. Concerns were raised about misinterpretation of advertising any benefits for cancer patients from chiropractic care. Lack of evidence in this area was acknowledged.


Murine mammary tumor virus expression during mammary tumorigenesis in ICRC mice.
The expression of murine mammary tumor virus (MuMTV) antigens was examined in the mammary epithelium of strains ICRC and C3H/Jax mice during sequential events leading to mammary tumorigenesis, employing immunoperoxidase technique and competition radioimmunoassays (RIA). The MuMTV antigens could be localized in the lobule alveolar structures of normal, lactating, preneoplastic and neoplastic mammary epithelium as well as in metastatic nodules of mammary tumors of ICRC force breeders. A graded increase in staining reaction was evident with increase in cellularity of the mammary gland due to age and parity. These observations compared well with the quantitation of MuMTV antigens by RIA. The levels of MuMTV antigens in the mammary glands of ICRC mice of different experimental groups were consistently lower than those in C3H/Jax mice. The differential response of the mammary glands to ovariectomy observed in these two strains was reflected in the MuMTV expression.


Evidence for the establishment of aphid-eubacterium endosymbiosis in an ancestor of four aphid families.
Aphids (superfamily Aphidoidea) contain eubacterial endosymbionts localized within specialized cells (mycetocytes). The endosymbionts are essential for the survival of the aphid hosts. Sequence analyses of the 16S rRNAs from endosymbionts of 11 aphid species from seven tribes and four families have indicated that the endosymbionts are monophyletic. Furthermore, phylogenetic relationships within the symbiont clade parallel the relationships of the corresponding aphid hosts. Our findings suggest that this endocytobiotic association was established in a common ancestor of the four aphid families with subsequent diversification into the present species of aphids and their endosymbionts.


Breast reconstruction using delayed pedicled transverse rectus abdominis muscle flap with supercharging: reports of three cases.
Breast reconstruction using a pedicled transverse rectus abdominis muscle (TRAM) flap is a well-established surgical procedure. Although studies suggest that transplanting this flap using a delayed method reduces the risk of partial flap necrosis, challenges persist. Hence, we present three cases of breast reconstruction using a pedicled TRAM flap with both delaying and supercharging. Patient age, excised tissue volume for mastectomy, and follow-up period were as follows: Case 1, 58 years, 429 cm3, 5 months; Case 2, 35 years, 910 cm3, 6 months; and Case 3, 56 years, 489 cm3, 4 months. One patient (Case 2) required a large flap tissue volume to achieve breast symmetry, whereas the other two (Cases 1 and 3) had long, longitudinal scars from previous cesareans sections. In a delayed surgery, the flap was partially elevated with partial dissection and no ligation of the deep inferior epigastric artery and vein (DIEAV). An artificial dermis with a silicone membrane (Teldermis®) was used to prevent adhesion of the rectus abdominal muscles and DIEAV to the surrounding tissue. Supercharging was performed by anastomosis between the ipsilateral DIEAV and internal thoracic AV. Flaps in zones I-III and in half of zone IV for Case 2, and zones I-III for Cases 1 and 3, were transferred; all survived without infection. This method allowed the transferring of a larger tissue volume compared with the conventional pedicled TRAM flap-transfer method. Thus, it may be useful for patients who require larger tissue volume or high-risk patients.


Identification of an Immunogenic Subset of Metastatic Uveal Melanoma.
Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma. We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing. Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed cutaneous melanoma TIL were predominantly composed of CD8(+) T cells, whereas uveal melanoma TIL were CD4(+) dominant. Reactivity against autologous tumor was significantly greater in cutaneous melanoma TIL compared with uveal melanoma TIL. However, we identified TIL from a subset of uveal melanoma patients which had robust antitumor reactivity comparable in magnitude with cutaneous melanoma TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive uveal melanoma TIL. The discovery of this immunogenic group of uveal melanoma metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous antitumor T-cell populations. Clin Cancer Res; 22(9); 2237-49. ©2015 AACR.


