Isolation and characterization of beta-cyclodextrin sulfates by preparative gradient polyacrylamide gel electrophoresis, capillary electrophoresis and electrospray ionization - mass spectrometry.
A beta-cyclodextrin sulfate mixture has been fractionated using discontinuous gradient polyacrylamide gel electrophoresis. Semidry electrotransfer of the sample onto a positively charged nylon membrane and visualization of a portion of this membrane with Alcian blue stain showed multiple bands. The bands were cut from the remaining portion of the membrane and after washing with 8 M urea, the beta-cyclodextrin sulfate fractions were eluted with 2 M sodium chloride and dialyzed. Analysis of each fraction using high resolution analytical gradient polyacrylamide gel electrophoresis as well as capillary electrophoresis, using indirect detection, showed some of the fractions to be pure while others were mixtures. Each beta-cyclodextrin sulfate fraction was complexed with a basic synthetic peptide and analyzed by electrospray ionization mass spectrometry to define the mass of the components in each mixture and thereby to determine the purity of each sample.


A twin study of genetic and environmental determinants of abnormal persistence of psychotic experiences in young adulthood.
Evidence suggests that subclinical psychotic experiences are more likely to cause transition to psychotic disorder if their expression becomes persistent. The study of longitudinal patterns of subclinical psychotic experiences may help to distinguish subgroups with transient and persistent psychotic symptoms, who may differ in risk of later psychosis. The current study investigated patterns of developmental course of subclinical psychotic experiences in a general population sample of 566 female twins, aged 18-45 years. The positive symptoms subscale of the Community Assessment of Psychic Experiences (CAPE), completed three times in 2 years, was analyzed with growth modeling. Using Latent Class Analysis, two developmental courses were distinguished: a Persistent and a Low (expression of subclinical psychotic experiences) group. The Persistent group reported significantly higher levels of depressive and negative symptoms and worse functioning in daily life. Childhood trauma (OR: 3.26, P < 0.0001) and stressful life events over the study period (OR: 3.15, P = 0.031) predicted membership of the Persistent group. Of the monozygotic (MZ) twins with their co-twin in the Persistent group, 49% also were in the Persistent group themselves (OR: 9.32, P < 0.0001), compared to only 14% in the dizygotic (DZ) co-twins (OR: 1.56, P = 0.42) (χ(2)(2) = 22.97; P < 0.001). The findings suggest that persistence of subclinical psychosis is influenced by both genetic and environmental factors, providing the possibility to study the (possibly modifiable) etiology underlying the longitudinal process of persistence of the early expression of psychosis liability.


Interventions Using Social Media for Cancer Prevention and Management: A Systematic Review.
Regarding cancer awareness, social media effectively promotes health and supports self-management. Given the diverse study designs, methodologies, and approaches of social media interventions in oncology, it is difficult to determine the effects of social media on cancer prevention and management. We aim to systematically review intervention studies using social media for cancer care. A systematic search, using 7 electronic databases (PubMed, Web of Science, CINAHL, Cochrane Library, Scopus, EMBASE, and PsycINFO), was conducted to identify surveys and interventions using contemporary social media tools with a focus on cancer. Of the 18 selected studies, 7 were randomized controlled trials. Most studies were conducted for all types of cancer, and some were conducted for breast cancer in the United States, with mostly white female participants. Facebook was the most frequently used platform. Most studies targeted healthy participants providing cancer prevention education. With social media platforms as part of a larger intervention, or the main component of interventions, interventions were overall feasible and showed a significant improvement in cancer prevention and management. Social media tools have the potential to be effective in delivering interventions for cancer prevention and management. However, there was a dearth of studies with rigorous study methodologies to test social media effects on various cancer-related clinical outcomes. Social media use in cancer care will facilitate improved communication and support among patients, caregivers, and clinicians and, ultimately, improved patient care. Clinicians need to carefully harness social media to enhance patient care and clinical outcomes.


Size-dependent density of zirconia nanoparticles.
The correlation between density and specific surface area of ZrO2 nanoparticles (NPs) was studied. The NPs were produced using a hydrothermal process involving microwave heating. The material was annealed at 1100 °C which resulted in an increase in the average grain size of the ZrO2 NPs from 11 to 78 nm and a decrease in the specific surface area from 97 to 15 m(2)/g. At the same time, the density increased from 5.22 g/m(3) to 5.87 g/m(3). This effect was interpreted to be the result of the presence of a hydroxide monolayer on the NP surface. A smaller ZrO2 grain size was correlated with a larger contribution of the low density surface layer to the average density. To prove the existence of such a layer, the material was synthesized using 50% heavy water. Fourier transform infrared spectroscopy (FTIR) permitted the identification of the -OD groups created during synthesis. It was found that the -OD groups persisted on the ZrO2 surface even after annealing at 1100 °C. This hydroxide layer is responsible for the decrease in the average density of the NPs as their size decreases. This study of the correlation between particle size and density may be used to assess the quality of the NPs. In most cases, the technological aim is to avoid an amorphous layer and to obtain fully crystalline nanoparticles with the highest density possible. However, due to the effect of the surface layers, there is a maximum density which can be achieved for a given average NP diameter. The effect of the surface layer on the NP density becomes particularly evident for NPs smaller than 50 nm, and thus, the density of nanoparticles is size dependent.


Hospital characteristics associated with highly automated and usable clinical information systems in Texas, United States.
A hospital's clinical information system may require a specific environment in which to flourish. This environment is not yet well defined. We examined whether specific hospital characteristics are associated with highly automated and usable clinical information systems. This was a cross-sectional survey of 125 urban hospitals in Texas, United States using the Clinical Information Technology Assessment Tool (CITAT), which measures a hospital's level of automation based on physician interactions with the information system. Physician responses were used to calculate a series of CITAT scores: automation and usability scores, four automation sub-domain scores, and an overall clinical information technology (CIT) score. A multivariable regression analysis was used to examine the relation between hospital characteristics and CITAT scores. We received a sufficient number of physician responses at 69 hospitals (55% response rate). Teaching hospitals, hospitals with higher IT operating expenses (>$1 million annually), IT capital expenses (>$75,000 annually) and hospitals with larger IT staff (> or = 10 full-time staff) had higher automation scores than hospitals that did not meet these criteria (p < 0.05 in all cases). These findings held after adjustment for bed size, total margin, and ownership (p < 0.05 in all cases). There were few significant associations between the hospital characteristics tested in this study and usability scores. Academic affiliation and larger IT operating, capital, and staff budgets are associated with more highly automated clinical information systems.


Molecular interactions between Vestigial and Scalloped promote wing formation in Drosophila.
Scalloped (Sd) and Vestigial (Vg) are each needed for Drosophila wing development. We show that Sd is required for Vg function and that altering their relative cellular levels inhibits wing formation. In vitro, Vg binds directly to both Sd and its human homolog, Transcription Enhancer Factor-1. The interaction domains map to a small region of Vg that is essential for Vg-mediated gene activation and to the carboxy-terminal half of Sd. Our observations indicate that Vg and Sd function coordinately to control the expression of genes required for wing development, which implies that Vg is a tissue-specific transcriptional intermediary factor of Sd.


State of the science: molecular classifications of breast cancer for clinical diagnostics.
Over the past few years, the study of genomics has embarked on developing gene expression-based classifications for tumors-an initiative that promises to revolutionize cancer medicine. High-throughput genomic platforms, such as microarray and SAGE, have found gene expression signatures that correlate to important clinical parameters used in current staging and are providing additional information that will improve standard of care. Although implementing a molecular taxonomy for prognosis and treatment would likely benefit cancer patients, there remain significant obstacles to using these assays within the current diagnostic framework. Since most genomic assays are being performed from fresh tissue, there is a need to either change the practice of formalin-fixing and paraffin-embedding tissue or adapting the assays for use on degraded RNA specimens. To date, even the most mature data sets, such as molecular classifications for breast cancer, still fall short of the number of patients needed to generalize the results to treating large populations. To implement these assays in large scale, there will need to be standardization of sample procurement, preparation, and analysis. Certainly, the greatest improvements in patient care will come through tailored therapies as genomics is coupled with clinical trials that randomize cohorts to different treatments. This manuscript reviews the current standards of care, presents progress that is being made in the development of genomic assays for breast cancer and discusses options for implementing these new tests into the clinical setting.


