Iron-superoxide dismutase expression in transgenic alfalfa increases winter survival without a detectable increase in photosynthetic oxidative stress tolerance.
To determine whether overexpression of Fe-superoxide (SOD) dismutase would increase superoxide-scavenging capacity and thereby improve the winter survival of transgenic alfalfa (Medicago sativa L.) plants, two genotypes were transformed with the vector pEXSOD10, which contains a cDNA for Arabidopsis Fe-SOD with a chloroplast transit peptide and cauliflower mosaic virus 35S promoter. A novel Fe-SOD was detected by native PAGE in both greenhouse- and field-grown transgenic plants, but activity varied among independent transgenic plants. The increased Fe-SOD activity was associated with increased winter survival over 2 years in field trials, but not with oxidative stress tolerance as measured by resistance of leaves to methyl viologen, a superoxide generator. Total shoot dry matter production over 2 harvest years was not associated with Fe-SOD activity. There was no detectable difference in the pattern of primary freezing injury, as shown by vital staining, nor was there additional accumulation of carbohydrates in field-acclimated roots of the transgenic alfalfa plants. We did not detect any difference in growth of one transgenic plant with high Fe-SOD activity compared with a non-transgenic control. Therefore, the improvement in winter survival did not appear to be a consequence of improved oxidative stress tolerance associated with photosynthesis, nor was it a consequence of a change in primary freezing injury. We suggest that Fe-SOD overexpression reduced secondary injury symptoms and thereby enhanced recovery from stresses experienced during winter.


Weaning from the breast.
Exclusive breastfeeding provides optimal nutrition for infants until they are six months of age. After six months, infants require complementary foods to meet their nutritional needs. This is when weaning begins. Weaning is the gradual process of introducing complementary foods to an infant's diet while continuing to breastfeed. There is no universally accepted or scientifically proven time when all breastfeeding must stop. The timing and process of weaning need to be individualized by mother and child. Weaning might be abrupt or gradual, take weeks or several months, be child-led or mother-led. Physicians need to guide and support mothers through the weaning process. This document replaces a previous Canadian Paediatric Society position statement on weaning published in 2004.


FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma.
Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy. We generated primary cell cultures and patient cSCC-derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance. cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors. EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.


NAMPT signaling is critical for the proangiogenic activity of tumor-associated neutrophils.
Tumor-associated neutrophils (TANs) regulate many processes associated with tumor progression, and depending on the microenvironment, they can exhibit pro- or antitumor functions. However, the molecular mechanisms regulating their tumorigenicity are not clear. Using transplantable tumor models, we showed here that nicotinamide phosphoribosyltransferase (NAMPT), a molecule involved in CSF3R downstream signaling, is essential for tumorigenic conversion of TANs and their pro-angiogenic switch. As a result tumor vascularization and growth are strongly supported by these cells. Inhibition of NAMPT in TANs leads to their antitumor conversion. Adoptive transfer of such TANs into B16F10-tumor bearing mice attenuates tumor angiogenesis and growth. Of note, we observe that the regulation of NAMPT signaling in TANs, and its effect on the neutrophil tumorigenicity, are analogous in mice and human. NAMPT is up-regulated in TANs from melanoma and head-and-neck tumor patients, and its expression positively correlates with tumor stage. Mechanistically, we found that targeting of NAMPT suppresses neutrophil tumorigenicity by inhibiting SIRT1 signaling, thereby blocking transcription of pro-angiogenic genes. Based on these results, we propose that NAMPT regulatory axis is important for neutrophils to activate angiogenic switch during early stages of tumorigenesis. Thus, identification of NAMPT as the critical molecule priming protumor functions of neutrophils provides not only mechanistic insight into the regulation of neutrophil tumorigenicity, but also identifies a potential pathway that may be targeted therapeutically in neutrophils. This, in turn, may be utilized as a novel mode of cancer immunotherapy.


Living with uncertainty: temporomandibular disorders.
Temporomandibular disorders (TMDs) are a common group of chronic illnesses. There is evidence that health professionals find them difficult to diagnose and manage. A consequence of this difficulty in diagnosis might be that sufferers of TMDs have an experience of illness comparable with other chronic illnesses. To explore the sufferers' experience of TMDs, we conducted a qualitative study with a purposive maximum variation sample of secondary care TMD patients. Semi-structured interviews were conducted with the sample and were recorded and transcribed verbatim. Data collection and analysis continued until data saturation (n = 19). For analysis, we broadly followed the constant comparative method and used frameworks to organize the data. The key finding was that a lack of diagnosis caused uncertainty over the nature of the cause of the sufferer's complaint. This uncertainty reportedly caused negative impacts on sufferers' daily lives. Clearly, diagnosis of TMDs needs to be encouraged at the first point of contact.


Clinical application and results of the assessment of coronary blood flow by the regional precordial xenon residue detection technique.
Methodological and technical aspects as well as application and results of the precordial Xenon-residue-detection technique are critically reviewed. The results concern mainly normal flow in various regions of the heart esp. in the free wall of the right and left ventricle, poststenotic flow in patients with coronary artery disease in relation to the degree of proximal narrowings as well as wall motion of the corresponding LV segment, bypassgraft flow and flow after drug interventions esp. nitrates, betablockers, the calcium-antagonist Nifedipine and the coronary dilator Dipyridamole. In spite of its serious limitations (high affinity of Xenon for fatty tissue, geometrical problems in the assessment of flow and its relation to anatomy, gas exchange in situations of high flow etc.), the technique is found to be a useful investigatory tool. Due to its technical display and the related high costs routine application is, however, prohibitive.


CTCF physically links cohesin to chromatin.
Cohesin is required to prevent premature dissociation of sister chromatids after DNA replication. Although its role in chromatid cohesion is well established, the functional significance of cohesin's association with interphase chromatin is not clear. Using a quantitative proteomics approach, we show that the STAG1 (Scc3/SA1) subunit of cohesin interacts with the CCTC-binding factor CTCF bound to the c-myc insulator element. Both allele-specific binding of CTCF and Scc3/SA1 at the imprinted IGF2/H19 gene locus and our analyses of human DM1 alleles containing base substitutions at CTCF-binding motifs indicate that cohesin recruitment to chromosomal sites depends on the presence of CTCF. A large-scale genomic survey using ChIP-Chip demonstrates that Scc3/SA1 binding strongly correlates with the CTCF-binding site distribution in chromosomal arms. However, some chromosomal sites interact exclusively with CTCF, whereas others interact with Scc3/SA1 only. Furthermore, immunofluorescence microscopy and ChIP-Chip experiments demonstrate that CTCF associates with both centromeres and chromosomal arms during metaphase. These results link cohesin to gene regulatory functions and suggest an essential role for CTCF during sister chromatid cohesion. These results have implications for the functional role of cohesin subunits in the pathogenesis of Cornelia de Lange syndrome and Roberts syndromes.


Occurrence and risk characterization of per- and polyfluoroalkyl substances in seafood from the Persian Gulf.
Potential exposure to 14 per- and polyfluoroalkyl substances (PFAS) through seafood consumption was investigated in widely consumed seafood (Platycephalus indicus, Lethrinus nebulosus, and Penaeus semisulcatus) from the Persian Gulf. A total of 61 samples of fish and prawns were purchased from local fishers at Bushehr port (Persian Gulf, South-West of Iran) and were analyzed for PFAS compounds. In addition, potential factors influencing factor of PFAS bioaccumulation in fish and invertebrates such as age, sex, and habitat, were investigated. ƩPFAS concentrations were in the range of 2.3- 6.1 ng/g-d.w (mean = 3.9 ± 1.9) in studied species which are equal to 0.46-1.2 ng/g-w.w according to their conversion factor. Perfluorooctane sulfonic acid (PFOS) was the most abundant perfluorinated compound in studied organisms and tissues. The results of correlation analysis showed that the bioaccumulation of PFAS in aquatic organisms is significantly correlated to the length of the compound's carbon chain, the identity of anionic group, and organism's age, sex, and habitant. The risk assessment using hazard index calculation and Monte-Carlo simulation indicated that weekly consumption of prawn and fish fillets does not pose a health risk to adults but might threaten children's health. However, the risk posed by PFAS exposure via entire fish or fish liver intake is an important issue for wild marine mammals (i.e., dolphins). So, accurate and routine monitoring of PFAS in aquatic environments seems mandatory to preserve wildlife and human health in the Persian Gulf.


Contrastive learning of heart and lung sounds for label-efficient diagnosis.
Data labeling is often the limiting step in machine learning because it requires time from trained experts. To address the limitation on labeled data, contrastive learning, among other unsupervised learning methods, leverages unlabeled data to learn representations of data. Here, we propose a contrastive learning framework that utilizes metadata for selecting positive and negative pairs when training on unlabeled data. We demonstrate its application in the healthcare domain on heart and lung sound recordings. The increasing availability of heart and lung sound recordings due to adoption of digital stethoscopes lends itself as an opportunity to demonstrate the application of our contrastive learning method. Compared to contrastive learning with augmentations, the contrastive learning model leveraging metadata for pair selection utilizes clinical information associated with lung and heart sound recordings. This approach uses shared context of the recordings on the patient level using clinical information including age, sex, weight, location of sounds, etc. We show improvement in downstream tasks for diagnosing heart and lung sounds when leveraging patient-specific representations in selecting positive and negative pairs. This study paves the path for medical applications of contrastive learning that leverage clinical information. We have made our code available here: https://github.com/stanfordmlgroup/selfsupervised-lungandheartsounds.