Effects of cyanocobalamin on immunity in patients with pernicious anemia.
The aim of the study was to evaluate the role of vitamin B(12) in patients with pernicious anemia. This study was conducted prospectively at the Turgut Ozal Medical Center, Department of Hematology, between April and November 2002. Absolute numbers and ratio of the surface antigens of T and B lymphocyte subgroups, CD4/CD8 ratio were calculated in order to evaluate changes in leukocyte and lymphocyte numbers; natural killer (NK) cell count, serum C3, C4, and levels of immunoglobulins G, A, and M were also measured to evaluate vitamin B(12) effect on immunity. Values obtained before treatment with cyanocobalamin were compared with those found during peak reticulocyte count. In vitamin B(12)-deficient patients, absolute numbers of CD4+ and especially CD8+ lymphocytes were found to be decreased; CD4/CD8 ratio increased, and NK cell activity was depressed. After cyanocobalamin treatment, absolute numbers and percentage of lymphocyte subgroups were elevated. Increased CD4/CD8 ratio and depressed NK cell activity were restored and levels of C3, C4, and immunoglobulins were elevated. These findings suggest that vitamin B(12) has important immunomodulatory effects on cellular immunity, and abnormalities in the immune system in pernicious anemia are restored by vitamin B(12) replacement therapy.


Existence of a photoinducible phase for ovarian development and photoperiod-related alteration of clock gene expression in a damselfish.
The sapphire devil, Chrysiptera cyanea, is a reef-associated damselfish and their ovarian development can be induced by a long photoperiod. In this study, we demonstrated the existence of a photoinducible phase for the photoperiodic ovarian development in the sapphire devil. Induction of ovarian development under night-interruption light schedules and Nanda-Hamner cycles revealed that the photoinducible phase appeared in a circadian manner between ZT12 and ZT13. To characterize the effect of photoperiod on clock gene expression in the brain of this species, we determined the expression levels of the sdPer1, sdPer2, sdCry1, and sdCry2 clock genes under constant light and dark conditions (LL and DD) and photoperiodic (short and long photoperiods). The expression of sdPer1 exhibited clear circadian oscillation under both LL and DD conditions, while sdPer2 and sdCry1 expression levels were lower under DD than under LL conditions and sdCry2 expression was lower under LL than under DD conditions. These results suggest a key role for sdPer1 in circadian clock cycling and that sdPer2, sdCry1, and sdCry2 are light-responsive clock genes in the sapphire devil. After 1 week under a long photoperiod, we observed photoperiod-related changes in sdPer1, sdPer2, and sdCry2 expression, but not in sdCry1 expression. These results suggest that the expression patterns of some clock genes exhibit seasonal variation according to seasonal changes in day length and that such seasonal alteration of clock gene expression may contribute to seasonal recognition by the sapphire devil.


A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth.
The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR's functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.


A conditionally expressed third partner stabilizes or prevents the formation of a transcriptional activator in a three-hybrid system.
We describe a three-hybrid system that involves three polypeptides that allow or prevent the formation of the transcriptional activator. Beside the two-hybrid fusion proteins, the third partner is under the control of the Met25 promoter, which is positively regulated in medium lacking methionine. We document a situation where such a third partner promotes interaction between two proteins, one fused to a DNA-binding domain and the other fused to an activator domain. This is demonstrated for cdk7-MAT1 interaction stabilized by the presence of cyclin H; these three polypeptides are found either free or associated with the transcription/DNA repair factor TFIIH. We also document the capacity of our system to conditionally inhibit the interaction between two polypeptides that otherwise elicit a positive two-hybrid response. This is demonstrated for Ras-Raf interaction precluded by an excess of Raf. The presence of a methionine-regulated promoter provides an "on" or "off" switch for the formation of the transcriptional activator, thus also providing an excellent control to evaluate the activation or inhibition properties of the third partner.


Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1.
Studies have shown that ticagrelor has a further adenosine-mediated mechanism of action in addition to its potent inhibition of the P2Y12 receptor, which may explain some of ticagrelor's clinical characteristics. This study aimed to further characterize the adenosine pharmacology of ticagrelor, its major metabolites, and other P2Y12 receptor antagonists. Inhibition of nucleoside transporter-mediated [(3)H]adenosine uptake by ticagrelor, its major metabolites, and alternative P2Y12 antagonists was examined in recombinant Madin-Darby canine kidney (MDCK) cells. The pharmacology of ticagrelor and its major metabolites at adenosine A1, A2A, A2B, and A3 receptor subtypes was examined using in vitro radioligand binding and functional assays and ex vivo C-fiber experiments in rat and guinea pig vagus nerves. Ticagrelor (and less effectively its metabolites) and the main cangrelor metabolite inhibited [(3)H]adenosine uptake in equilibrative nucleoside transporter (ENT) 1-expressing MDCK cells, whereas cangrelor and the active metabolites of prasugrel or clopidogrel had no effect. No significant inhibitory activity was observed in MDCK cells expressing ENT2 or concentrative nucleoside transporters 2/3. Ticagrelor demonstrated high affinity (inhibition constant [Ki] = 41 nmol/L) for ENT1. In adenosine receptor-binding experiments, ticagrelor and its major circulating metabolite, AR-C124910XX, had low affinity (Ki > 6 µmol/L) for each of the adenosine A1, A2A, and A2B receptors, whereas ticagrelor had a submicromolar (Ki = 190 nmol/L) affinity for the adenosine A3 receptor. However, in functional assays, at high concentrations (10 µmol/L) ticagrelor only partially inhibited 3 mmol/L adenosine-induced depolarizations in the guinea pig and rat vagus nerve preparations (by 35% and 49%, respectively). Ticagrelor inhibits cellular adenosine uptake selectively via ENT1 inhibition at concentrations of clinical relevance. However, the low-binding affinity and functional inhibition of adenosine receptors observed with ticagrelor or its metabolites indicate that they possess a negligible adenosine-like activity at clinically relevant concentrations.


T-cell immune response assessment as a complement to serology and intranasal protection assays in determining the protective immunity induced by acellular pertussis vaccines in mice.
The relative value of antibodies and/or T-cell immune responses to Bordetella pertussis antigens in the immunity induced by acellular pertussis (aP) vaccines is still an open issue, probably due to the incomplete knowledge on the mechanisms of protective immunity to pertussis. The relevance of T-cell immune responses in protection from pertussis has been demonstrated in murine and human models of infection; thus, in this study, the ability of different vaccine preparations of three component (pertussis toxin, filamentous hemagglutinin, and pertactin) aP vaccines to induce T-cell responses was investigated in mice. All vaccine preparations examined passed the immunogenicity control test, based on antibody titer assessment, according to European Pharmacopoeia standards, and protected mice from B. pertussis intranasal challenge, but not all preparations were able to prime T cells to pertussis toxin, the specific B. pertussis antigen. In particular, one vaccine preparation was unable to induce proliferation and gamma interferon (IFN-gamma) production while the other two gave borderline results. The evaluation of T-cell responses to pertussis toxin antigen may provide information on the protective immunity induced by aP vaccines in animal models. Considering the critical role of the axis interleukin-12-IFN-gamma for protection from pertussis, our results suggest that testing the induction of a key protective cytokine such as IFN-gamma could be an additional tool for the evaluation of the immune response induced by aP vaccines.