Moderate dietary protein and energy restriction modulate cAMP-dependent protein kinase activity in rat liver.
Very low protein diets result in a desensitization of hepatic cAMP signaling in rats, which is characterized by a loss of cAMP-dependent protein kinase (PKA) activity and type I regulatory subunit (RI). Here we have tested whether more moderate protein restriction (Trial 1) or energy restriction (Trial 2) also modulates hepatic PKA quantity and activity. In trial 1, weanling rats were allowed free access to diets containing normal protein (15%, AL-NP), moderately restricted protein (12.5%, AL-MP) and low protein (7.5%, AL-LP); in trial 2, rats were allowed free access to diet containing 15% (AL-NP) or 0.5% protein (very low protein, AL-VLP) or were energy restricted by pair-feeding a diet isonitrogenous to AL-NP but at 65% of the energy intake (ER-IN) for 14 d. Body weights were lower (P < 0.05) by d 14 in all restricted groups compared with the AL-NP group. The quantity of cytosolic RI was lower (P < 0.05) in AL-LP and AL-VLP, but not in AL-MP or ER-IN, compared with AL-NP. In contrast, there was no effect of diet on RI in the particulate fraction. RII was not changed by moderate and low protein diets in either the cytosol or particulate fraction. However, type II regulatory subunit (RII) was greater in the cytosol of ER-IN and in the particulate fraction of AL-VLP (P < 0.05) compared with AL-NP. Specific activity of PKA was lower in the cytosol and particulate fraction (P < 0.05) in the AL-VLP and ER-IN groups compared with the AL-NP group. In contrast, specific activity of PKA was maintained in cytosol from AL-LP, but lower in the particulate fraction (P < 0.05) compared with AL-NP. In summary, protein restricted-diets lower RI subunit in the cytosol; however, only in rats fed very low protein diets is this loss of RI associated with lower cytosolic PKA activity. In contrast, energy restriction lowers PKA activity in the cytosol and particulate fractions, independent of signficant reduction in RI or RII subunits. Taken together, these data indicate that moderate protein and energy restrictions have differential effects on activity and quantity of PKA.


[An autopsy case of chronic granulomatous disease diagnosed by biopsy].
This report concerns a male patient aged 25 years, diagnosed at the age of 12 years as suffering from chronic granulomatous disease. This patient had p47-phox deficiency. He was admitted to this hospital because of fever and dyspnea accompanied by right spontaneous pneumothorax. He failed to respond to medical treatment. He died from respiratory failure four months after admission. Autopsy demonstrated pigmented lipid histiocytes characteristic of CGD. These characteristic pigmented cells were distributed in the spleen, liver, lymph nodes and in the small intestine. As for the nature of the pigment, lipofuschin-like compound were identified. Granulomatous component was seen in the mucosa of the stomach obtained by operation. The presence and characteristic distribution of such pigmented macrophages in tissue in young adults may suggest the diagnosis of CGD.


Modelling metabolic networks using power-laws and S-systems.
Mathematical modelling has great potential in biochemical network analysis because, in contrast with the unaided human mind, mathematics has no problems keeping track of hundreds of interacting variables that affect each other in intricate ways. The scalability of mathematical models, together with their ability to capture all imaginable non-linear responses, allows us to explore the dynamics of complicated pathway systems, to study what happens if a metabolite, gene or enzyme is altered, and to optimize biochemical systems, for instance toward the goal of increased yield of some desired organic compound. Before we can utilize models for such purposes, we must define their mathematical structure and identify suitable parameter values. Because nature has not provided us with guidelines for selecting the best model design, the choice of the most useful model is not trivial. In the present chapter I show that power-law modelling within BST (Biochemical Systems Theory) offers guidance for model selection, construction and analysis that is otherwise difficult to find.


Oral adenoviral-based vaccines: historical perspective and future opportunity.
Adenoviral vaccines delivered orally have been used for decades to prevent respiratory illness, but are now being seriously explored again as a platform technology to make vaccines against a variety of pathogens. Years of use in military populations as a preventative measure for adenoviral infection have demonstrated the safety of oral administration of adenovirus. The advantages of using this approach as a platform technology for vaccines include rapid development and distribution, as well as ease of administration. Recent discoveries may allow this platform approach to reach the clinic within a few years.


The rational patient and beyond: implications for treatment adherence in people with psychiatric disabilities.
Many people with psychiatric disabilities do not benefit from evidence-based practices because they often do not seek out or fully adhere to them. One way psychologists have made sense of this rehabilitation and health decision process and subsequent behaviors (of which adherence might be viewed as one) is by proposing a "rational patient"; namely, that decisions are made deliberatively by weighing perceived costs and benefits of intervention options. Social psychological research, however, suggests limitations to a rational patient theory that impact models of health decision making. The research literature was reviewed for studies of rational patient models and alternative theories with empirical support. Special focus was on models specifically related to decisions about rehabilitation strategies for psychiatric disability. Notions of the rational patient evolved out of several psychological models including the health belief model, protection motivation theory, and theory of planned behavior. A variety of practice strategies evolved to promote rational decision making. However, research also suggests limitations to rational deliberations of health. (1) Rather than carefully and consciously considered, many health decisions are implicit, potentially occurring outside awareness. (2) Decisions are not always planful; often it is the immediate exigencies of a context rather than an earlier balance of costs and benefits that has the greatest effects. (3) Cool cognitions often do not dictate the process; emotional factors have an important role in health decisions. Each of these limitations suggests additional practice strategies that facilitate a person's health decisions. Old models of rational decision making need to be supplanted by multiprocess models that explain supradeliberative factors in health decisions and behaviors.


Guidelines for resident training in veterinary clinical pathology. I. Clinical chemistry.
The Education Committee of the American Society for Veterinary Clinical Pathology identified a need for improved structure and guidance of clinical pathology resident training in clinical chemistry. The committee's goal was to develop learning objectives and competencies in knowledge, abilities, and skills in clinical chemistry; provide options and ideas for training activities; and identify clinical chemistry resources useful for clinical pathology faculty, training program coordinators, and residents. Guidelines were developed and written with the input of Education Committee members and peer experts. The primary objectives of clinical chemistry training are: 1) to accrue a thorough, extensive, and relevant knowledge base of the types, principles, and properties of clinical chemistry tests and concepts of pathophysiology in animals; 2) to develop abilities to reason, think critically, and exercise judgment in clinical chemistry data interpretation, investigative problem-solving, and hypothesis-driven research; and 3) to acquire technical and statistical skills important in clinical chemistry and laboratory operations. These guidelines define expected competencies that will help ensure proficiency, leadership, and the advancement of knowledge in veterinary clinical chemistry and provide a useful framework for didactic and clinical activities in resident training programs. The learning objectives can readily be adapted to institutional and individual needs, interests, goals, and resources.


Yield of vancomycin-resistant enterococci and multidrug-resistant Enterobacteriaceae from stools submitted for Clostridium difficile testing compared to results from a focused surveillance program.
It has been suggested that a method of performing surveillance for vancomycin-resistant enterococci (VRE) is to screen specimens submitted for Clostridium difficile testing. We compared this approach to our focused surveillance program of high-risk units during October 1997 to compare the yield of VRE and multidrug-resistant Enterobacteriaceae (MDRE) with both methods. Of the stools submitted for C. difficile testing, 14% were positive for VRE or MDRE, whereas rectal swabs from routine surveillance yielded 11% VRE- or MDRE-positive results. Although stools submitted for C. difficile testing resulted in a higher percentage of positive cultures, 14 VRE- and 2 MDRE-positive patients from our high-risk population were missed because many patients had no stool submitted for C. difficile testing. Therefore, while screening stools submitted for C. difficile testing cannot replace our focused surveillance program, it appears advantageous to assess these stools at various intervals to detect new patient reservoirs of drug-resistant organisms that may benefit from routine surveillance cultures.