Nutritional status and its determinants in the Eastern Mediterranean region. A review.
To review relevant literature on the determinants of the nutritional status of the children below 5 years of age in the Eastern Mediterranean Regional (EMR) countries and investigate the updates related to risk factors associated with malnutrition. A search of pertinent literature and databases was conducted using the PubMed and Google Scholar databases by applying some keywords. From the available literature reviewed, the mean prevalence of underweight, wasting, and stunting of the children below 5 years of age in the EMR were 12.8% (6.4%-22.6%), 7.5% (5.9%-9.4%), and 24.2% (15.6%-35.5%) respectively. The EMR countries like Sudan, Yemen, Libya, Afghanistan and Pakistan showed the highest rate of stunting amongst the children (>30%). Furthermore, on average, 5.7% of the children were seen to be overweight. Countries such as Lebanon, Egypt, Syria, Libya, and Tunisia reported the maximal prevalence of overweight children. The study also identified a positive and negative relationship between demographic and socioeconomic and health determinants with nutritional status of these children under 5 years old. In this review, the researchers have highlighted the prevalence of malnutrition in EMR countries. Thereafter, the review findings recommend for prioritization of different policies which aimed to improve the nutritional status of the people.


Localization of HIV-1 RNA in mammalian nuclei.
The Rev protein of human immunodeficiency virus type 1 (HIV-1) facilitates the nuclear export of unspliced and partially spliced viral RNAs. In the absence of Rev, these intron-containing HIV-1 RNAs are retained in the nucleus. The basis for nuclear retention is unclear and is an important aspect of Rev regulation. Here we use in situ hybridization and digital imaging microscopy to examine the intranuclear distributions of intron-containing HIV RNAs and to determine their spatial relationships to intranuclear structures. HeLa cells were transfected with an HIV-1 expression vector, and viral transcripts were localized using oligonucleotide probes specific for the unspliced or spliced forms of a particular viral RNA. In the absence of Rev, the unspliced viral RNAs were predominantly nuclear and had two distinct distributions. First, a population of viral transcripts was distributed as approximately 10-20 intranuclear punctate signals. Actinomycin D chase experiments indicate that these signals represent nascent transcripts. A second, stable population of viral transcripts was dispersed throughout the nucleoplasm excluding nucleoli. Rev promoted the export of this stable population of viral RNAs to the cytoplasm in a time-dependent fashion. Significantly, the distributions of neither the nascent nor the stable populations of viral RNAs coincided with intranuclear speckles in which splicing factors are enriched. Using splice-junction-specific probes, splicing of human beta-globin pre-mRNA occurred cotranscriptionally, whereas splicing of HIV-1 pre-mRNA did not. Taken together, our results indicate that the nucleolus and intranuclear speckles are not involved in Rev regulation, and provide further evidence that efficient splicing signals are critical for cotranscriptional splicing.


Schistosomiasis in Cambodia: a review.
Human schistosomiasis has been known in Cambodia only since 1968. In 1968-1970, many cases were detected in the provincial capital of Kratié. Infection seemed to be confined to the ethnic Vietnamese fishermen who inhabited raft houses (= floating villages) on the Mekong River at Kratié. Overall prevalence in fishermen of all ages was between 7 and 10%. In the children of fishermen between the ages of 1 to 14, the prevalence was between 14 and 22%. Transmission was apparently limited to floating houses stationed more or less permanently near shore and connected to each other in a chain. It is believed that transmission occurred only in the areas of still water which were created between raft and shore. The principal focus of schistosomiasis in Cambodia appears to be Kratié. Only a few cases have been detected elsewhere in the country. The parasite is undoubtedly identical with the Schistosoma reported from humans and dogs at Khong Island, Laos. However, the transmitting snail in Laos, Lithoglyphopsis aperta, has thus far not been reported from the Mekong River in Cambodia.


Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites.
The primary cilium is a microtubule-based organelle that functions in sensory and signalling pathways. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies. However, the regulatory mechanisms of primary ciliogenesis in normal and cancer cells are incompletely understood. Here we demonstrate that autophagic degradation of a ciliopathy protein, OFD1 (oral-facial-digital syndrome 1), at centriolar satellites promotes primary cilium biogenesis. Autophagy is a catabolic pathway in which cytosol, damaged organelles and protein aggregates are engulfed in autophagosomes and delivered to lysosomes for destruction. We show that the population of OFD1 at the centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient Atg5 or Atg3 null mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, leading to fewer and shorter primary cilia and a defective recruitment of BBS4 (Bardet-Biedl syndrome 4) to cilia. These defects are fully rescued by OFD1 partial knockdown that reduces the population of OFD1 at centriolar satellites. More strikingly, OFD1 depletion at centriolar satellites promotes cilia formation in both cycling cells and transformed breast cancer MCF7 cells that normally do not form cilia. This work reveals that removal of OFD1 by autophagy at centriolar satellites represents a general mechanism to promote ciliogenesis in mammalian cells. These findings define a newly recognized role of autophagy in organelle biogenesis.


Lyso-glycosphingolipids mobilize calcium from brain microsomes via multiple mechanisms.
Recently, we demonstrated that the GSL (glycosphingolipid), GlcCer (glucosylceramide), modulates Ca2+ release from intracellular stores and from microsomes by sensitizing the RyaR (ryanodine receptor), a major Ca2+-release channel of the endoplasmic reticulum, whereas the lyso derivative of GlcCer, namely GlcSph (glucosylsphingosine), induced Ca2+ release via a mechanism independent of the RyaR [Lloyd-Evans, Pelled, Riebeling, Bodennec, de-Morgan, Waller, Schiffmann and Futerman (2003) J. Biol. Chem. 278, 23594-23599]. We now systematically examine the mechanism by which GlcSph and other lyso-GSLs modulate Ca2+ mobilization from rat brain cortical and cerebellar microsomes. GlcSph, lactosylsphingosine and galactosylsphingosine all mobilized Ca2+, but at significantly higher concentrations than those required for GlcCer-mediated sensitization of the RyaR. GlcSph-induced Ca2+ mobilization was partially blocked by heparin, an inhibitor of the Ins(1,4,5) P3 receptor, and also partially blocked by thapsigargin or ADP, inhibitors of SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), but completely blocked when both acted together. In contrast, neither lactosylsphingosine nor galactosylsphingosine had any effect on Ca2+ release via either the Ins(1,4,5) P3 receptor or SERCA, but acted as agonists of the RyaR. Finally, and surprisingly, all three lyso-GSLs reversed inhibition of SERCA by thapsigargin. We conclude that different lyso-GSLs modulate Ca2+ mobilization via different mechanisms, and discuss the relevance of these findings to the GSL storage diseases in which lyso-GSLs accumulate.


Hidden epidemic of macrolide-resistant pneumococci.
Community-acquired respiratory tract infections (RTIs) account for a substantial proportion of outpatient antimicrobial drug prescriptions worldwide. Concern over the emergence of multidrug resistance in pneumococci has largely been focused on penicillin-resistant Streptococcus pneumoniae. Macrolide antimicrobial drugs have been widely used to empirically treat community-acquired RTIs because of their efficacy in treating both common and atypical respiratory pathogens, including S. pneumoniae. However, increased macrolide use has been associated with a global increase in pneumococcal resistance, which is leading to concern over the continued clinical efficacy of the macrolides to treat community-acquired RTIs. We provide an overview of macrolide-resistant S. pneumoniae and assess the impact of this resistance on the empiric treatment of community-acquired RTIs.


How do team experience and relationships shape new divisions of labour in robot-assisted surgery? A realist investigation.
Safe and successful surgery depends on effective teamwork between professional groups, each playing their part in a complex division of labour. This article reports the first empirical examination of how introduction of robot-assisted surgery changes the division of labour within surgical teams and impacts teamwork and patient safety. Data collection and analysis was informed by realist principles. Interviews were conducted with surgical teams across nine UK hospitals and, in a multi-site case study across four hospitals, data were collected using a range of methods, including ethnographic observation, video recording and semi-structured interviews. Our findings reveal that as the robot enables the surgeon to do more, the surgical assistant's role becomes less clearly defined. Robot-assisted surgery also introduces new tasks for the surgical assistant and scrub practitioner, in terms of communicating information to the surgeon. However, the use of robot-assisted surgery does not redistribute work in a uniform way; contextual factors of individual experience and team relationships shape changes to the division of labour. For instance, in some situations, scrub practitioners take on the role of supporting inexperienced surgical assistants. These changes in the division of labour do not persist when team members return to operations that are not robot-assisted. This study contributes to wider literature on divisions of labour in healthcare and how this is impacted by the introduction of new technologies. In particular, we emphasise the need to pay attention to often neglected micro-level contextual factors. This can highlight behaviours that can be promoted to benefit patient care.


Using Maize δ15N values to assess soil fertility in fifteenth- and sixteenth-century ad Iroquoian agricultural fields.
Native Americans developed agronomic practices throughout the Western Hemisphere adapted to regional climate, edaphic conditions, and the extent of dependence on agriculture for subsistence. These included the mounding or "corn hill" system in northeastern North America. Iroquoian language speakers of present-day New York, USA, and Ontario and Québec, Canada were among those who used this system. While well-known, there has been little archaeological documentation of the system. As a result, there is scant archaeological evidence on how Iroquoian farmers maintained soil fertility in their often-extensive agricultural fields. Using δ15N values obtained on fifteenth- and sixteenth-century AD maize kernels from archaeological sites in New York and Ontario, adjusted to take into account changes that result from charring as determined through experiments, we demonstrate that Iroquoian farmers were successful at maintaining nitrogen in their agricultural fields. These results add to our archaeological knowledge of Iroquoian agronomic practices. Our results also indicate the potential value of obtaining δ15N values on archaeological maize in the investigation of Native American agronomic practices.