Hepatic fibrosis as wound repair: a progress report.
The injury response of the liver fits within the general paradigm of wound repair. The overall repair response requires close coordination of several cell types and synthetic processes and is orchestrated by an interacting group of cytokines, extracellular matrix (ECM) proteins, and products of metabolism such as oxygen radicals. Many cytokines act over short distances, engaging specific receptors on their parent cell (autocrine) or on immediately adjacent cells (paracrine). The most prominent of these is transforming growth factor-beta (TGFbeta). The ECM also mediates cellular crosstalk and does so in two ways. Firstly, as a binder of cytokines, it is capable of concentrating, presenting, or sequestering these factors at specific locations. Secondly, like cytokines, individual ECM proteins interact with cells via specific receptors, many of which belong to the integrin family. Engagement of a receptor leads to its activation, followed by intracellular signaling events and modification of cell behavior. Recent work has identified a specific integrin on stellate cells (alpha1beta1) as critical to the contractility of these cells. Finally, contrary to the view once held of ECM as relatively inert "ground substance", this extracellular complex is highly dynamic, its cytokine- and cell-binding activities being subject to rapid change. Therefore, matrix proteinases also are important, both during the initiation of fibrosis in association with stellate cell activation, and during the resolution of the injury. As current research reveals the key elements of this regulatory network, new therapeutic modalities are emerging. The goal of therapy is to modify the extent of the repair response without deleting it. Strategies directed at several levels of regulation are under consideration, including agents that block cytokine effects (e.g., TGFbeta receptor antagonists) and direct inhibitors of stellate cell activation or contraction.


Lhx4 deficiency: increased cyclin-dependent kinase inhibitor expression and pituitary hypoplasia.
Defects in the Lhx4, Lhx3, and Pitx2 genes can cause combined pituitary hormone deficiency and pituitary hypoplasia in both humans and mice. Not much is known about the mechanism underlying hypoplasia in these mutants beyond generally increased cell death and poorly maintained proliferation. We identified both common and unique abnormalities in developmental regulation of key cell cycle regulator gene expression in each of these three mutants. All three mutants exhibit reduced expression of the proliferative marker Ki67 and the transitional marker p57. We discovered that expression of the cyclin-dependent kinase inhibitor 1a (Cdkn1a or p21) is expanded dorsally in the pituitary primordium of both Lhx3 and Lhx4 mutants. Uniquely, Lhx4 mutants exhibit reduced cyclin D1 expression and have auxiliary pouch-like structures. We show evidence for indirect and direct effects of LHX4 on p21 expression in αT3-1 pituitary cells. In summary, Lhx4 is necessary for efficient pituitary progenitor cell proliferation and restriction of p21 expression.


Plasmid-encoded metallo-beta-lactamase (IMP-6) conferring resistance to carbapenems, especially meropenem.
In 1996, Serratia marcescens KU3838 was isolated from the urine of a patient with a urinary tract infection at a hospital in northern Japan and was found to contain the plasmid pKU501. Previously, we determined that pKU501 carries bla(IMP) and the genes for TEM-1-type beta-lactamases as well as producing both types of beta-lactamases (H. Yano, A. Kuga, K. Irinoda, R. Okamoto, T. Kobayashi, and M. Inoue, J. Antibiot. 52:1135-1139, 1999). pKU502 is a recombinant plasmid that contains a 1.5-kb DNA fragment, including the metallo-beta-lactamase gene, and is obtained by PCR amplification of pKU501. The sequence of the metallo-beta-lactamase gene in pKU502 was determined and revealed that this metallo-beta-lactamase gene differed from the gene encoding IMP-1 by one point mutation, leading to one amino acid substitution: 640-A in the base sequence of the IMP-1 gene was replaced by G, and Ser-196 was replaced by Gly in the mature enzyme. This enzyme was designated IMP-6. The strains that produced IMP-6 were resistant to carbapenems. The MICs of panipenem and especially meropenem were higher than the MIC of imipenem for these strains. The k(cat)/K(m) value of IMP-6 was about sevenfold higher against meropenem than against imipenem, although the MIC of meropenem for KU1917, which produced IMP-1, was lower than that of imipenem, and the MIC of panipenem was equal to that of imipenem. These results support the hypothesis that IMP-6 has extended substrate profiles against carbapenems. However, the activity of IMP-6 was very low against penicillin G and piperacillin. These results suggest that IMP-6 acquired high activity against carbapenems, especially meropenem, via the point mutation but in the process lost activity against penicillins. Although IMP-6 has reduced activity against penicillins due to this point mutation, pKU501 confers resistance to a variety of antimicrobial agents because it also produces TEM-1-type enzyme.