Antimicrobial activity of some medicinal plants used by herbalists in Eastern province, Kenya.
The aqueous extracts from medicinal plants commonly used by herbalists in Mbeere, and Embu districts of Eastern province, Kenya, were tested for their inhibitory activity against three selected strains of bacteria. All the selected plant extracts (infusions: 1.0 g sample in 100 ml water) investigated showed activity against Escherichia coli with inhibition zone diameters ranging from 5.8-18.0 mm. Terminalia brownii gave the largest inhibition zones against E. coli and Staphylococcus aureus. Vernonia lasiopus and Tithonia diversifolia were inactive to S. aureus and Bacillus subtilis, respectively. Eighteen and sixteen plants showed sensitivity of greater than 10 mm against S. aureus and B. subtilis, respectively. All control discs gave zones of inhibition of 12-24 mm, which were larger than those of the extracts. The present study validated the use of the selected medicinal plants by the herbalists in the treatment of bacterial ailments caused by the strains of bacteria investigated. Medicinal plants used for non-bacterial diseases also exhibited sensitivity towards bacterial strains tested. This implied they could be used as multi-purpose medicinal plants.


Novel mutations in the FOXC1 gene in Japanese patients with Axenfeld-Rieger syndrome.
Mutations in the forkhead transcription factor (FOXC1) gene have been shown to cause juvenile glaucoma associated with a variety of anterior-segment anomalies. The purpose of this study was to determine the ocular and genetic characteristics of two Japanese families with Axenfeld-Rieger syndrome (ARS). Genomic DNA was extracted from the leukocytes of six members of two families with ARS. The DNA from one exon of the FOXC1 gene were amplified by polymerase chain reaction (PCR) and directly sequenced. The patients received standard systemic and ophthalmological examinations. Sequence analysis of the FOXC1 gene revealed a novel Ala85Pro missense mutation in Helix1 in family 1 and a deletion of 17 nucleotides (437-453) in Wing1 and Beta2 within the forkhead domain of the FOXC1 gene in family 2. This deletion predicted a loss of the forkhead domain by a premature termination of translation. These mutations segregated with the ARS phenotype in an autosomal dominant pattern. The affected individuals in family 1 had posterior embryotoxon, iris hypoplasia, corectopia with early-onset severe glaucoma, atrial septal defect, aortic stenosis, and pulmonary stenosis. The affected members in family 2 had posterior embryotoxon and iris hypoplasia with early-onset glaucoma, and systemically they had hearing loss, hypertelorism, and telecanthus. A novel mutation in Helix1 and a novel deletion in Wing1 and Beta2 of the forkhead domain of the FOXC1 gene have been identified in two families with ARS. FOXC1 mutations cause a variety of developmental abnormalities in the anterior segment of the eye, and they also induce an elevation in intraocular pressures and early-onset glaucoma.


Impact of MUC1 mucin downregulation in the phenotypic characteristics of MKN45 gastric carcinoma cell line.
Gastric carcinoma is the second leading cause of cancer-associated death worldwide. The high mortality associated with this disease is in part due to limited knowledge about gastric carcinogenesis and a lack of available therapeutic and prevention strategies. MUC1 is a high molecular weight transmembrane mucin protein expressed at the apical surface of most glandular epithelial cells and a major component of the mucus layer above gastric mucosa. Overexpression of MUC1 is found in approximately 95% of human adenocarcinomas, where it is associated with oncogenic activity. The role of MUC1 in gastric cancer progression remains to be clarified. We downregulated MUC1 expression in a gastric carcinoma cell line by RNA interference and studied the effects on cellular proliferation (MTT assay), apoptosis (TUNEL assay), migration (migration assay), invasion (invasion assay) and aggregation (aggregation assay). Global gene expression was evaluated by microarray analysis to identify alterations that are regulated by MUC1 expression. In vivo assays were also performed in mice, in order to study the tumorigenicity of cells with and without MUC1 downregulation in MKN45 gastric carcinoma cell line. Downregulation of MUC1 expression increased proliferation and apoptosis as compared to controls, whereas cell-cell aggregation was decreased. No significant differences were found in terms of migration and invasion between the downregulated clones and the controls. Expression of TCN1, KLK6, ADAM29, LGAL4, TSPAN8 and SHPS-1 was found to be significantly different between MUC1 downregulated clones and the control cells. In vivo assays have shown that mice injected with MUC1 downregulated cells develop smaller tumours when compared to mice injected with the control cells. These results indicate that MUC1 downregulation alters the phenotype and tumorigenicity of MKN45 gastric carcinoma cells and also the expression of several molecules that can be involved in tumorigenic events. Therefore, MUC1 should be further studied to better clarify its potential as a novel therapeutic target for gastric cancer.


Auditory spatial attention using interaural time differences.
Previous probe-signal studies of auditory spatial attention have shown faster responses to sounds at an expected versus an unexpected location, making no distinction between the use of interaural time difference (ITD) cues and interaural-level difference cues. In 5 experiments, performance on a same-different spatial discrimination task was used in place of the reaction time metric, and sounds, presented over headphones, were lateralized only by an ITD. In all experiments, performance was better for signals lateralized on the expected side of the head, supporting the conclusion that ITDs can be used as a basis for covert orienting. The performance advantage generalized to all sounds within the spatial focus and was not dissipated by a trial-by-trial rove in frequency or by a rove in spectral profile. Successful use by the listeners of a cross-modal, centrally positioned visual cue provided evidence for top-down attentional control.


Vertical rectus abdominis musculocutaneous flap for chest wall reconstruction after irradiation.
We have used a contralateral vertical rectus abdominis musculocutaneous flap based upon the superior epigastric vessels in six patients to provide coverage after resection of locally recurrent breast carcinoma in irradiated tissues. Primary healing of defects as large as 16 cm X 35 cm has been obtained using this technique. Although there is no evidence to suggest that such a procedure significantly lengthens survival, it was clearly beneficial to the quality of life in these patients. Our results suggest that older patients with relatively indolent disease receive the greatest benefit from this procedure.


Hypoxic markers in non-small cell lung cancer (NSCLC) - A review.
Surgery, chemotherapy and radiotherapy have been the main pillars of cancer treatment. Some of the recent improvements in survival of other cancers can be attributed to novel treatment therapies. Such therapies mostly target specific molecules involved in cancer progression and metastasis. Development and clinical introduction of targeted therapies involve identification of new and potentially important molecules in cancer progression. The next important step is to evaluate its prognostic value. Prognostication by molecular markers is also important as this may identify subgroups of patients in need for additional treatment or not, which was not possible with the traditional clinic-pathological prognosticators. Hypoxic markers have been widely explored in the recent past for their prognostic efficacy in non-small cell lung cancer. The present review article will enlighten importance of hypoxic markers with special reference to non-small cell lung carcinoma.


Antimicrobial Titanium Surface via Click-Immobilization of Peptide and Its in Vitro/Vivo Activity.
The use of antimicrobial peptides (AMPs)-functionalized titanium implants is an efficient method for preventing bacterial infection. However, the attachment of AMPs to the surface of titanium implants remains a challenge. In this study, a "clickable" titanium surface was developed by using a silane coupling agent with an alkynyl group. The antimicrobial titanium implant was then constructed through the reaction between the "clickable" surface and azido-AMPs (PEG-HHC36:N3-PEG12-KRWWKWWRR) via click chemistry of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Such an antimicrobial titanium implant, with an AMP density of 897.4 ± 67.3 ng/cm2 (2.5 ± 0.2 molecules per nm2) on the surface, exhibited good and stable antimicrobial activity, inhibited 90.2% of Staphylococcus aureus and 88.1% of Escherichia coli after 2.5 h of incubation, and even inhibited 69.5% of Staphylococcus aureus after 4 days of degradation. The CCK-8 assay indicated that the antimicrobial titanium implant exhibited negligible cytotoxicity to mouse bone mesenchymal stem cells. In vivo assay illustrated that this implant could kill 78.8% of Staphylococcus aureus after 7 days. This method has great potential for the preparation of antimicrobial titanium implants and the prevention of infections in the clinic.