Selective autoregulation of endothelins in primary astrocyte cultures: endothelin receptor-mediated potentiation of endothelin-1 secretion.
Observations that primary rat astrocytes express high-affinity binding sites for endothelins and, in addition, are capable of producing not only endothelin-3 but also endothelin-1 prompted the investigation of a possible relation between endothelin peptides and receptors in these cells. Sarafotoxin S6b, an endothelin receptor agonist, was used as a tool to study endothelin receptor-mediated changes in the secretion of endothelin-1 and -3. The effects of sarafotoxin S6b and endothelin-1 in stimulating inositolphospholipid turnover as well as in inducing AP1 in primary astrocyte cultures were found to be similar. A low cross-reactivity of sarafotoxin S6b with endothelin-1 and -3 in the endothelin radioimmunoassays used here, along with a distinctly different elution position in high-performance liquid chromatography, allowed a clear discrimination between sarafotoxin and endothelins in the culture media. Stimulation of primary rat astrocytes with 10(-7) M sarafotoxin S6b for 1 hour resulted in a substantial increase in endothelin-1 immunoreactivity in the medium. This immunoreactivity reached a peak at 3 hours and showed no further increase after 8 and 24 hours. Treatment of our cultures with phorbol myristate acetate, lipopolysaccharide, tumor necrosis factor alpha, and norepinephrine for 24 hours led to only a moderate elevation of endothelin-1 immunoreactivity. Immunoreactive endothelin-3 was not affected by any of the treatments tested. Thus, our data suggest that endothelins in primary rat astrocytes are subject to selective autoregulation, as demonstrated by the potentiation of endothelin-1 secretion after activation of glial endothelin receptors.


A comparison of private and public sector intensive care unit infrastructure in South Africa.
Intensive care units (ICUs) are designed to care for patients who are often at increased risk of acquiring healthcare-associated infections. The structure of ICUs should be optimally designed to facilitate the care of these critically ill patients, and minimise their risk of infection. National regulations (R158) were developed to govern the building and registration of private hospitals, and until recently equivalent regulations were not available for public hospitals. To assess and compare the compliance of ICUs in the private and public sectors with the R158 regulations. A cross-sectional study design was used to assess the infrastructure of 25 private sector and 6 public sector ICUs in eThekwini Health District, KwaZulu-Natal Province, South Africa. We used the R158 checklist, which was developed by the KwaZulu-Natal Department of Health Private Licensing Unit and Infection Prevention and Control Unit. The aspects covered in the R158 checklist were categorised into the design, general safety and patient services of the ICUs. Most of the ICUs in both sectors met the general safety requirements. There were varying levels of compliance with the design criteria. Only 7 (28.0%) and 1 (16.7%) of the private and public ICUs, respectively, had sufficient space around the beds. Twenty-two private ICUs (88.0%) and 4 public ICUs (66.7%) had isolation rooms, but only some of these isolation rooms (15 private and 2 public) had appropriate mechanical ventilation. None of the ICUs had clinical hand-wash basins in the nurse stations and dirty utility rooms. The majority of the ICUs had the required number of oxygen and electric outlets at the bedside. None of the public ICUs met the light intensity requirement over the bed area. Adequate spacing in ICUs is an issue in many cases. Interventions need to be put in place to ensure that ICUs meet the relevant design standards. There is an urgent need to revise the R158 regulations to reflect current best practices, particularly with regard to infection control. The same standards should be applied to ICUs in the private and public health sectors to maintain quality of care to patients.


COVID-19 in Patients with Cancer.
With more than 5 million cases and 333,212 deaths, COVID-19 (or SARS-CoV-2) continues to spread. General symptoms of this disease are similar to that of many other viral respiratory diseases, including fever, cough, dyspnea, and fatigue, with a chance of progression to more severe complications. However, the virus does not affect all people equally, and cases with comorbidities such as malignancies, cardiovascular diseases, respiratory diseases, and kidney diseases are at higher risk of developing severe events, including requiring intensive ventilation, intensive care unit (ICU) admission, and death. Patients with cancer are more likely to be infected with COVID-19, which is possibly due to their immunological dysfunction or frequent clinic visits. Also, there is a higher chance that these patients experience severe events because of the medication they receive. In this chapter, we will review the main clinical manifestations of COVID-19 in patients with cancer. Recommendations and challenges for managing resources, organizing cancer centers, treatment of COVID-19-infected cancer patients, and performing cancer research during this pandemic will also be discussed.


Italian Oncological Pain Survey (IOPS): a multicentre Italian study of breakthrough pain performed in different settings.
A survey of breakthrough pain (BTP) was performed in five palliative care units (PCU), seven oncology departments (ONC), and nine pain clinics (OPC). A standard algorithm was used to confirm the diagnosis of BTP of patients refereed to different settings. 1,412 evaluable cancer patients were enrolled. 53.9% were males and the mean age was 63.7±13.1 years. The mean intensity of background pain was 2.8±0.73. Patients reported 2.4±1.1 BTP episodes/day with a mean intensity of 7.37±1.28. 80.6% patients reported that the BTP had a significant negative impact in everyday life. The majority of patients reported a fast onset of BTP, which was predictable in 50.7% of cases, while BTP with a gradual onset (>10 min) was less predictable (29%) (P=0.001). PCU patients were older, had lower Karnofsky levels, a lower number of BTP episodes/day, a slow onset of BTP onset, and a less predictable BTP. Cancer diagnosis was performed a mean of 23.5 months (SD±32.8) before the assessment. The mean duration of background pain was 3.5 months (SD±3.5), and the mean duration of any analgesic treatment was 2.5 months (SD±3). BTP started a mean of 2.2 months (SD±1.9) before the assessment. Characteristics of BTP were influenced by the course of disease, as well as the duration of background pain and initiation of BTP. Most patients took rapid onset opioids and were satisfied with the treatment. BTP diagnosis was prevalently made by ONC and OPC physicians, and rarely by GPs. This survey performed by an Italian observatory expert review group, has confirmed that the BTP represents a clinically relevant condition with a negative impact on the patient's quality of life. BTP was detected in all settings involved. A number of factors are associated with the BTP. Also factors regarding the course of disease and setting of care have been assessed. This information may help in stratifying patients or predicting the risk of development of BTP with specific characteristics.


How can we Preserve Sexual Function after Ablative Surgery for Benign Prostatic Hyperplasia?
Our aim was to provide a narrative review regarding the prevalence, the associated pathophysiologic pathways and the potential management methods of sexual dysfunction related to ablative surgical techniques for Benign Prostatic Enlargement (BPE). Men suffering from BPE are at high risk of sexual dysfunction due to the disease itself, comorbidities, and pharmacological/surgical treatments. Transurethral resection of the prostate, as the gold standard treatment option for BPE, has historically been associated with relatively high rates of postoperative sexual dysfunction problems, mainly retrograde ejaculation but also erectile dysfunction. Ablative surgical techniques, including photoselective vaporization of the prostate (PVP), transurethral needle ablation (TUNA), Transurethral Microwave Therapy (TUMT), Convective Water Vapor Energy Ablation (Rezum®) and Aquablation®, have been proposed as treatment methods able to reduce treatment-related complications for BPE patients, including adverse effects on erectile and ejaculatory function, without compromising the efficacy rates for BPE. The neurovascular bundles can be damaged during TURP due to posterolateral capsular perforation. Ablative techniques and especially PVP theoretically seem to skip this hazard, as the distance created from the necrotic area to the capsule is generally larger compared to the distance induced after TURP. However, indirect thermal injury of erectile nerves, which could also be induced by the majority of available ablative techniques, could potentially lead to ED. Two special technical characteristics (physiological saline use for tissue ablation and real time penetration depth control) of Aquablation® could be proved beneficial with regard to the effect of the method on erectile function. In general, ablative techniques seem to have a minor impact on sexual function. However, low methodological quality characterizes most of the studies included in this review mainly due to the impossibility, in many cases, to perform blind randomization. Also, many studies did not have an erectile and ejaculatory function as primary outcomes limiting that way their statistical power to identify significant variations. Management of sexual dysfunction problems arising from ablative surgeries for BPE treatment could be divided into two levels. Firstly, intraoperatively the avoidance of manipulation of crucial structures regarding ejaculatory (bladder neck or ejaculatory ducts) and erectile function (neurovascular bundles) could possibly decrease the negative effect of these procedures on sexual function. Thus, in this direction, modifications of classic ablative techniques have been proposed resulting in encouraging outcomes regarding postoperative sexual function. Secondly, if EjD and/or ED are established, the already known treatment choices should be chosen in order for sexual function rehabilitation to be achieved. Thus, regarding ED: PDE5i daily or on-demand remains the gold standard first-line treatment choice followed by intracavernosal alprostadil injections in cases of failure, while penile prosthesis implantation must be kept as the final definitive solution when all the other methods have failed. Regarding ejaculation disorders (retrograde ejaculation or anejaculation): medical therapy with a-agonists (pseudoephedrine), sperm retrieval from the urine, bladder neck reconstruction, prostatic massage, electroejaculation, penile vibratory stimulation and surgical sperm retrieval are the available treatment options. Furthermore, high-quality studies are required to investigate the potential side effects of BPE surgery on sexual function and efficient treatment methods to manage them.