Pitfalls of nonstandardized photography in facial plastic surgery patients.
The authors tested the hypothesis that certain maneuvers (neck flexion/extension and head protrusion/retrusion) alter the appearance of the submental area, jawline, and melolabial groove. They used a questionnaire survey of 20 naïve judges who assessed a standardized photograph album of three subjects. The subjects' faces (frontal and lateral views) were photographed in neutral, neck flexion/extension, and head protrusion/retrusion positions. High Kendall coefficients of correlation were observed in 10 of 12 questions evaluating an improvement in jawline definition with neck extension or head protrusion, as well as in 11 of 12 questions assessing decreased submental soft tissue. All questions relating to the melolabial groove had a correlation coefficient of less than 0.70. Small changes in patient positioning during photodocumentation for facial plastic surgical procedures can cause dramatic changes in the appearance of certain parameters. Standardizing patient positioning for preoperative and postoperative photographs is imperative.


Report of two paediatric cases of central line infections caused by species of the genus Kocuria.
Species of the genus Kocuria are Gram-positive cocci of the family Micrococcacceae that are ubiquitous in the environment and part of the normal skin and oral flora in humans. A paucity of cases have been reported of Kocuria as human pathogens and there are currently no evidence-based guidelines for managing these uncommon infections. We present two paediatric cases of central line infections with species of the genus Kocuria that required line removal despite antimicrobial therapy. Species of the genus Kocuria are uncommon human pathogens that have rarely been reported to cause opportunistic infections in both adult and paediatric populations. The cases presented here add to the growing body of literature documenting the pathogenicity of these organisms and the possible need for line removal to achieve clinical cure in central line-associated bacteraemia caused by species of the genus Kocuria.


Long-term Outcomes After Gamma Knife Radiosurgery for Meningiomas.
Gamma knife stereotactic radiosurgery (SRS) has become an important management strategy for patients with meningiomas. Although prior reports have studied early tumor control, neurological response, and associated morbidity, our purpose was to use clinical and imaging studies to determine whether long-term outcomes remain stable over time. We studied 290 consecutive patients (92 men and 198 women) who underwent gamma knife SRS for a meningioma between 1987 and 1997. The median tumor margin dose was 15 Gy and the median tumor volume was 5.5 mL. Target definition was performed using contrast enhanced computed tomography in 72 patients and magnetic resonance imaging in 218 patients. The median patient age at radiosurgery was 61 years. Twenty patients had a history of fractionated radiation therapy, 136 patients had undergone a subtotal resection, and 22 patients had recurrences after initial gross total resection. The overall tumor control rate was 91%. Twenty-six patients (9%) had evidence of delayed local tumor growth and 44 (15%) had regional tumor progression, which occurred at a median of 38 months. The 10- and 20-year actuarial rates of freedom from tumor progression of the targeted tumor were 87.7%±2.5% and 87.2%±4.2%. Of 234 patients who had symptoms before SRS (n=62, 26%) improved, 126 (54%) had no change in symptoms and 46 (20%) gradually worsened. Thirty-two of 34 (94%) asymptomatic patients remained asymptomatic. We found no difference in long-term tumor control rates between patients who had undergone craniotomy before radiosurgery (89%) and patients who underwent primary radiosurgery (93.1%). Adverse radiation effects were detected in 3.1% of patients. Factors associated with worse progression-free survival included prior radiation therapy (P<0.0001) and higher grade meningioma (P<0.0001). At a median of 8.7 years after SRS, 137 patients were dead at a median age of 77 years. We found that gamma knife SRS provided durable tumor control with low morbidity in meningioma patients.