Open Surgical Stabilization of Glenohumeral Dislocations.
Traumatic anterior shoulder dislocations are the most common dislocations of the shoulder, and the recurrence rate is high when they are treated nonoperatively in young patients (<30 years old). This has led to a trend toward early surgical stabilization. Originally open Bankart repair was considered the standard of care, with good clinical outcomes and a low recurrence rate. However, the majority of Bankart repairs are now performed with newer arthroscopic techniques because of their potential advantages and similar results. Both open and arthroscopic repairs have been shown to decrease the recurrence rate to 6% to 23%. Although arthroscopic Bankart repair is now more common, open repair should be considered for younger patients participating in contact sports or military activity, osseous Bankart lesions, revision cases, shoulder instability with "subcritical" (20% to 25%) glenoid bone loss, ligamentous laxity, or cases not considered repairable with arthroscopic techniques. Therefore, knowing how to perform an open Bankart repair is essential. The major steps of the procedure are (1) preoperative planning, (2) induction of anesthesia, (3) patient positioning and setup, (4) examination under anesthesia, (5) possible arthroscopic examination of the shoulder, (6) incision along the anterior axillary fold, (7) exposure using the deltopectoral interval, (8) clavipectoral fascia incision, (9) vertical tenotomy of the subscapularis tendon, (10) dissection of the capsule from the subscapularis, (11) assessment of the quality of the capsule, (12) "T" capsulotomy, (13) repair of the Bankart lesion, (14) anterior capsulorrhaphy, (15) subscapularis repair, (16) possible closure of the rotator interval, (17) wound closure, and (18) postoperative rehabilitation. Studies have shown that surgical stabilization after traumatic anterior shoulder instability decreases the recurrence rate, and open and arthroscopic techniques have similar clinical outcomes.


Hormonal therapy for locally advanced prostate cancer.
A patient with locally advanced prostate cancer (stages C and D1) has a poor prognosis with a high risk of developing and dying of distant metastases. Hormonal therapy is the major form of systemic therapy for metastatic (stage D2) prostate cancer. The most commonly used forms of hormonal therapy are orchiectomy, diethylstilbestrol, and luteinizing hormone releasing hormone, agonists that prevent the stimulation of tumor cells by testosterone. They produce a 60%-80% symptomatic or objective response rate, but their ability to prolong overall survival remains uncertain. Surgical adrenalectomy, hypophysectomy, and pharmacologic adrenal suppression prevent the clinically less significant adrenal androgen stimulation of tumor cells. Antiandrogens competitively inhibit the interaction between androgens and cytosolic androgen receptors. Complete androgen blockade (luteinizing hormone releasing hormone agonist and antiandrogen) was initially espoused to be superior to single-agent hormonal therapy, but preliminary results from a multigroup randomized trial suggest that it has only a minimal advantage. The benefit of hormonal therapy in stages C and D1 prostate cancer at the time of diagnosis has not been clearly established. Available studies are few, and most often they are uncontrolled or include only small numbers of patients. However, they suggest that the early use of hormonal therapy prolongs disease-free survival but does not prevent ultimate disease progression or prolong overall survival. Hormone receptor assays may be helpful in the selection of patients who would benefit from early hormonal therapy.


beta- and gamma-catenin expression in oral dysplasia.
Cell-cell and cell-matrix interactions regulate important cellular functions; they involve a number of specialised molecules and the corresponding receptors, among which a key role is played by cadherins and the associated catenins. Deregulation of these molecules has been associated with tumour progression in many human malignancies. While catenins expression has been extensively studied in many human cancers, including oral carcinoma (OSCC), less is known about their expression in oral epithelial dysplasia. The objective of this study was to evaluate the expression of these proteins in a large group of displastic lesions of the oral mucosa and their relation with subsequent malignant transformation. Expression of beta- and gamma-catenin was investigated by immunohistochemistry using specific monoclonal antibodies in 49 cases of oral epithelial dysplasia and 10 samples of normal oral mucosa. The presence and absence of beta- and gamma-catenin staining was expressed differently in relation to dysplasia grade; while the degree of dysplasia became more severe, we observed a statistically significant loss and/or reduction of catenins expression, the loss of the exclusive membranous expression and a cytoplasmic delocalisation. Progression to OSCC occurred in 10 out of our 49 cases (20.4%); all of them, except one, showed a concurrent and concordantly located beta- and gamma-catenin staining even, if no statistically significant differences were found between cases progressed to invasive OSCC or not. Catenins physiology alterations may be involved in the transformation process; however, the role of catenins expression as possible prognostic markers in precancerous oral lesions seems to be limited. Nonetheless, further studies on larger series of samples are necessary in order to clarify the role of catenins expression in oral carcinogenesis from both a biological and clinical point of view.


Natural and anthropogenic events influence the soundscapes of four bays on Hawaii Island.
The soundscapes of four bays along the Kona Coast of Hawaii Island were monitored between January 2011 and March 2013. Equivalent, unweighted sound pressure levels within standard 1/3rd-octave bands (dB re: 1μPa) were calculated for each recording. Sound levels increased at night and were lowest during the daytime when spinner dolphins use the bays to rest. A tsunami provided an opportunity to monitor the soundscape with little anthropogenic component. We detected a decrease in sound levels and variability in one of the busiest bays. During the daytime in the 3.15kHz 1/3rd octave band, we detected 92 loud outliers from vessels, aquaculture, and military mid-frequency active sonar. During one military mid-frequency active sonar event sound levels reached 45.8dB above median ambient noise levels. The differences found in the bays illustrate the importance of understanding soundscapes to effectively manage noise pollution in marine ecosystems.


Unequal staffing: A snapshot of nurse staffing in critical care units in New South Wales, Australia.
Abstract A growing body of research provides evidence of the link between nurse-to-patient ratios (NTPRs) and skill mix with adverse patient outcomes. This paper reports an investigation into nurse staffing patterns, skill mix and patient movement in critical care units in NSW, Australia. A 'snapshot' of staffing patterns and patient movement over 1 week in October 2012 was obtained by use of a cross-sectional design using retrospective survey and administrative data. A wide variation was found in NTPRs, skill mix and the number of nursing staff vacancies in coronary care and high dependency units. These variations suggest that the quality of patient care may vary between facilities in New South Wales.


Effects of Water Deficit Irrigation on Phenolic Composition and Antioxidant Activity of Monastrell Grapes under Semiarid Conditions.
The high phenolic compound content of grapes makes them an important source of natural antioxidants, among other beneficial health properties. Vineyard irrigation might affect berry composition and quality. Regulated deficit irrigation (RDI) is a widely used strategy to reduce the possible negative impact of irrigation on grapes, improving grape composition and resulting in water savings. Monastrell grapevines (Vitis vinifera L.) grown in eastern Spain were subjected to two water regime strategies: rainfed (non-irrigation) and RDI. The content of anthocyanins, flavonols, flavanols, hydroxybenzoic and hydroxycinnamic acids, and stilbenes was determined by HPLC and was related with total phenolic content and three antioxidant activity methods (ABTS, DPPH, and ORAC). The study aimed to evaluate and compare the phenolic composition and antioxidant potential of Monastrell grapes. The rainfed regime concentrated grapes in terms of phenolic compounds. Thus, total content of anthocyanins, flavonols, flavanols, hydroxybenzoic acids, and total phenols were higher in the rainfed grapes than in the RDI ones. Besides, the rainfed grapes doubled their antioxidant potential with respect to the RDI grapes with the ORAC method. Total phenolic content and antioxidant activity by ORAC assay positively correlated with most of the total phenolic compounds analyzed. This study demonstrates how field practices can modulate final grape composition in relation to their antioxidant activity.