Infliximab paediatric Crohn's disease educational plan: a European, cross-sectional, multicentre evaluation.
The infliximab (Remicade; Schering-Plough, Kenilworth, NJ, USA) Risk Management Plan included the development, execution and tracking of an education programme directed towards prescribers of infliximab for patients with paediatric Crohn's disease (the Infliximab Paediatric Crohn's Disease Educational Plan). The programme content consisted of educational materials and communications aimed at educating prescribers on the risks associated with infliximab use. To evaluate the effectiveness of the risk minimization plan. Evaluation focused on two components: documentation of training of sponsors' personnel, and evaluation of awareness among prescribing physicians in European countries. Treating physicians, identified both independently of the sponsor (6 countries) and by the sponsor (24 countries), were surveyed using a structured questionnaire. Training of internal staff on the educational programme was performed and completed by every person designated an appropriate candidate for the programme in all European countries. The independent survey conducted in Germany, France, Italy, Spain, Sweden and the UK indicated that around 90% of the physicians were either paediatric gastroenterologists (57%) or paediatricians (33%). The great majority (96%) of the interviewed physicians were currently treating paediatric Crohn's disease, and most were currently using infliximab in their treatment of the disease. More specifically, 82% of gastroentrologists treating paediatric Crohn's disease were using infliximab; among paediatricians, the proportion was lower (42%). Ninety-six percent of paediatric gastroenterologists or gastroenterologists declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn's disease; in comparison, fewer paediatricians (82%) declared themselves aware of these benefits and risks. The majority initially gained awareness through congresses and workshops, and at the time of the survey only 25% declared that they were made aware of the benefits and risks through the educational programme. However, the majority of physicians reported that they had been approached by the sponsor's personnel in France (98%), Italy (100%), Spain (83%) and Sweden (70%). In Germany and the UK this proportion was 42%. Almost all physicians were aware of the need to perform tuberculosis (TB) and cancer screening prior to initiating therapy with infliximab, and to screen for hypersensitivity reactions before, during and after treatment. Ninety percent of the physicians were aware of the need to update immunization therapy before initiating therapy and, except in Italy (92% aware), around 50% of the physicians were aware of the need to provide patients with the infliximab Patient Alert Card. In the other European countries where the survey took place among physicians identified by the sponsor, 99% of paediatric gastroenterologists and 90% of gastroenterologists or paediatricians declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn's disease, and all of them were aware of the risk of TB and opportunistic infections and the need to perform TB and cancer screening prior to initiating therapy with infliximab. Overall, the results of the evaluation of the Infliximab Paediatric Crohn's Disease Educational Plan were satisfactory. The objective of education of internal personnel of the pharmaceutical companies distributing infliximab was completely achieved; over 90% of physicians reported being aware of the benefits and risks of infliximab for the treatment of paediatric Crohn's disease. Further work should be carried out across all countries to educate physicians on providing patients with the infliximab Patient Alert Card. In Germany and the UK in particular, where <50% of physicians reported having been approached by the sponsor's personnel, further work is needed to raise awareness of the educational programme.


Cytokine regulation of liver injury and repair.
By comparing the hepatic responses to tumor necrosis factor (TNF)-alpha that occur during situations that promote liver injury (such as obesity or chronic exposure to ethanol) with those that occur after stimuli (such as partial hepatectomy) that lead to liver regeneration, it is apparent that hepatocytes are usually able to constrain noxious responses to TNF-alpha, such as the release of reactive oxygen from mitochondria. It appears that by promptly upregulating survival genes that regulate mitochondrial membrane permeability, hepatocytes are usually able to constrain noxious responses, including the release of mitochondrial-generated reactive oxygen species, that follow exposure to potentially toxic cytokines, such as TNF-alpha. Indeed, transient TNF-alpha-mediated increases in ROS may even be exploited by hepatocytes to evoke a subsequent proliferative response. Thus, the healthy liver has well-developed defense mechanisms that permit hepatocytes to adapt to cytokine-initiated stress, protecting them from cytokine-mediated lethality. Nevertheless, these same cytokines may cause liver injury when hepatocytes have been pre-exposed to toxins (e.g. ethanol) that interfere with their usual protective responses. Furthermore, while transient adaptations to cytokine-initiated stress permit hepatocytes to survive and proliferate, persistence of these anti-apoptotic, adaptative responses (as occurs, for example, in fatty livers) may inadvertently enhance hepatocyte vulnerability to necrosis when the liver is confronted by secondary insults that promote mitochondrial membrane depolarization.


Activity-dependent subcellular cotrafficking of the small GTPase Rem2 and Ca2+/CaM-dependent protein kinase IIα.
Rem2 is a small monomeric GTP-binding protein of the RGK family, whose known functions are modulation of calcium channel currents and alterations of cytoskeletal architecture. Rem2 is the only RGK protein found predominantly in the brain, where it has been linked to synaptic development. We wished to determine the effect of neuronal activity on the subcellular distribution of Rem2 and its interacting partners. We show that Rem2 undergoes activity-and N-Methyl-D-Aspartate Receptor (NMDAR)-dependent translocation in rat hippocampal neurons. This redistribution of Rem2, from a diffuse pattern to one that is highly punctate, is dependent on Ca(2+) influx, on binding to calmodulin (CaM), and also involves an auto-inhibitory domain within the Rem2 distal C-terminus region. We found that Rem2 can bind to Ca(2+)/CaM-dependent protein kinase IIα (CaMKII) a in Ca(2+)/CaM-dependent manner. Furthermore, our data reveal a spatial and temporal correlation between NMDAR-dependent clustering of Rem2 and CaMKII in neurons, indicating co-assembly and co-trafficking in neurons. Finally, we show that inhibiting CaMKII aggregation in neurons and HEK cells reduces Rem2 clustering, and that Rem2 affects the baseline distribution of CaMKII in HEK cells. Our data suggest a novel function for Rem2 in co-trafficking with CaMKII, and thus potentially expose a role in neuronal plasticity.


Quality indicators and technique for analyzing permanent I-125 prostate seed implants: seven years postimplant dosimetry evaluation.
The roles of postimplant dosimetry (PID) after permanent I-125 implant are to identify and rectify inadequate implants, assess the dosimetric quality indicators, and evaluate dose to the organs at risk. The aim of the current work was to assess the progress of prostate implant quality via postimplant dosimetry over seven years. The following factors were investigated to assess the PID results obtained over seven years: the improvement in implant technique, the computed tomography (CT) delineation-based PID versus ultrasound-CT (US-CT) fusion-based PID, and the evolution of parameters such as D90 and NDR (natural dose ratio). The correlation between dosimetric parameters and clinical outcomes were also evaluated. The seven years PID learning curve shows clear changes in dosimetric trend for the 265 patients studied. Manual target contouring on CT was shown to overestimate the prostate volume when compared to ultrasound data, translating to CT-based D90 values being lower than US-CT D90. It was found that NDR does not contribute with additional dosimetric information to postimplant dosimetry evaluation. Patient follow-up data show that 4.7% patients have relapsed, and urinary retention was reported in 2.7% of the patients. CT-based PID was found less reliable than US-CT fusion-based PID due to target volume overestimation. This result shows the biased interpretation of low D90 values based on CT-based targeting, providing unreliable correlations between D90 and relapse probability. The low urinary retention statistics are in accordance with the PID data for the organ, as only 5.2% of patients had their PID D10 > 218 Gy, i.e., above the recommended GEC-ESTRO guidelines. Besides the "learning" component, the PID D90 curve is influenced by the PID technique.


Living donor right lobe liver transplantation as a treatment for hepatic alveolar echinococcosis: report of three cases.
Echinococcus alveolaris is a parasite from tenia family which causes tumor-like lesions in the livers of infected people. If it is not diagnosed in the early stage of the disease, it frequently causes multiple cysts in the liver. The clinical importance of the disease is rapid progression, infiltration into different tissues like a malignant tumor and capacity of creating metastatic masses. The disease could be treated either by surgical resection or liver transplantation. The resection of the cystic disease is the preferred treatment method. In cases where resection is not possible, liver transplantation is the choice of treatment. Here we present three cases which were admitted to the hospital with unresectable hepatic alveolar echinococcosis and treated by liver transplantation successfully. Patients for whom surgical resection is not possible, we recommend liver transplantation as the treatment method.


Survey of virally mediated permeability changes.
1. Sendai virus causes permeability changes when added to freshly isolated brain cells (cerebellum or ependymal cells) or to a culture of forebrain cells. 2. Sendai virus causes permeability changes when added to organ cultures of ferret lung or nasal turbinate. Influenza virus causes no permeability changes under these conditions. 3. Rabies virus and vesicular-stomatitis virus, in contrast with Sendai virus, do not cause permeability changes in BHK cells or Lettrée cells. 4. Serum from patients suffering from viral hepatitis does not cause permeability changes in human leucocytes; addition to Sendai virus causes permeability changes. 5. It is concluded that permeability changes accompanying viral entry occur only with certain types of paramyxovirus, but that there is little restriction on cell type. 6. MDBK cells infected with Sendai virus show permeability changes during viral release, similar to those that occur during viral entry. Because these changes do not appear to be restricted to paramyxoviruses, they may have considerable clinical significance.


Limited small cell lung cancer--the role of radiotherapy.
At this time there is no standard therapy for limited small cell lung cancer. Chemotherapy regimens are usually cyclophosphamide-based, but vary in dose, intensity, and in other agents used. Radiotherapy varies in dose, duration, and course (split or continuous). Combinations of the two modalities include sequential therapy, concurrent therapy, and alternating therapy. What emerges from recent trials is the fact that radiotherapy is clearly active in small cell lung cancer and improves local control. What must still be determined are the optimal type of combined chemotherapy/radiotherapy and the best method of integration and timing.


Disability as a predictor of outcome for the elderly in a department of internal medicine. A comparison of predictions based on index of ADL and physician predictions.
The predictive validity of ratings based on Katz' Index of ADL (Activities of Daily Living) and of physician ratings of patient outcome was studied in a department of internal medicine, 129 patients, 65 years of age or older, were assessed independently and simultaneously by licensed practical nurses using Katz' Index of ADL and by a physician using clinical judgement. These assessments were related to observed outcome regarding survival or death in the ward, length of stay, and type of hospital discharge. Two alternative ADL-groupings were used, grade A-E versus grade F-G and grade A-F versus grade G. Sensitivity and specificity of ADL-ratings and of physician ratings were found to be rather similar regarding length of stay less than 10 days and discharge to own home. Predictions regarding patient deaths based on ADL-grades F-G and G had a higher sensitivity than predictions based on physician ratings. The specificity of the two types of predictions was about the same. There was only a fair correlation between age and ADL-grade. ADL-assessments may thus be useful for planning purposes for elderly patients also in acute medical wards.


Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum.
Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Recent studies have demonstrated that elevated cyclin D1 levels correlate with decreased survival in human pancreatic cancer. In this study we expressed in a stable manner a cyclin D1 antisense cDNA construct in PANC-1 human pancreatic cancer cells. Expression of the antisense construct caused a decrease in cyclin D1 mRNA and protein levels and in cyclin D1-associated kinase activity. Antisense expressing clones displayed significantly increased doubling times, decreased anchorage-dependent and -independent basal growth, and complete loss of tumorigenicity in nude mice. EGF, FGF-2, and IGF-I enhanced mitogen-activated protein kinase activity in antisense expressing clones, but failed to stimulate their proliferation. In contrast, all three growth factors were mitogenic in parental cells. Furthermore, the inhibitory effect of cisplatinum on cell proliferation was enhanced markedly in the antisense expressing clones. These findings indicate that cyclin D1 overexpression contributes to abnormal growth and tumorigenicity in human pancreatic cancer and to the resistance of pancreatic cancer to chemotherapeutic agents.


The grey mouse lemur uses season-dependent fat or protein sparing strategies to face chronic food restriction.
During moderate calorie restriction (CR) the heterotherm Microcebus murinus is able to maintain a stable energy balance whatever the season, even if only wintering animals enter into torpor. To understand its energy saving strategies to respond to food shortages, we assessed protein and energy metabolisms associated with wintering torpor expression or summering torpor avoidance. We investigated body composition, whole body protein turnover, and daily energy expenditure (DEE), during a graded (40 and 80%) 35-day CR in short-days (winter; SD40 and SD80, respectively) and long-days (summer; LD40 and LD80, respectively) acclimated animals. LD40 animals showed no change in fat mass (FM) but a 12% fat free mass (FFM) reduction. Protein balance being positive after CR, the FFM loss was early and rapid. The 25% DEE reduction, in LD40 group was mainly explained by FFM changes. LD80 animals showed a steady body mass loss and were excluded from the CR trial at day 22, reaching a survival-threatened body mass. No data were available for this group. SD40 animals significantly decreased their FM level by 21%, but maintained FFM. Protein sparing was achieved through a 35 and 39% decrease in protein synthesis and catabolism (protein turnover), respectively, overall maintaining nitrogen balance. The 21% reduction in energy requirement was explained by the 30% nitrogen flux drop but also by torpor as DEE FFM-adjusted remained 13% lower compared to ad-libitum. SD80 animals were unable to maintain energy and nitrogen balances, losing both FM and FFM. Thus summering mouse lemurs equilibrate energy balance by a rapid loss of active metabolic mass without using torpor, whereas wintering animals spare protein and energy through increased torpor expression. Both strategies have direct fitness implication: 1) to maintain activities at a lower body size during the mating season and 2) to preserve an optimal wintering muscle mass and function.


Intrauterine device (IUD) associated pathology: a review of pathogenic mechanisms.
This paper summarizes our studies of IUD-related disease with those previously published by others. Our data are based upon 51 IUDs and 42 index cases of IUD-related disease demonstrating specific processes. Gross, dissecting microscope, scanning electron microscope and X-ray microanalysis examinations were made of selected IUDs and associated tissues. Tissue associated with the IUDs revealed inflammation in 59.4%, calcific material in 6.3% and no abnormality in 34.4%. IUD-associated tissue responses were accompanied by changes of the IUD; these changes involved deposition of substances upon the IUD surface and degradation of the IUD itself. Disintegration of the IUD, its string or both, has been repeatedly observed. The material deposited upon the surface of the IUD included proteins and calcium salts. The changes which involve the IUD and the host appear to be operative in the genesis of IUD-related disease. Inflammatory changes and infections are the most common IUD-related disease processes and are also the mechanisms commonly associated with the most serious complications of IUD use, reproductive failure and death. We propose that serious IUD-related disease is caused by or is a direct consequence of processes which alter the IUD and which potentiate inflammation and infection. A model amenable to testing is proposed.


A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13.
The proteolysis of VWF by ADAMTS13 is an essential step in the regulation of its hemostatic and thrombogenic potential. The cleavage occurs at strand β4 in the structural core of the A2 domain of VWF, so unfolding of the A2 domain is a prerequisite for cleavage. In the present study, we present the crystal structure of an engineered A2 domain that exhibits a significant difference in the α3-β4 loop compared with the previously reported structure of wild-type A2. Intriguingly, a metal ion was detected at a site formed mainly by the C-terminal region of the α3-β4 loop that was later identified as Ca(²+) after various biophysical and biochemical studies. Force-probe molecular dynamic simulations of a modeled structure of the wild-type A2 featuring the discovered Ca(²+)-binding site revealed that an increase in force was needed to unfold strand β4 when Ca(²+) was bound. Cleavage assays consistently demonstrated that Ca(²+) binding stabilized the A2 domain and impeded its unfolding, and consequently protected it from cleavage by ADAMTS13. We have revealed a novel Ca(²+)-binding site at the A2 domain of VWF and demonstrated a relationship between Ca(²+) and force in the regulation of VWF and primary hemostasis.


Enthalpy-entropy contributions to salt and osmolyte effects on molecular-scale hydrophobic hydration and interactions.
Salts and additives can significantly affect the strength of water-mediated interactions in solution. We present results from molecular dynamics simulations focused on the thermodynamics of hydrophobic hydration, association, and the folding-unfolding of a hydrophobic polymer in water and in aqueous solutions of NaCl and of an osmolyte trimethylamine oxide (TMAO). It is known that addition of NaCl makes the hydration of hydrophobic solutes unfavorable and, correspondingly, strengthens their association at the pair as well as the many-body level (Ghosh, T.; Kalra, A.; Garde, S. J. Phys. Chem. B 2005, 109, 642), whereas the osmolyte TMAO has an almost negligible effect on the hydrophobic hydration and association (Athawale, M. V.; Dordick, J. S.; Garde, S. Biophys. J. 2005, 89, 858). Whether these effects are enthalpic or entropic in origin is not fully known. Here we perform temperature-dependent simulations to resolve the free energy into entropy and enthalpy contributions. We find that in TMAO solutions, there is an almost precise entropy-enthalpy compensation leading to the negligible effect of TMAO on hydrophobic phenomena. In contrast, in NaCl solutions, changes in enthalpy dominate, making the salt-induced strengthening of hydrophobic interactions enthalpic in origin. The resolution of total enthalpy into solute-solvent and solvent-solvent terms further shows that enthalpy changes originate primarily from solvent-solvent energy terms. Our results are consistent with experimental data on the hydration of small hydrophobic solutes by Ben-Naim and Yaacobi (Ben-Naim, A.; Yaacobi, M. J. Phys. Chem. 1974, 78, 170). In combination with recent work by Zangi, Hagen, and Berne (Zangi, R.; Hagen, M.; Berne, B. J. J. Am. Chem. Soc. 2007, 129, 4678) and the experimental data on surface tensions of salt solutions by Matubayasi et al. (Matubayasi, N.; Matsuo, H.; Yamamoto, K.; Yamaguchi, S.; Matuzawa, A. J. Colloid Interface Sci. 1999, 209, 398), our results highlight interesting length scale dependences of salt effects on hydrophobic phenomena. Although NaCl strengthens hydrophobic interactions at both small and large length scales, that effect is enthalpy-dominated at small length scales and entropy-dominated for large solutes and interfaces. Our results have implications for understanding of additive effects on water-mediated interactions, as well as on biocompatibility of osmolyte molecules in aqueous solutions.


Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.


Probing the nanoadhesion of Streptococcus sanguinis to titanium implant surfaces by atomic force microscopy.
As titanium (Ti) continues to be utilized in great extent for the fabrication of artificial implants, it is important to understand the crucial bacterium-Ti interaction occurring during the initial phases of biofilm formation. By employing a single-cell force spectroscopy technique, the nanoadhesive interactions between the early-colonizing Streptococcus sanguinis and a clinically analogous smooth Ti substrate were explored. Mean adhesion forces between S. sanguinis and Ti were found to be 0.32±0.00, 1.07±0.06, and 4.85±0.56 nN for 0, 1, and 60 seconds contact times, respectively; while adhesion work values were reported at 19.28±2.38, 104.60±7.02, and 1,317.26±197.69 aJ for 0, 1, and 60 seconds, respectively. At 60 seconds surface delays, minor-rupture events were modeled with the worm-like chain model yielding an average contour length of 668±12 nm. The mean force for S. sanguinis minor-detachment events was 1.84±0.64 nN, and Poisson analysis decoupled this value into a short-range force component of -1.60±0.34 nN and a long-range force component of -0.55±0.47 nN. Furthermore, a solution of 2 mg/mL chlorhexidine was found to increase adhesion between the bacterial probe and substrate. Overall, single-cell force spectroscopy of living S. sanguinis cells proved to be a reliable way to characterize early-bacterial adhesion onto machined Ti implant surfaces at the nanoscale.


[The effect of androgens upon the differentiation of Cowper and Bartholin glands in rat fetuses (author's transl)].
In the present paper, a study is made of the normal structure shown in Bartholin and Cowper glands of 100 female fetuses and 100 male fetuses of Wistar rats at the end of gestation, with the structure of bulbouretral glands that formed in 70 female fetuses of the same species and period of gestation masculinized by androgens. In relation to the Bartholin glands, whose bilateral sketch is constant in the fetuses, we can affirm that it shows significant differences of structure with regards to the sketch of the Cowper gland. On the opposite, the histologycal details of the latter, are entirely identical to those shown by the bulbouretral glands of the masculinized female fetuses, a fact which permits us to affirm that these are authentic Cowper glands, not only because of their position, but also because of their structure. This morphological data corresponds to a masculinization phenomenon and demonstrates that the Bartholin and Cowper glands are very sensitive to the effect of androgens during gestation.