Modelling phosphorus intake, digestion, retention and excretion in growing and finishing pigs: model description.
Low phosphorus (P) digestibility combined with intensive pig production can increase P diffuse pollution and environmental load. The aim of this paper was to develop a deterministic, dynamic model able to represent P digestion, retention and ultimately excretion in growing and finishing pigs of different genotypes, offered access to diets of different composition. The model represented the limited ability of pig endogenous phytase activity to dephosphorylate phytate as a linear function of dietary calcium (Ca). Phytate dephosphorylation in the stomach by exogenous microbial phytase enzymes was expressed by a first order kinetics relationship. The absorption of non-phytate P from the lumen of the small intestine into the blood stream was set at 0.8 and the dephosphorylated phytate from the large intestine was assumed to be indigestible. The net efficiency of using digested P was set at 0.94 and assumed to be independent of BW, and constant across genotype and sex. P requirements for both maintenance and growth were made simple functions of body protein mass, and hence functions of animal genotype. Undigested P was assumed to be excreted in the feaces in both soluble and insoluble forms. If digestible P exceeded the requirements for P then the excess digestible P was excreted through the urinary flow; thus the model represented both forms of P excretion (soluble and insoluble) into the environment. Using a UK industry standard diet, model behaviour was investigated for its predictions of P digestibility, retention and excretion under different levels of inclusion of microbial phytase and dietary Ca, and different non-phytate P : phytate ratios in the diet, thus covering a broad space of potential diet compositions. Model predictions were consistent with our understanding of P digestion, metabolism and excretion. Uncertainties associated with the underlying assumptions of the model were identified. Their consequences on model predictions, as well as the model evaluation are assessed in a companion paper.


Effects of a health promotion advertising campaign on sales of ready-to-eat cereals.
The objective of this study was to determine how the sales of various segments of the high fiber and nonhigh fiber, ready-to-eat (RTE) cereal market were influenced by a health message advertising campaign about the possible benefits of a high fiber, low fat diet for preventing some types of cancer. The fiber statements in the media campaign were endorsed by the National Cancer Institute (NCI). The campaign was undertaken by the Kellogg Company to promote its line of high fiber cereal products, including Kellogg's All-Bran. The data base consisted of computerized purchase data from 209 Giant Food, Inc., supermarkets in the Baltimore, MD, and Washington, DC, metropolitan areas. All the RTE cereal products in the stores were classified according to their fiber content and competitive market positions compared with Kellogg high fiber cereals. Estimates of market share for the various classes of RTE cereal products were obtained weekly for each store during a period of 64 weeks, beginning 16 weeks before the start of the campaign. Shifts in market share between high fiber and nonhigh fiber cereal classifications indicate substantial increases in consumer purchases of Kellogg high fiber cereals, particularly All-Bran, beginning with the start of the Kellogg advertising campaign. Growth in market share of high fiber cereals continued during the entire 48-week evaluation period, with much of the later growth in non-Kellogg high fiber cereals. Growth in sales of high fiber cereals was mainly at the expense of low fiber cereals such as granola-type products. The implications of these results for the competitive and educational effectiveness of commercially sponsored health and diet messages are discussed.


Patient load effects on response time to critical arrhythmias in cardiac telemetry: a randomized trial.
Remotely monitored patients may be at risk for a delayed response to critical arrhythmias if the telemetry watchers who monitor them are subject to an excessive patient load. There are no guidelines or studies regarding the appropriate number of patients that a single watcher may safely and effectively monitor. Our objective was to determine the impact of increasing the number of patients monitored on response time to simulated cardiac arrest. Randomized trial. Laboratory-based experiment. Forty-two remote telemetry technicians and nurses from cardiac units. Number of patients monitored in a simulation of cardiac telemetry monitoring work. We carried out a study to compare response times to ventricular fibrillation across five patient loads: 16, 24, 32, 40, and 48 patients. The simulation replicated the work of telemetry watchers using a combination of real recorded patient electrocardiogram signals and a simulated patient experiencing ventricular fibrillation. Study participants were assigned to one of the five patient loads and completed a 4-hour monitoring session, during which they performed tasks-including event documentation and phone calls to report events-similar to real monitoring work. When the simulated patient sustained ventricular fibrillation, the time required to report this arrhythmia was recorded. As patient loads increased, there was a statistically significant increase in response times to the ventricular fibrillation. In addition, frequency of failure to meet a response time goal of less than 20 seconds was significantly higher in the 48-patient condition than in all other conditions. Task performance decreased as patient load increased. As participants monitored more patients in a laboratory setting, their performance with respect to recognizing critical and noncritical events declined. This study has implications for the design of remote telemetry work and other patient monitoring tasks in critical and intermediate care units.