Fine structure of the motile cells and flagella in a member of the Actinoplanaceae (Actinomycetales).
The motile cells (sporangiospores) of an undescribed member of the Actinoplanaceae are studied by electron microscopy as shadowed, negatively stained, and sectioned preparations. The rod-shaped spores exhibit a typically bacterial internal structure. However, a single tubular structure (rhapidosome) is positioned just inside the site of flagellar attachment of each spore and is oriented perpendicular to the direction of the flagella. Flagella arise from basal dises and pass through the plasma membrane and the two-layered cell wall to become associated with other flagella to function as a posteriorly directed unit. Each flagellum consists of a helical band or ribbon which dissociates into 5 or 6 subfibrils.


A new paradigm of cardiovascular risk factor modification.
Atherosclerotic cardiovascular diseases (CVDs) are the leading cause of death and disability in the United States. While multiple studies have demonstrated that modification of atherosclerotic cardiovascular risk factors (CVRFs) significantly reduces morbidity and mortality rates, clinical control of CVDs and CVRFs remains poor. By 2010, the American Heart Association seeks to reduce coronary heart disease, stroke, and risk by 25%. To meet this goal, clinical practitioners must establish new treatment paradigms for CVDs and CVRFs. This paper discusses one such treatment model--a comprehensive atherosclerosis program run by physician extenders (under physician supervision), which incorporates evidence-based CVD and CVRF interventions to achieve treatment goals.


A Lab-on-Chip Analyzer for in Situ Measurement of Soluble Reactive Phosphate: Improved Phosphate Blue Assay and Application to Fluvial Monitoring.
Here, we present a new in situ microfluidic phosphate sensor that features an improved "phosphate blue" assay which includes polyvinylpyrrolidone in place of traditional surfactants-improving sensitivity and reducing temperature effects. The sensor features greater power economy and analytical performance relative to commercially available alternatives, with a mean power consumption of 1.8 W, a detection limit of 40 nM, a dynamic range of 0.14-10 μM, and an infield accuracy of 4 ± 4.5%. During field testing, the sensor was continuously deployed for 9 weeks in a chalk stream, revealing complex relations between flow rates and phosphate concentration that suggest changing dominance in phosphate sources. A distinct diel phosphorus signal was observed under low flow conditions, highlighting the ability of the sensor to decouple geochemical and biotic effects on phosphate dynamics in fluvial environments. This paper highlights the importance of high resolution in situ sensors in addressing the current gross under-sampling of aquatic environments.


Immune mechanisms in epileptogenesis.
Epilepsy is a chronic brain disorder that affects 1% of the human population worldwide. Immune responses are implicated in seizure induction and the development of epilepsy. Pre-clinical and clinical evidence have accumulated to suggest a positive feedback cycle between brain inflammation and epileptogenesis. Prolonged or recurrent seizures and brain injuries lead to upregulation of proinflammatory cytokines and activated immune responses to further increase seizure susceptibility, promote neuronal excitability, and induce blood-brain barrier breakdown. This review focuses on the potential role of innate and adaptive immune responses in the pathogenesis of epilepsy. Both human studies and animal models that help delineate the contributions of brain inflammation in epileptogenesis will be discussed. We highlight the critical role of brain-resident immune mediators and emphasize the contribution of brain-infiltrating peripheral leukocytes. Additionally, we propose possible immune mechanisms that underlie epileptogenesis. Several proinflammatory pathways are discussed, including the interleukin-1 receptor/toll-like receptor signaling cascade, the pathways activated by damage-associated molecular patterns, and the cyclooxygenase-2/prostaglandin pathway. Finally, development of better therapies that target the key constituents and processes identified in these mechanisms are considered, for instance, engineering antagonizing agents that effectively block these pathways in an antigen-specific manner.


Data compression of the ECG using neural network for digital Holter monitor.
A data-compression algorithm for digital Holter recording using artificial neural networks (ANNs) is described. A three-layer ANN that has a hidden layer with a few units is used to extract features of the ECG (electrocardiogram) waveform as a function of the activation levels of the hidden layer units. The number of output and input units is the same. The backpropagation algorithm is used for learning. The network is tuned with supervised signals that are the same as the input signals. One network (network 1) is used for data compression and another (network 2) is used for learning with current signals. Once the network is tuned, the common waveform features are encoded by the interconnecting weights of the network. The activation levels of the hidden units then express the respective features of the waveforms for each consecutive heartbeat.


Role of Natural Radiosensitizers and Cancer Cell Radioresistance: An Update.
Cancer originates from genetic mutations accumulation. Cancer stem cells have been depicted as tumorigenic cells that can differentiate and self-renew. Cancer stem cells are thought to be resistant to conventional therapy like chemotherapy and radiation therapy. Radiation therapy and chemotherapy damage carcinomic DNA cells. Because of the ability of cancer stem cells to self-renew and reproduce malignant tumors, they are the subject of intensive research. In this review, CSCs radioresistant mechanisms which include DNA damage response and natural radiosensitizers have been summed up. Reactive oxygen species play an important role in different physiological processes. ROS scavenging is responsible for regulation of reactive oxygen species generation. A researcher has proved that microRNAs regulate tumor radiation resistance. Ionizing radiation does not kill the cancer cells; rather, IR just slows down the signs and symptoms. Ionizing radiation damages DNA directly/indirectly. IR is given mostly in combination with other chemo/radiotherapies. We briefly described here the behavior of cancer stem cells and radioresistance therapies in cancer treatment. To overcome radioresistance in treatment of cancer, strategies like fractionation modification, treatment in combination, inflammation modification, and overcoming hypoxic tumor have been practiced. Natural radiosensitizers, for example, curcumin, genistein, and quercetin, are more beneficial than synthetic compounds.


Derivation and validation of a model to predict daily risk of death in hospital.
As electronic patient data from automated hospital databases become increasingly available, it is important to explore the ways in which these data could be used for the purposes other than patient care, such as quality assurance and improvement. To determine if information from automated patient databases can be used to derive a model that can predict patients' daily risk of death in hospital. Such a model could be used to improve the ability to risk-adjust hospital mortality rates. Retrospective cohort study of 159,794 hospitalizations at The Ottawa Hospital between April 1, 2004 and March 31, 2009. The model was derived using time-dependent Cox regression methods on a random two-thirds of admissions. The model was validated by applying the coefficients to the other third of admissions. Inpatient mortality was 5%. The final model included: patient age; admission type; intensive care unit status; alternative level of care status; and separate scores for patient comorbidity, in-hospital procedures, and acute illness (using information from 14 laboratory tests). In the validation set, the model had excellent discrimination (c-statistic 0.879, 95% confidence interval: 0.872-0.886) and calibration in all risk strata over all admission days. We found that information from our hospital's automated patient databases could be used to accurately predict patients' daily risk of death in hospital. The predictions from this model could be used in quality of care analyses to more accurately risk-adjust hospital mortality rates and by hospitals to improve triage processes and patient flow.


Massive in Silico Study of Noble Gas Binding to the Structural Proteome.
Noble gases are chemically inert, and it was therefore thought they would have little effect on biology. Paradoxically, it was found that they do exhibit a wide range of biological effects, many of which are target-specific and potentially useful and some of which have been demonstrated in vivo. The underlying mechanisms by which useful pharmacology, such as tissue and neuroprotection, anti-addiction effects, and analgesia, is elicited are relatively unexplored. Experiments to probe the interactions of noble gases with specific proteins are more difficult with gases than those with other chemicals. It is clearly impractical to conduct the large number of gas-protein experiments required to gain a complete picture of noble gas biology. Given the simplicity of atoms as ligands, in silico methods provide an opportunity to gain insight into which noble gas-protein interactions are worthy of further experimental or advanced computational investigation. Our previous validation studies showed that in silico methods can accurately predict experimentally determined noble gas binding sites in X-ray structures of proteins. Here, we summarize the largest reported in silico reverse docking study involving 127 854 protein structures and the five nonradioactive noble gases. We describe how these computational screening methods are implemented, summarize the main types of interactions that occur between noble gases and target proteins, describe how the massive data set that this study generated can be analyzed (freely available at group18.csiro.au), and provide the NDMA receptor as an example of how these data can be used to understand the molecular pharmacology underlying the biology of the noble gases. We encourage chemical biologists to access the data and use them to expand the knowledge base of noble gas pharmacology, and to use this information, together with more efficient delivery systems, to develop "atomic drugs" that can fully exploit their considerable and relatively unexplored potential in medicine.