Specific interaction of oxidized low-density lipoprotein with macrophage-derived foam cells isolated from rabbit atherosclerotic lesions.
Interaction of oxidized LDL (OxLDL) with macrophage-derived foam cells is one of the key events in the development and progression of atherosclerosis. To study this interaction, macrophage-derived foam cells were isolated from rabbit atherosclerotic lesions and the expression of scavenger receptors for OxLDL was examined. Atherosclerosis was induced in rabbits by denudation of the large arteries, followed by a hypercholesteremic diet. Macrophage-derived foam cells, characterized by immunostaining with an RAM-11 antibody (a macrophage marker), contained a high content of intracellular lipid. Maximal binding of radiolabeled OxLDL to isolated macrophage-derived foam cells (1652+/-235 ng 125I-OxLDL/mg of cell protein) was 20-fold higher compared with Bmax values of monocytes. Levels of association of OxLDL to macrophage-derived foam cells isolated from atherosclerotic lesions 12 weeks after denudation were >3-fold higher compared with the levels expressed by macrophage-derived foam cells isolated after 6 weeks. Association of 125I-OxLDL could be completely blocked by OxLDL, and partially by acetylated LDL and polyinosinic acid, indicating the presence of a specific binding site for OxLDL on macrophage-derived foam cells. The induction of scavenger receptors for OxLDL on macrophage-derived foam cells during the development of atherosclerosis, as described in this study, may facilitate the lipid accumulation in macrophage-derived foam cells, as observed in advanced atherosclerotic lesions.


Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia.
Chemotherapy treated cancer patients are prone to neutropaenia and life-threatening infections. Early, empirical antibiotic treatment is therefore administered routinely to febrile neutropaenic patients. Currently, either beta-lactam-aminoglycoside combination treatment or beta-lactam monotherapy are recommended. We compared beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutroepaenia. Cochrane Library (Issue 4,2001), the Cochrane Cancer Network Register of trials (July 2000), EMBASE (January 1980-2000), MEDLINE (1966-8/2001), and ICAAC conference proceedings (1995 onwards). We scanned references of all included studies, pertinent reviews, and contacted the first author of each included trial and the pharmaceutical companies. Randomised controlled trials comparing any beta-lactam antibiotic monotherapy to any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial, empirical treatment of febrile neutropaenic cancer patients. Data concerning mortality, treatment failure (including treatment modifications), superinfections, adverse effects and study quality measures were extracted independently by two reviewers. Relative risks with their 95% confidence intervals (CI) were estimated. Outcomes were extracted by intention-to-treat analysis whenever possible. Forty-six trials and 7642 patients were included. All cause mortality was the primary outcome assessed. For all mortality comparisons, no significant difference between monotherapy and combination therapy was seen, relative risk 0.85 (95% CI 0.72-1.02) for all studies combined. Treatment failure was the outcome reported in all included trials. No significant difference between study groups was shown for studies comparing the same beta-lactam, relative risk 1.12 (95% CI 0.96-1.29). A significant advantage to monotherapy was observed for studies comparing different beta-lactams, relative risk 0.86 (95% CI 0.80-0.93). Bacterial and fungal superinfections developed with similar frequencies in the monotherapy and combination treatment groups. Adverse events were significantly more common in the combination treatment group, relative risk 0.83, (95% CI 0.72-0.97). These included events associated with significant morbidity, primarily renal toxicity. Results were consistent for subgroup and sensitivity analyses. We have shown an advantage to broad-spectrum beta-lactam monotherapy over beta-lactam-aminoglycoside combination therapy for febrile neutropaenia. This advantage comprises of 1) a similar, if not better, survival, 2) a significantly lower treatment failure rate, 3) comparable probability for secondary infections and, 4) most importantly, a lower rate of adverse events associated with significant morbidity. Monotherapy can be regarded, therefore, as the standard of care for febrile neutropaenic patients.


Energy transfer within the hydrogen bonding network of water following resonant terahertz excitation.
Energy dissipation in water is very fast and more efficient than in many other liquids. This behavior is commonly attributed to the intermolecular interactions associated with hydrogen bonding. Here, we investigate the dynamic energy flow in the hydrogen bond network of liquid water by a pump-probe experiment. We resonantly excite intermolecular degrees of freedom with ultrashort single-cycle terahertz pulses and monitor its Raman response. By using ultrathin sample cell windows, a background-free bipolar signal whose tail relaxes monoexponentially is obtained. The relaxation is attributed to the molecular translational motions, using complementary experiments, force field, and ab initio molecular dynamics simulations. They reveal an initial coupling of the terahertz electric field to the molecular rotational degrees of freedom whose energy is rapidly transferred, within the excitation pulse duration, to the restricted translational motion of neighboring molecules. This rapid energy transfer may be rationalized by the strong anharmonicity of the intermolecular interactions.


Moving research on resilience into the 21st century: theoretical and methodological considerations in examining the biological contributors to resilience.
Empirical investigations of resilience over the past 30 years have examined a wide range of psychosocial correlates of, and contributors to, this phenomenon. Thus far, theoretical treatments of resilience have focused almost exclusively on psychosocial levels of analysis to derive explanatory models. However, there have been no formal discussions of either theory or research that have examined the biological contributors to, or correlates of, competent functioning despite the experience of adversity. This paper seeks to fill this gap and sets forth a preliminary theoretical framework and outline of empirical strategies for studying the biological underpinnings of resilience. The initial sections of the paper discuss the particular suitability of a transactional organizational theoretical perspective as a conceptual foundation for including a biological level of analysis within the extant theoretical framework of resilience. Subsequently, other important theoretical considerations for the inclusion of a biological perspective on resilience are discussed, including the avoidance of an approach that would reduce resilience to merely a biological process, the application of the constructs of multifinality and equifinality to a biological perspective on resilience, as well as a general discussion of the potential for utilization of brain imaging and other technologies in the study of resilience. The possible relation between the mechanisms of neural plasticity and resilience are examined in some detail, with specific suggestions concerning research questions needed to examine this association. Sections of the paper discuss the likely relation of several areas of brain and biological functioning with resilience, including emotion, cognition, neuroendocrine and immune functioning, and genetics. The paper concludes with a discussion of the implications of a biological perspective on resilience for preventive interventions.


3DCoffee@igs: a web server for combining sequences and structures into a multiple sequence alignment.
This paper presents 3DCoffee@igs, a web-based tool dedicated to the computation of high-quality multiple sequence alignments (MSAs). 3D-Coffee makes it possible to mix protein sequences and structures in order to increase the accuracy of the alignments. Structures can be either provided as PDB identifiers or directly uploaded into the server. Given a set of sequences and structures, pairs of structures are aligned with SAP while sequence-structure pairs are aligned with Fugue. The resulting collection of pairwise alignments is then combined into an MSA with the T-Coffee algorithm. The server and its documentation are available from http://igs-server.cnrs-mrs.fr/Tcoffee/.


[The choice of the optimal plan for treating dystopia of individual teeth combined with arch defects of the maxilla].
Treatment of patients requires cooperation of an orthodontist and prosthesis-maker as early as during treatment planning. An adequate clinical situation of treatment can be chosen only after preliminary modeling and prediction of results using dismountable diagnostic models of the jaws and computer simulation of the graphic scheme of the teeth position and transposition, described in this paper. Two-staged orthodontic and orthopedic treatment is needed for patients with early removed teeth and delayed prostheses, congenital cleft alveolar process and palate, and lack of two lateral incisors. However, for 25% of patient lacking two lateral incisors, orthodontic treatment alone is sufficient.


Immunopathogenesis of juvenile dermatomyositis.
There is increasing evidence for involvement of the mechanisms of the innate immune system in the pathogenesis of idiopathic inflammatory myopathies (IIMs), especially in the adult and juvenile forms of dermatomyositis. Juvenile dermatomyositis (JDM) is the most common form of childhood IIM, and this review focuses on recent advances in understanding the actions of the innate immune system in this condition. Over the last few years, great strides have been made in understanding immune dysregulation in IIM, including JDM. Novel autoantibodies have been identified, and new genetic contributions have been described. Among the most striking findings is type I interferon activity in JDM tissue and peripheral blood. This is in conjunction with the description of dysregulation of the major histocompatibility complex (MHC) class I gene and identification of plasmacytoid dendritic infiltrates as the possible cellular source of type I interferons. These findings also point toward the potential prognostic value of muscle biopsies and have helped expand our understanding of the etiopathogenesis of IIM.


Left Ventricular Assist Device-Associated Carbon Monoxide and Iron-Enhanced Hypercoagulation: Impact of Concurrent Disease.
Left ventricular assist device (LVAD) therapy is associated with thrombophilia despite anticoagulation. Of interest, LVAD patients have increased carboxyhemoglobin, a measure of upregulated heme oxygenase (Hmox) activity that releases carbon monoxide (CO) and iron. Given that CO and iron enhance plasmatic coagulation, we determined if LVAD patients had hypercoagulability and decreased fibrinolytic vulnerability with measurable CO and iron-mediated effects. Blood samples were obtained a month or more after implantation of the LVAD. Thrombelastographic methods to assess coagulation kinetics, fibrinolytic kinetics, formation of carboxyhemefibrinogen, and iron-mediated enhancement of clot growth were utilized. Coagulation and fibrinolytic parameter normal individual (n = 30) plasma values were determined. Sixteen LVAD patients were studied. CO and iron enhancement of coagulation were observed in the majority of LVAD patients, contributing to hypercoagulation. However, most patients demonstrated abnormally increased rates of clot lysis. Critically, hemolysis as assessed by circulating lactate dehydrogenase activity was small in this cohort, and only four patients without comorbid states (e.g., obesity, diabetes, sleep apnea) were hypercoagulable with evidence of Hmox upregulation. However, seven patients with comorbidities were hypercoagulable with Hmox upregulation. Future investigation of CO and iron-related thrombophilia and comorbid disease is warranted to define its role in LVAD-related thrombosis.