[Surgical technics for implantation of hepatic intra-arterial catheters for local chemotherapy. Experience with 42 cases].
Based on the experience of 42 cases of surgical implantation of hepatic intra-arterial catheters (HIAC) for local chemotherapy, the techniques used are analyzed principally as a function of anatomical variations of the hepatic artery. A conventional procedure (HIAC implanted into gastroduodenal artery) was performed in 60% of cases, while in 26% of patients this was possible only after section of a right and/or left hepatic artery. Atypical implantation was necessary in 14% of cases to ensure complete perfusion of liver. The different methods employed and the reasons for their choice are discussed.


Mass Detection and Segmentation in Digital Breast Tomosynthesis Using 3D-Mask Region-Based Convolutional Neural Network: A Comparative Analysis.
Digital breast tomosynthesis (DBT) is an emerging breast cancer screening and diagnostic modality that uses quasi-three-dimensional breast images to provide detailed assessments of the dense tissue within the breast. In this study, a framework of a 3D-Mask region-based convolutional neural network (3D-Mask RCNN) computer-aided diagnosis (CAD) system was developed for mass detection and segmentation with a comparative analysis of performance on patient subgroups with different clinicopathological characteristics. To this end, 364 samples of DBT data were used and separated into a training dataset (n = 201) and a testing dataset (n = 163). The detection and segmentation results were evaluated on the testing set and on subgroups of patients with different characteristics, including different age ranges, lesion sizes, histological types, lesion shapes and breast densities. The results of our 3D-Mask RCNN framework were compared with those of the 2D-Mask RCNN and Faster RCNN methods. For lesion-based mass detection, the sensitivity of 3D-Mask RCNN-based CAD was 90% with 0.8 false positives (FPs) per lesion, whereas the sensitivity of the 2D-Mask RCNN- and Faster RCNN-based CAD was 90% at 1.3 and 2.37 FPs/lesion, respectively. For breast-based mass detection, the 3D-Mask RCNN generated a sensitivity of 90% at 0.83 FPs/breast, and this framework is better than the 2D-Mask RCNN and Faster RCNN, which generated a sensitivity of 90% with 1.24 and 2.38 FPs/breast, respectively. Additionally, the 3D-Mask RCNN achieved significantly (p < 0.05) better performance than the 2D methods on subgroups of samples with characteristics of ages ranged from 40 to 49 years, malignant tumors, spiculate and irregular masses and dense breast, respectively. Lesion segmentation using the 3D-Mask RCNN achieved an average precision (AP) of 0.934 and a false negative rate (FNR) of 0.053, which are better than those achieved by the 2D methods. The results suggest that the 3D-Mask RCNN CAD framework has advantages over 2D-based mass detection on both the whole data and subgroups with different characteristics.


Physical and mental health, cognitive development, and health care use by housing status of low-income young children in 20 American cities: a prospective cohort study.
We assessed the independent effect of homeless and doubled-up episodes on physical and mental health, cognitive development, and health care use among children. We used data from 4 waves of the Fragile Families and Child Wellbeing Study, involving a sample of 2631 low-income children in 20 large US cities who have been followed since birth. Multivariate analyses involved logistic regression using the hybrid method to include both fixed and random effects. Of the sample, 9.8% experienced homelessness and an additional 23.6% had a doubled-up episode. Housing status had little significant adverse effect on child physical or mental health, cognitive development, or health care use. Family and environmental stressors common to many children in poverty, rather than just homeless and doubled-up episodes, were associated with young children's poor health and cognitive development and high health care use. Practitioners need to identify and respond to parental and family needs for support services in addition to housing assistance to effectively improve the health and development of young children who experience residential instability, particularly those in homeless families.