Host odor and visual stimulus interaction during intratree host finding behavior ofRhagoletis pomonella flies.
Responses ofRhagoletis pomonella (Walsh) (Diptera: Tephritidae) flies to host fruit visual stimuli (apples or models of apples) and chemical stimuli (synthetic apple volatile blend) were studied in semidwarf field-caged apple trees. Three different fruit or model densities (1, 4, or 16 fruit or models/ tree) and two odor release rates [ca. 0.7μg/hr (close to the natural release rate of a ripe apple) and ca. 500μg/hr (amount of odor released by commercially sold apple maggot traps)] were tested. Individually released flies were followed as they moved within a tree for a maximum of 20 min. We recorded three-dimensional search paths followed by foraging flies and computed such variables as total relative distance traveled before alighting on a fruit or model, track length between individual alightment sites, and directness of flight to fruits or models. Effect of odor on propensity to alight on fruit or models and host-searching behavior prior to alighting on fruit or on models varied according to fruit or model color and density. If the fruit visual stimulus was strong (e.g., red color), odor did not increase the probability of finding fruit or fruit models. As the visual stimulus became progressively weaker (red to green to clear), odor (irrespective of concentration) appeared to aid flies during the fruit-finding process. As density of fruit or models increased, the probability of flies finding a fruit or model also increased (e.g., 50% of flies found a red fruit model at 1 model/tree while 90% found a red model at 16 models/tree; 4% of flies found a clear model with odor at 1 model/tree while 35% found a clear model with odor at 16 models/tree). Findings reported elsewhere indicate thatR. pomonella flies are able to discover a point source of odor (an odor-bearing tree in a patch of trees) by flying upwind (in the tree patch) in response to intermittent exposure to odor. Findings here indicate that after arrival on a host tree (point source), flies discover individual apparent and abundant host fruit on the basis of vision. If fruit are less apparent or scarce, odor appears to interact with vision during the fruit-finding process.


Tactics of the tobacco industry in an Arab nation: a review of tobacco documents in Oman.
Few studies have investigated tobacco industry interference in the tobacco control policies of Arab nations. This paper explores the tactics used by the industry to subvert tobacco control policies in Oman and offers lessons on how to prevent such interference in the future. We searched the Truth Tobacco Industry Documents Archive using the word 'Oman', names of government institutions, policymakers and local tobacco distributors. Extracted data were noted chronologically by key elements of tobacco control measures. Gulf Cooperation Council (GCC) Health Ministers' Council resolutions on tobacco control were also reviewed. Out of 1020 tobacco documents located, 327 were closely related to policy interference. Documents revealed that the industry met key government officials, offered in-kind services, used local diplomatic missions to influence Omani policymakers, opposed smoking bans, delayed regulations to lower tar and nicotine content of cigarettes, and to require effective health warnings, circumvented a tobacco advertising, promotion and sponsorship ban and provided voluntary codes as an alternative to effective regulations. Additionally, industry representatives lobbied individual countries in the GCC to veto tax increments and defeat consensus on agreed resolutions of the Health Ministers' Council. The tobacco industry interfered in all key public health policies aimed to reduce tobacco use in Oman. There is an urgent need for the Omani government to enforce the Civil Code of Conduct and develop guidelines for all policymakers through implementing Article 5.3 of the WHO Framework Convention on Tobacco Control to curb the tobacco epidemic.


Spinal cord injury-induced expression of the immune-regulatory chemokine interleukin-16 caused by activated microglia/macrophages and CD8+ cells.
Spinal cord injury (SCI) elicits a strong inflammatory response that readily participates in lipid oxygenation, edema formation, apoptotic cell death, and tissue remodeling. Because cytokines determine the postinjury inflammatory milieu, the authors analyzed the expression of the immunomodulatory chemokine interleukin- 16 (IL- 16) after SCI. The authors detected a highly significant, persistent, lesional accumulation of parenchymal IL-16+ microglia/macrophages, which reached a maximal level 3 days postinjury compared with control rats. The majority of cells that demonstrated positive labeling for IL-16 also had positive labeling for ED1 (> 70%) and OX-8/CD8; these cells exhibited the morphological hallmarks of activated microglia/macrophages and pronounced MHC Class II expression. In contrast to IL-16+ED1+ cells, IL-16+ microglia/macrophages that coexpressed OX-8 were exclusively seen in the pannecrotic lesion core. In addition, clustering of IL-16+ cells was observed in perivascular Virchow-Robin-like spaces in areas of the primary injury (lesion core) and in immediately adjacent areas of secondary injury. Furthermore, on Day 3 postinjury, IL-16+ microglia/macrophages were frequently observed in a perineuronal position. The early lesional accumulation of IL-16+ microglia/macrophages suggests a role for IL-16 in the early postinjury immune response such as recruitment and activation of immune cells, leading to microvessel clustering and secondary damage progression.


Lipid specificity of the immune effector perforin.
Perforin is a pore forming protein used by cytotoxic T lymphocytes to remove cancerous or virus-infected cells during the immune response. During the response, the lymphocyte membrane becomes refractory to perforin function by accumulating densely ordered lipid rafts and externalizing negatively charged lipid species. The dense membrane packing lowers the capacity of perforin to bind, and the negatively charged lipids scavenge any residual protein before pore formation. Using atomic force microscopy on model membrane systems, we here provide insight into the molecular basis of perforin lipid specificity.


Parenting for Lifelong Health for Young Children: a randomized controlled trial of a parenting program in South Africa to prevent harsh parenting and child conduct problems.
Parenting programs suitable for delivery at scale in low-resource contexts are urgently needed. We conducted a randomized trial of Parenting for Lifelong Health (PLH) for Young Children, a low-cost 12-session program designed to increase positive parenting and reduce harsh parenting and conduct problems in children aged 2-9. Two hundred and ninety-six caregivers, whose children showed clinical levels of conduct problems (Eyberg Child Behavior Inventory Problem Score, >15), were randomly assigned using a 1:1 ratio to intervention or control groups. At t0 , and at 4-5 months (t1 ) and 17 months (t2 ) after randomization, research assistants blind to group assignment assessed (through caregiver self-report and structured observation) 11 primary outcomes: positive parenting, harsh parenting, and child behavior; four secondary outcomes: parenting stress, caregiver depression, poor monitoring/supervision, and social support. ClinicalTrials.gov (NCT02165371); Pan African Clinical Trial Registry (PACTR201402000755243); Violence Prevention Trials Register (http://www.preventviolence.info/Trials?ID=24). Caregivers attended on average 8.4 sessions. After adjustment for 30 comparisons, strongest results were as follows: at t1 , frequency of self-reported positive parenting strategies (10% higher in the intervention group, p = .003), observed positive parenting (39% higher in the intervention group, p = .003), and observed positive child behavior (11% higher in the intervention group, p = .003); at t2, both observed positive parenting and observed positive child behavior were higher in the intervention group (24%, p = .003; and 17%, p = .003, respectively). Results with p-values < .05 prior to adjustment were as follows: At t1 , the intervention group self-reported 11% fewer child problem behaviors, 20% fewer problems with implementing positive parenting strategies, and less physical and psychological discipline (28% and 14% less, respectively). There were indications that caregivers reported 20% less depression but 7% more parenting stress at t1 . Group differences were nonsignificant for observed negative child behavior, and caregiver-reported child behavior, poor monitoring or supervision, and caregiver social support. PLH for Young Children shows promise for increasing positive parenting and reducing harsh parenting.


Atomic bomb and leukemia.
Characteristic features of leukemia among atomic bomb survivors were studied. The ratio of a single leukemia type to all leukemias was highest for CML in Hiroshima, and the occurrence of CML was thought to be most characteristic for atomic bomb radiation induced leukemia. In the distribution of AML subtypes of FAB classification, there was no M3 cases in 1Gy or more group, although several atypical AML cases of survivors were observed. Chromosome study was conducted using colony forming cells induced by hemopoietic stem cells of peripheral blood of proximal survivors. Same chromosome aberrations were observed in colony forming cells and peripheral blood of proximal survivors.