Effects of clotrimazole troches on tacrolimus dosing in heart transplant recipients.
Tacrolimus is a cornerstone of immunosuppression after transplantation but is highly susceptible to changes from interacting variables and has a narrow therapeutic index. Clotrimazole troches are commonly used as a non-systemic antifungal to prevent oral candidiasis. Studies suggest that clotrimazole troches, though minimally absorbed systemically, may affect tacrolimus concentrations by inhibition of metabolic enzyme activity in the intestines. However, the magnitude of the impact of clotrimazole on tacrolimus dosing requirements to maintain goal levels is not well described. To assess this, tacrolimus dose adjustments and trough concentrations were retrospectively examined in 95 heart transplant recipients before and after the discontinuation of clotrimazole. The median percent tacrolimus dose change was an increase of 66.7% (IQR 28.6%, 100%) after clotrimazole discontinuation, and the median trough concentration percent change from baseline to the first trough after clotrimazole discontinuation (in the absence of a dose change) was -42.5% (IQR -52.3%, -30.9%). Five cases of allograft rejection were observed. In conclusion, clotrimazole troches exert a meaningful interaction with tacrolimus that requires close monitoring and dose adjustment. The data from this single-center study provide novel information that could guide providers on the degree of tacrolimus dose adjustment needed when discontinuing clotrimazole prophylaxis after heart transplantation.


[Helicobacter pylori infection. Frequency of first-line treatment failure].
Antibiotic resistance may hinder the efficacy of eradication therapy against Helicobacter pylori infection and it has become a major concern worldwide. Due to the relatively scarce evidence published in Argentina on this topic, our aim was to describe factors associated with H. pylori persistence after antibiotic treatment. The therapeutic failure rate was described among 81 patients with H. pylori gastritis treated in our Hospital with a post-treatment urea breath test to determine successful eradication. Mean age was 58 ± 12 and 43.2% were male subjects. H. pylori persistence was observed in 17.3% of subjects. Therapeutic failure was more common among patients receiving clarithromycin + amoxicillin therapy that among those receiving levofloxacin + amoxicillin (25% vs. 6.6%, p = 0.04). The following variables were assessed: age, gender, referral symptoms, smoking, anti-inflammatory use, diabetes, obesity, treatment type and duration. Clarithromycin-based therapy and male gender were associated with infection persistence on univariate analysis [OR 4.2 (1.1-15.6) and 5.2 (1.1-26.4)]. On multivariate analysis, clarithromycin-based was associated with infection persistence [5.38 (1.1-29.5)]. We conclude that clarithromycinbased therapy is significantly associated with treatment failure. This failure may be due to an elevated prevalence of H. pylori resistance to clarithromycin in the population under study and raises the question on the utility of such therapeutic alternative.


Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants.
Low birth weight infants are at risk for iron deficiency (ID). Most LBW infants have marginally low birth weight (MLBW, 2000-2500 g) and it is not known whether they benefit from iron supplements. The objective of this trial was to study the effects of iron supplementation in MLBW infants. In a randomized controlled trial, we assigned 285 healthy, MLBW infants to receive iron supplements at a dose of 0 (placebo), 1, or 2 mg/kg per day between 6 weeks and 6 months of age. Hemoglobin levels, ferritin levels, transferrin saturation, mean cell volume, and transferrin receptor levels were analyzed at 6 months. Growth and morbidity were monitored. Iron supplementation resulted in significant dose-dependent effects on hemoglobin and all iron status indicators at 6 months. The prevalence of ID at 6 months was 36% in the placebo group, 8.2% in the 1 mg/kg per day group, and 3.8% in the 2 mg/kg per day group (P<.001). The prevalence rates of ID anemia (IDA) were 9.9%, 2.7%, and 0%, respectively (P=.004). Among infants who were exclusively breastfed at 6 weeks, the prevalence of IDA was 18% in the placebo group. There were no significant differences between groups in growth or morbidity. MLBW infants have relatively high risks of ID and IDA, especially if they are breastfed. Iron supplementation at 2 mg/kg per day from 6 weeks to 6 months reduces this risk effectively, with no short-term adverse effects on morbidity or growth.


The Fagerström and AUDIT Tests as Probable Screening Tools in Oral Cancer and Their Correlation with CYP1A1, GSTM1, GSTP1, and GSTT1 Gene Expression.
Cancer is currently a major public health problem worldwide, with a marked increase of about 70% in the number of expected diagnosed cases over the next two decades. The amount of tobacco and alcohol consumed is calculated based on the subjective information provided by the user. Tobacco exposure can be assessed using the Fagerström Test for Cigarette Dependence (FTCD) and alcohol consumption by the Alcohol Use Disorder Identification Test (AUDIT). Forty-eight subjects answered the Fagerström, and AUDIT tests and we studied them as likely screening tools for oral cancer and their correlation with the expression of CYP1A1, GSTM1, GSTP1, and GSTT1 genes by the RT-qPCR method. There were significant differences in the AUDIT score and CYP1A1 expression between cancer and control groups. Participants in advanced stages, whether due to tumor size or regional metastasis, showed significant differences in the duration of tobacco use, FTCD, AUDIT score, and CYP1A1 expression when compared to patients in early stages. Among subjects without cancer, we found a significant correlation between participant age and GSTP1 expression. Furthermore, the expression of GSTP1 was significantly correlated with the number of cigarettes smoked per day, duration of tobacco use, and FTCD. Questionnaires designed to evaluate the degree of tobacco and alcohol exposure and dependence combined with gene expression tests can be useful to assess the risk of developing oral cancer. Furthermore, raising the awareness of individuals regarding their degree of dependence and encouraging them to participate in cessation programs are important educational measures for the prevention of tobacco-related malignancies.


[New derivatives of pantolactonyl N-phthalimido-2-arylpropanoate].
We present the crystal and molecular structures of two new N-phthalyl-3-amino-2-arylpropionic acid pantolactonyl ester derivatives with 4-fluorophenyl and 3,4-dimethoxyphenyl as the aryl group, 2,3,4,5-tetrahydro-4,4-dimethyl-2-oxofuran-3-yl 3-phthalimido-2-(4-fluorophenyl)propanoate, C23H20FNO6, and 2,3,4,5-tetrahydro-4,4-dimethyl-2-oxofuran-3-yl 3-phthalimido-2-(3,4-dimethoxyphenyl)propanoate ethyl acetate hemisolvate, C25H25NO8.0.5C4H8O2. This structural study confirms the S configuration of the C2 and validates the stereospecificity of our synthesis strategy.


Unveiling the phase behavior of CiEj non-ionic surfactants in water through coarse-grained molecular dynamics simulations.
Poly(oxyethylene) alkyl ethers, usually denoted by CiEj surfactants, exhibit a rich phase behavior in water, self-assembling to form a variety of 3-D structures with a controllable morphology that find multiple applications across different industrial segments. Hence, being able to describe and understand the effect of molecular structure on the phase behavior of these systems is highly relevant for the efficient design of new materials and their applications. Considering the promising results obtained over the last decade using the MARTINI model to describe ethylene-oxide containing compounds, an extensive assessment of the ability of such a model to describe the phase behavior of CiEj in water was carried out and results are presented here. Given the overall poor temperature transferability of the MARTINI model, mostly due to the lack of an accurate representation of hydrogen bonding, simulations were carried out at a single temperature of 333 K, where most phases are expected to occur according to experiments. Different chain lengths of both the hydrophobic and hydrophilic moieties, spanning a wide range of hydrophilic-lipophilic balance values, were investigated and the phase diagrams of various CiEj surfactants explored over a wide concentration range. The model was able to satisfactorily describe the effect of surfactant structure and concentration on mesophase formation. The stability and dimensions of the obtained phases, and the prediction of some unique features such as the characterization of a singular lamellar phase are presented. The results obtained in this work highlight both the predictive ability and the transferability of the MARTINI forcefield in the description of such systems. Moreover, the model was shown to provide adequate descriptions of the micellar phase in terms of micelle dimensions, critical micelle concentration, and average aggregation number.


Risk factors and immunomodulators use in steroid-refractory checkpoint inhibitor pneumonitis.
Checkpoint inhibitor pneumonitis (CIP) that does not respond to corticosteroids is termed steroid-refractory CIP. We aimed to find risk factors of steroid-refractory CIP and evaluate the management strategies of immunomodulators (IMs). Patients with CIP were identified between August 2019 and August 2022 retrospectively. Clinical characteristics, peripheral blood biomarkers, and radiologic images were collected. Among 1209 patients with solid tumor receiving programmed death (ligand)-1 antibody, 28 patients developed steroid-refractory CIP and 38 patients developed steroid-response CIP. Patients with steroid-refractory CIP had a higher proportion of previous interstitial lung disease (p=0.015) and grade 3-4 (p<0.001) at diagnosis. Otherwise, absolute neutrophil count (ANC), procalcitonin were higher and albumin was lower in steroid-refractory patients (ANC, p=0.009; procalcitonin, p=0.024; albumin, p=0.026). After multivariate analysis, grade 3-4 and higher ANC at diagnosis were confirmed to be independent risk factors for steroid-refractory CIP (grade, p=0.001; ANC, p=0.046). For grade 2 steroid-refractory CIP, additional IMs did not affect the prognosis (p=1.000). However, additional IMs reduced the risk of deterioration significantly in grade 3-4 steroid-refractory CIP (p=0.036). Grade 3-4 and higher peripheral blood ANC at diagnosis are associated with higher risk of steroid-refractory CIP. The use of additional IMs improves the outcome of grade 3-4 steroid-refractory CIP. These results can offer new insights to the decision-making of CIP management.


A possible role for plasmids in mediating the cell-cell proximity required for gene flux.
One of the major requirements for successful gene flux is a close proximity between participating organisms. In previous articles, we have proposed that plasmids act as powerful vehicles transporting genes collected by integration and transposition, mainly via the process of conjugation. However, in addition to conjugation, there are other processes, also mediated by plasmids, in which different cells come into very close contact with each other, such as symbiosis and the formation of multi-specific cellular communities. There is evidence that suggests that such intimate associations between cells may facilitate gene transfer events, even between distantly related organisms. Examples of symbiotic endosymbiotic, and parasitic associations provide evidence in support of the role of plasmids in bridging the genetic gap between species. In this purely theoretical article we attempt to conceptualize existing data on this subject, provide new insights and present testable predictions on how plasmids may facilitate gene flux by bringing cells together.