Letters of William Halsted and René Leriche: "Our friendship seems so deep".
The friendship of William Halsted and René Leriche is little appreciated in the annals of surgery. Although Halsted was Leriche's senior by almost 30 years, they enjoyed a relationship on both professional and surprisingly personal levels. Halsted's sincere concern for his younger French colleague was manifested by a constant fostering of Leriche's surgical research and creative ideas. Leriche was to become a life-long admirer of Halsted's surgical philosophies. He often stated that a 3-day visit with Halsted in 1913 persuaded him to stop considering surgery as a purely clinical and technical subject. During their 10-year relationship, extensive correspondence was maintained. This article will explore their friendship through analysis of their personal letters, recently found in the archives of the Johns Hopkins Medical Institutions. Written in French, they remained undisturbed for 65 years. Their present translation into English represents the first time they have been published. Vascular surgery was the major topic of discussion. Included among the many topics are surgical management of aneurysmal disease, utilization of sympathectomy, and investigations into physiologic effects of arterial ligation. In addition, many aspects of the savagery of World War I, as encountered by Leriche at the French front, and Halsted's views on various events of the conflict, are chronicled. The letters reveal a deep and abiding association between the two men which is of interest because Halsted shared his nonsurgical life with very few younger men. Their insight into specific areas of experimental surgery and ideas about various medical problems and other medical personalities are recounted.


Local photo-mechanical stiffness revealed in gold nanoparticles supracrystals by ultrafast small-angle electron diffraction.
We demonstrate that highly ordered two-dimensional crystals of ligand-capped gold nanoparticles display a local photo-mechanical stiffness as high as that of solids such as graphite. In out-of-equilibrium electron diffraction experiments, a strong temperature jump is induced in a thin film with a femtosecond laser pulse. The initial electronic excitation transfers energy to the underlying structural degrees of freedom, with a rate generally proportional to the stiffness of the material. Using femtosecond small-angle electron diffraction, we observe the temporal evolution of the diffraction feature associated with the nearest-neighbor nanoparticle distance. The Debye-Waller decay for the octanethiol-capped nanoparticle supracrystal, in particular, is found to be unexpectedly fast, almost as fast as the stiffest solid known and observed by the same technique, i.e., graphite. Our observations unravel that local stiffness in a dense supramolecular assembly can be created by van der Waals interactions up to a level comparable to crystalline systems characterized by covalent bonding.


Management of stable coronary artery disease.
Results of two randomised controlled trials for the management of mild-to-moderate chronic stable coronary artery disease (Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluation [COURAGE] and Bypass Angioplasty Revascularization Investigation type-2 Diabetes [BARI-2D]) have stimulated a vigorous debate about whether an initial strategy of revascularisation or a conservative approach with drugs is most effective. The conclusions of these two trials were clear: for some patients randomly assigned after angiography to revascularisation or pharmacological therapy, rates of death and myocardial infarction did not differ between the two strategies. What remains unresolved is how to generalise these data to patients without angiography, the role of stress testing, and the preferred approach to patients with relevant ischaemia on stress testing. This Review draws attention to the controversial issues in both management approaches, analyses the strengths and limitations of recent trials, and proposes a treatment algorithm that is applicable to daily clinical practice. Findings suggest that the severity of anginal symptoms and the extent of ischaemia in stress testing could help to identify patients who are at increased risk and who might benefit from an early invasive strategy. On the basis of the data and considerations presented, a strategy of initial optimum pharmacological therapy or direct invasive management can be tailored to an individual's circumstances and preferences.


The role for surgical management of HPV-related oropharyngeal carcinoma.
Human papillomavirus (HPV)-associated oropharyngeal carcinoma has become the predominate cause of oropharyngeal carcinoma in the United States and Europe. Management of this disease is controversial. Traditional open surgical techniques gave way to concurrent chemoradiotherapy following several American and European organ-preservation trials suggesting that both modalities were equally efficacious. More recently, minimally invasive surgical techniques have gained popularity. These techniques provide an opportunity to achieve a complete surgical resection without the treatment-related morbidity associated with open surgery. Proponents of this technique contend that transoral surgical techniques provide a means to analyze the tumor tissue, prognosticate, and personally direct therapy. Skeptics suggest that HPV-associated oropharyngeal carcinoma responds well to chemoradiotherapy and that surgery may not provide a treatment advantage. Both approaches provide a unique perspective and both are currently being studied under trial.