The health burden of pollution: the impact of prenatal exposure to air pollutants.
Exposure to atmospheric pollutants in both open and closed environments is a major cause of morbidity and mortality that may be both controlled and minimized. Despite growing evidence, several controversies and disagreements exist among the studies that have analyzed the effects of prenatal pollutant exposure. This review article aims to analyze primary scientific evidence of the effects of air pollution during pregnancy and the impact of these effects on the fetus, infant health, and in particular, the respiratory system. We performed a review of articles from the PubMed and Web of Science databases that were published in English within the past 5 years, particularly those related to birth cohorts that began in pregnancy with follow-up until the first years of life. The largest reported effects are associated with prenatal exposure to particulate matter, nitrogen dioxide, and tobacco smoke. The primary effects affect birth weight and other parameters of fetal biometry. There is strong evidence regarding the impact of pollutants on morbidity secondary to respiratory problems. Growing evidence links maternal smoking to childhood asthma and wheezing. The role of passive maternal smoking is less clear. Great heterogeneity exists among studies. There is a need for additional studies on birth cohorts to monitor the relationship between the exposure of pregnant women to pollutants and their children's progress during the first years of life.


The activities of lipoprotein lipase and of enzymes involved in triacylglycerol synthesis in rat adipose tissue. Effects of starvation, dietary modification and of corticotropin injection.
1. The effects of dietary modification, including starvation, and of corticotropin injection on the activities of acyl-CoA synthetase, glycerol phosphate acyltransferase, dihydroxyacetone phosphate acyltransferase, phosphatidate phosphohydrolase, diacylglycerol acyltransferase and lipoprotein lipase were measured in adipose tissue. 2. Lipoprotein lipase activities in heart were increased and those in adipose tissue were decreased when rats were fed on diets enriched with corn oil or beef tallow rather than with sucrose or starch. The lipoprotein lipase activity was lower in the adipose tissue of rats fed on the sucrose rather than on the starch diet. 3. Rats fed on the beef tallow diet had slightly higher activities of the total glycerol phosphate acyltransferase in adipose tissue than did rats fed on the sucrose or starch diet. The diacylglycerol acyltransferase and the mitochondrial glycerol phosphate acyltransferase activities were higher for the rats fed on the tallow diet than for those fed on the corn-oil diet. 4. Starvation significantly decreased the activities of lipoprotein lipase (after 24 and 48 h), acyl-CoA synthetase (after 24 h) and of the mitochondrial glycerol phosphate acyltransferase and the N-ethylmaleimide-insensitive dihydroxyacetone phosphate acyltransferase (after 48 h) in adipose tissue. The activities of the microsomal glycerol phosphate acyltransferase, diacylglycerol acyltransferase and the soluble phosphatidate phosphohydrolase were not significantly changed after 24 or 48 h of starvation. 5. The activities of lipoprotein lipase and phosphatidate phosphohydrolase in adipose tissue were decreased 15 min after corticotropin was injected into rats during November to December. No statistically significant differences were found when these experiments were performed during March to September. These differences may be related to the seasonal variation in acute lipolytic responses. 6. These results are discussed in relation to the control of triacylglycerol synthesis and lipoprotein metabolism.


Limiting dilution analysis of helper T-cell function. II. An approach to the study of the function of single helper T cells.
Procedures have been described which are suitable for experiments utilizing a microculture system whereby one can easily study the function of single helper T cells. These are: (a) the elimination of the background anti-hapten response by preliminary anti-theta + guinea-pig complement complement treatment of the 'hapten-primed' population; (b) the removal of any contaminating hapten-specific B cells from the carrier-primed population by passage through nylon wool; (c) irradiation of long-term primed 'nylon wool' enriched helper cells tp prevent cell division; (d) the partition of individual helper cells by limiting dilution.


Predictors and outcomes of cyberbullying among college students: A two wave study.
Existing research on cyberbullying has primarily focused on adolescents in cross-sectional survey studies, with less research focusing on college students or employed adults over longer periods of time. To extend this literature, the current study examined new predictors and outcomes of cyberbullying perpetration (CP) and victimization (CV) among college students from two different universities that were followed across two time points. Risk factors were measured in line with previous theoretical models, including biological or personality-related variables (e.g., low self-control, dark-side personality traits, empathy) and environmental variables (e.g., perceived social support, lack of rule clarity, and internet use). Additionally, we examined several possible outcomes of CV and CP. Results from path analyses revealed that involvement with traditional bullying (either as a perpetrator or a victim) as well as Machiavellianism significantly predicted CV and CP. With regard to the cross-lagged associations between CV and CP, we found that Time 1 CV predicted time 2 CP, but Time 1 CP did not predict Time 2 CV. That is, being a victim of cyberbullying during the Fall semester predicted involvement as a perpetrator in the Spring semester. However, being a perpetrator during the Fall semester did not predict being a victim during the Spring semester. Regarding outcomes, we found that CV significantly predicted anxiety, depression, and helping behavior, and CP significantly predicted deviant behavior, but not GPA nor alcohol consumption. These findings have practical implications for college students as well as university student support services.


Should doctors stop taking the generic history? A comparison of house officers' and nursing staff clerking in general surgery.
The purpose of this paper is to show how the implementation of the European Working Time Directive in August 2004 has dramatically decreased junior doctors' working hours, as a consequence of which new ways of working will need to be found. Traditionally both doctors and nurses record the same generic history (past medical history, social and family history, drug history and allergies) in their own notes. This is unnecessary duplication and maybe only nursing staff should record this information. This study is undertaken to identify the differences between junior doctors' and nurses' clerking to assess whether they are comparable. A prospective study of 100 case notes from elective and emergency admissions was undertaken. The completeness of various parts of the history and the recording of the vital signs were compared between nurses and house officers. The Past Medical History was complete in only 30 per cent of the house officers' notes and 42 per cent of nursing records. The social history was complete in all the nursing records but only 35 per cent of the doctors' notes. Nurses recorded a complete personal history more than doctors (62 per cent v. 13 per cent respectively). The drug history was poorly recorded in house officers' notes, being complete in 22 per cent, whereas this was complete in 73 per cent of nursing records. The record of the history of allergies was poor in both groups at just over 10 per cent. Finally 87 per cent of nurses managed to record vital signs but these were missing from nearly half of the house officers' notes. The study has shown that details of the generic medical history are recorded more completely by the nursing staff and only they should record this information. This will allow junior doctors more time to deal with the increased demands and reduced hours of work.


Determining variables to measure the impact of information systems on nursing practice.
Evaluations of nursing information systems (NIS) are complex. Current research and evaluative results on the impact of computer technology and information systems (IS) in nursing practice have been mixed. Clear cost and performance benefits have not been documented, because the variables and indicators of these gains are not well identified. The purpose of this discussion is to present a conceptual framework of the nursing practice and to group and organize specific variables, or indicators.


The effect of proteoglycans inhibited on the neurotropic growth of salivary adenoid cystic carcinoma.
To evaluate the relationship between inhibition of proteoglycans which secreted by salivary adenoid cystic carcinoma cell line (SACC-83) and the neurotropic ability of the tumor cells. The expression vector of short hairpin RNA (shRNA-WJ4) targeting xylosyltransferase-I gene was constructed and transfected into SACC-83 cells (group SACC83-WJ4), shRNA-HK used as negative control was transfected into SACC-83 cells (group SACC-83-HK), SACC-83 cells without transfection was used as black control (group SACC-83). The xylosyltransferase-I gene expression was measured by real-time PCR. The content of proteoglycans was detected by Blyscan Assay Kit. The effect of down-regulated proteoglycans on the perineural invasion of nude mice was observed. All data were analyzed by the software spss 13.0. The results showed that the transfected efficiency of shRNA was 43.3%. The expression of xylosyltransferase-I was inhibited by 43.0% 48 h after transfection of shRNA-WJ4. The content of proteoglycans was down-regulated by 30.25% 48 h after transfection. In the neurotropic experiment in vivo of nude mice, the rate of perineural invasion of group SACC-83-WJ4 was 33.33%, significantly lower than that of the negative control (100%) and the black control (100%) (P < 0.05). Xylosyltransferase-I gene of SACC cells was silenced by RNA interference technology, proteoglycans secretion was reduced and neurotropic invasion behavior of SACC was inhibited obviously.


Hepatitis B virus, hepatitis non-A, non-B virus and hepatitis delta virus in lyophilized antihemophilic factor: relative sensitivity to heat.
Lyophilized plasma derivatives are more stable to heat than when they are in the liquid state. Commercial Factor VIII (antihemophilic factor) was seeded with a measured quantity of hepatitis B virus. The contaminated material was then lyophilized and subjected to heat of 60 degrees C for 30 hr. Chimpanzees were inoculated with the heat-treated antihemophilic factor or sham-treated antihemophilic factor that had been held at 4 degrees C. Surprisingly, hepatitis B virus survived the heating procedure with no apparent loss in titer: the incubation period to appearance of HBsAg was that expected for the challenge dose of virus. Even more surprising, one chimpanzee (the recipient of the unheated antihemophilic factor) also developed non-A, non-B hepatitis and two chimpanzees (recipients of the heated antihemophilic factor) also developed delta hepatitis. Neither of these agents was a contaminant of the hepatitis B virus challenge pool, since the purity of this hepatitis B virus pool was established previously in chimpanzees. Thus, both a non-A, non-B agent and the delta agent apparently contaminated the commercial antihemophilic factor. This is the first direct evidence for contamination of antihemophilic factor with the delta agent and confirms previous seroepidemiologic evidence for its presence in pooled plasma derivatives. Subsequent inactivation studies were performed with antihemophilic factor experimentally contaminated with the Hutchinson strain of non-A, non-B hepatitis virus. In these studies, heating at 60 degrees C for 30 hr in the dry state rendered antihemophilic factor free of detectable non-A, non-B hepatitis virus.