The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of (188)re-labeled anti-E6 C1P5 antibody in cervical cancer in mice.
Human papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer, and >95% of all cervical cancers have detectable HPV sequences. The authors of this report recently demonstrated the efficacy of radioimmunotherapy (RIT) targeting viral oncoprotein E6 in the treatment of experimental cervical cancer. They hypothesized that the pretreatment of tumor cells with various agents that cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors. HPV type 16 (HPV-16)-positive CasKi cells were treated in vitro with up to 6 grays of external radiation, or with the proteasome inhibitor MG-132, or with unlabeled anti-E6 antibody C1P5; and cell death was assessed. The biodistribution of (188)Re-labeled C1P5 antibody was determined in both control and radiation MG-132-treated CasKi tumor-bearing nude mice. (188)Re-C1P5 antibody demonstrated tumor specificity, very low uptake, and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pretreatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by the authors' previous in vivo studies in a CasKi tumor model. The current results indicated that pretreatment of cervical tumors with the proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate nonviable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor the further development of RIT for cervical cancers targeting viral antigens.


Recruitment of herpes simplex virus type 1 immediate-early protein ICP0 to the virus particle.
Although the herpes simplex virus type 1 (HSV-1) tegument is comprised of a large number of viral and cellular proteins, how and where in the cell these proteins are recruited into the virus structure is poorly understood. We have shown previously that the immediate-early gene product ICP0 is packaged by a mechanism dependent on the major tegument protein VP22, while others have shown a requirement for ICP27. We now extend our studies to show that ICP0 packaging correlates directly with the ability of ICP0 to complex with VP22 in infected cells. ICP27 is not, however, present in this VP22-ICP0 complex but is packaged into the virion in a VP22- and ICP0-independent manner. Biochemical fractionation of virions indicated that ICP0 associates tightly with the virus capsid, but intranuclear capsids contained no detectable ICP0. The RING finger domain of ICP0 and the N terminus of VP22 were both shown to be essential but not sufficient for ICP0 packaging and complex formation. Strikingly, however, the N-terminal region of VP22, while unable to form a complex with ICP0, inhibited its translocation from the nucleus to the cytoplasm. PML degradation by ICP0 was efficient in cells infected with this VP22 mutant virus, confirming that ICP0 retains activity. Hence, we would suggest that VP22 is an important molecular partner of ICP0 that controls at least one of its activities: its assembly into the virion. Moreover, we propose that the pathway by which VP22 recruits ICP0 to the virion may begin in the nucleus prior to ICP0 translocation to its final site of assembly in the cytoplasm.


Delivery room continuous positive airway pressure and early pneumothorax in term newborn infants.
To assess the association between delivery room (DR) continuous positive airway pressure (CPAP) and pneumothorax (PT) in term newborns. Two studies performed in community hospitals used data extracted from computerized records of term newborns. Infants receiving positive pressure ventilation in the DR were excluded. Tabulated data included receipt of DR CPAP, PT on the day of birth, and gestational age (GA). In a case-control study from 2001-2013, infants with PT were compared to controls without PT but with respiratory distress or hypoxia persisting from birth for receipt of DR CPAP. In a cohort study from 2014-2016, infants receiving and not receiving DR CPAP were compared for the incidence of PT. In the case-control study, data were obtained for 169 cases and 850 controls. Compared to controls, PT infants were more likely to have received DR CPAP (16.8% vs. 40.2%, respectively, P < 0.001). Logistic regression revealed DR CPAP (Adjusted Odds Ratio [AOR] = 3.30, 95% confidence interval [CI] = 2.31, 4.72, P < 0.001) and GA (AOR = 1.21, 95% CI = 1.05, 1.39, P = 0.009) to be independent predictors of early PT.In the cohort study, PT was observed in 0.1% of 9255 control infants not receiving DR CPAP and 4.8% of 228 infants receiving DR CPAP (P < 0.001). In logistic regression analyses, DR CPAP significantly predicted PT (OR = 59.59, 95% CI = 23.34, 147.12, P < 0.001) and remained a significant predictor of PT after controlling for gestational age. Respiratory conditions treated with CPAP in delivery rooms are associated with increased risk of PT. A cause-and-effect relationship between CPAP and PT cannot be claimed in this study. Further research is needed to better understand this relationship.


The monotony of transferrin and esterase electrophoretic patterns in pirarucu, Arapaima gigas (Schinz, 1822) from Santa Cruz Lake, Tefé River, Amazonas, Brazil.
Starch gel electrophoresis was used for examining the transferrin gene locus (Tf) and two esterase gene loci (Est-1 and Est-D1) of a pirarucu (Arapaima gigas) population sample collected from Santa Cruz Lake, Tefé River, Amazonas, Brazil. The Tf locus was tentatively classified as being polymorphic, showing two double-banded patterns (Tf(12) and Tf(22)) of the three theoretically expected ones (Tf(11), Tf(12) and Tf(22)), presumably controlled by two co-dominant alleles, Tf(1) and Tf(2). The monotony detected in pirarucu Tf locus genotypes showing a very high proportion of the double-banded heterozygote pattern Tf(12) (95% of the sampled individuals) may indicate the possibility of their having come from representatives of the same brood begotten by a pair of fish, where a single-banded Tf(11) homozygote pattern male would have crossed with a single-banded Tf(22) homozygote pattern female, or vice versa. One zone of electrophoretic activity was detected in esterase, presumably controlled by a monomorphic Est-1 locus with the fixed allele Est-1(1) where all individuals showed the single-banded Est-1(11) homozygote pattern. Esterase-D also displayed one zone of electrophoretic activity, presumably controlled by a monomorphic Est-D1 locus with a fixed allele Est-D1(1) where all individuals revealed the single-banded Est-D1(11) genotype pattern. The monotony comprised by single-banded genotype patterns in both esterase systems tested may also indicate the possibility of the individuals from the sample examined having come from representatives of the same brood begotten by a pair of fish with both the male and female having the same genotypes.


Stroop test in Spanish: children's norms.
Three hundred and forty-nine first to sixth graders (ages 6 years and 6 months to 12 years and 11 months) from two Mexican schools (one private and one public) were administered the Comalli-Kaplan version of the Stroop test in Spanish, as part of a larger protocol. Findings are discussed in the context of current interpretations of the Stroop test, considered a measure of inhibition. No gender differences were observed. Parental education was a statistically significant but unimportant predictor of performance. Developmental norms are provided, together with analyses of the amount of interference encountered (in time and errors) for each age.


The Sigma-1 Receptor Is a Novel Target for Improving Cold Preservation in Rodent Kidney Transplants.
Kidney transplantation is the preferred treatment for patients with end-stage kidney disease. Maintaining organ viability between donation and transplantation, as well as minimizing ischemic injury, are critically important for long-term graft function and survival. Moreover, the increasing shortage of transplantable organs is a considerable problem; thus, optimizing the condition of grafts is a pivotal task. Here, rodent models of kidney transplantation and cold storage were used to demonstrate that supplementation of a preservation solution with Sigma-1 receptor (S1R) agonist fluvoxamine (FLU) reduces cold and warm ischemic injury. Post-transplant kidney function was improved, histological injury was mitigated, and mRNA expression of two tubular injury markers-kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin-was robustly reduced. In addition, renal inflammation was diminished, as shown by reduced leukocyte infiltration and pro-inflammatory cytokine expression. In the cold ischemia model, FLU ameliorated structural injury profoundly after 2 h as well as 24 h. The reduced number of TUNEL-positive and Caspase 3-positive cells suggests the anti-apoptotic effect of FLU. None of these beneficial effects of FLU were observed in S1R-/- mice. Of note, organ damage in FLU-treated kidneys after 24 h of cold storage was similar to just 2 h without FLU. These results indicate that S1R agonists can prolong storage time and have great potential in improving organ preservation and in alleviating the problem of organ shortages.


Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. To estimate risk and mortality reduction stratified by mutation and prior cancer status. Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.


Endothelial therapy of atherosclerosis and its risk factors.
Atherosclerosis is a chronic systemic disease of the vasculature with an inflammatory component. It accounts for the majority of cardiovascular morbidity and mortality in industrialized countries and its incidence is increasing in developing countries. The impairment of vascular endothelial cell function in atherosclerosis and in conditions associated with increased cardiovascular risk is an important determinant of disease progression. The reduction of endothelium-dependent relaxation in the coronary and systemic circulation in atherosclerosis is in part due to decreased bioavailability of nitric oxide and increased release of oxygen-derived free radicals. Atherosclerosis also increases the formation of vasoconstrictors and growth factors, adhesion of leukocytes, thrombosis, inflammation, cell proliferation, as well as increases in vascular tone. Here we review mechanisms and therapeutic approaches to improve endothelial pathways in atherosclerosis. Restoration of NO bioactivity through pharmacological inhibition of the renin-angiotensin system, statin therapy, or endothelin receptor blockade, ameliorates vascular function in experimental hypercholesterolemia, hypertension and heart failure. These treatments also have therapeutic benefit for patients at risk or with overt atherosclerosis, to reduce vascular and myocardial complications of this disease.


Low incidence of multidrug-resistant organisms in patients with healthcare-associated pneumonia requiring hospitalization.
Healthcare-associated pneumonia (HCAP) includes a broad spectrum of patients who acquire pneumonia through outpatient contact with the health system. Although limited prospective data exist, it has been suggested that all patients with HCAP should receive empirical therapy with a multidrug regimen directed against drug-resistant organisms. We aimed to determine the differences in aetiology and outcomes between HCAP groups and a community-acquired pneumonia (CAP) group, and to assess the presence of antibiotic-resistant bacteria. All consecutive non-immunocompromised adults hospitalized with pneumonia were prospectively included from 2001 to 2009. Patients who had had recent contact with the health system through nursing homes, home healthcare programmes, haemodialysis clinics or prior hospitalization were considered to have HCAP. A total of 2245 patients with pneumonia were hospitalized through the emergency room, of whom 577 (25.7%) had HCAP. Significant differences in causative pathogens were found between groups. Antibiotic-resistant organisms, including methicillin-resistant Staphylococcus aureus, resistant strains of Pseudomonas aeruginosa, and extended-spectrum β-lactamase-producing Enterobacteriaceae, were scarce in all groups. In contrast, aspiration pneumonia was particularly frequent. No differences were found regarding inappropriate initial empirical antibiotic therapy between groups. Overall mortality was higher in patients who attended a hospital or haemodialysis clinic or received intravenous chemotherapy in the 30 days before pneumonia, and among patients who resided in a nursing home or long-term-care facility. In conclusion, most HCAP patients could be treated in the same way as patients with CAP, after carefully ruling out the presence of aspiration pneumonia.


[Radiation and the heart].
The use of radiotherapy in the management of malignant tumors causes low or high radiation exposure doses to normal tissues and undesired side effects may occur in early and late period following irradiation. All mediastinal structures, lungs and heart can exposure to total therapeutic dose during radiation therapy for thoracal or mediastinal malignancies such as Hodgkin disease and breast cancer. While early deaths following irradiation are caused by primary malignancies among these patients, long-term mortalities are resulted from radiation-induced morphological and functional organ abnormalities. Cardiac changes are the most frequently seen. Significant cardiac anatomical changes occur particularly in pericardium, myocardium, valves and result in severe cardiac dysfunctions after 10 to 20 years following administration of radiation into mediastinal or thoracal areas. The precision of the development of radiation-induced cardiovascular complications has increased due to achieving the complete cure of primary tumor and to the extended survival time of irradiated cases by using advanced radiotherapy and adjuvant chemotherapy modalities. Early detection of radiation-induced morphological changes leading to cardiac dysfunction offers the possibility for early intervention such as administration of cardiovascular drugs and/or cardiac surgery in order to reduce or delay severe irreversible late complications.


Bro1 coordinates deubiquitination in the multivesicular body pathway by recruiting Doa4 to endosomes.
Ubiquitination directs the sorting of cell surface receptors and other integral membrane proteins into the multivesicular body (MVB) pathway. Cargo proteins are subsequently deubiquitinated before their enclosure within MVB vesicles. In Saccharomyces cerevisiae, Bro1 functions at a late step of MVB sorting and is required for cargo protein deubiquitination. We show that the loss of Bro1 function is suppressed by the overexpression of DOA4, which encodes the ubiquitin thiolesterase required for the removal of ubiquitin from MVB cargoes. Overexpression of DOA4 restores cargo protein deubiquitination and sorting via the MVB pathway and reverses the abnormal endosomal morphology typical of bro1 mutant cells, resulting in the restoration of multivesicular endosomes. We further demonstrate that Doa4 interacts with Bro1 on endosomal membranes and that the recruitment of Doa4 to endosomes requires Bro1. Thus, our results point to a key role for Bro1 in coordinating the timing and location of deubiquitination by Doa4 in the MVB pathway.


Foot-and-mouth disease outbreaks in Egypt during 2013-2014: Molecular characterization of serotypes A, O, and SAT2.
Foot-and-mouth disease virus (FMDV) serotypes A, O and South African Territories (SAT2) are endemic in Egypt; each is presented by a number of partially related topotypes and lineages, depending on their geographical origin. Continuous mutations and the emergence of new topotypes that lead to occasional vaccination failures were frequently recorded, so this study aimed to genetically characterize the circulating FMD virus strains in Egypt during 2013 and 2014 outbreaks, focusing on amino acids variations in VP1 region. A total of 51 oral tissue samples were collected from cattle and buffaloes in 13 farms, and 38 individual cases showed clinical signs suspected to be FMD in six Egyptian Governorates (Cairo, Giza, Qaliubia, Fayoum, Sharquia, and Assiut). FMDV in collected samples was characterized by reverse transcription-polymerase chain reaction (RT-PCR) amplification of full VP1 region, sequencing, and phylogenetic analysis. Out of 51 samples, 44 (86.27%) were positive by RT-PCR using universal primers. Serotype O was predominant and detected in 31 samples (70.45%), serotype A was detected in 9 samples (20.45%), and then serotype SAT2 was identified in 4 samples (9.10%). Sequencing and phylogenetic analysis of VP1 demonstrated clustering of serotype O, A, and SAT2 in EA-3 topotype, ASIA topotype, and topotype VII, respectively. Serotype O is closely related to O/SUD/8/2008 with 94.6% identity but showed 14.6% differences from vaccine strain (O/PanAsia-2) of ME-SA topotype. Furthermore, Serotype A and SAT2 were closely related to recent circulating Egyptian isolates and vaccine strains type A/EGY/1/2012 (Asia topotype, lineage Iran-05) with identity 96.4% and vaccine strain of SAT2/EGY/A/2012 (topotype VII, lineage SAT2/VII/ALX-12) with identity 95.3%, respectively. The present study recommended further studies of serotype O to determine the immunogenic relationship between the vaccine strain and the new strains to attain maximum protection against circulating viruses.


Anhedonia in young people with first episode psychosis: a longitudinal study.
Aim: Previous research observed deficits in pleasure experience in chronic schizophrenia, but little is known about anhedonia in early psychosis. Aim of this study is: (1) to examine anhedonia in distinct help-seeking subgroups of young people identified through the First Episode Psychosis (FEP) criteria, (2) to investigate its correlations with psychopathology in the FEP sample, and (3) to monitor longitudinally its stability in the FEP group along 1-year follow-up period.Materials and methods: All participants (137 FEP and 95 nonpsychotic psychiatric controls [i.e. non-FEP]), aged 13-35 years, completed the Comprehensive Assessment of At-Risk Mental States (CAARMS), the Schizotypal Personality Questionnaire - Brief version (SPQ-B), the Brief O-LIFE questionnaire (BOL), and the World Health Organization Quality of Life - Brief version (WHOQOL-BREF). We used two different indexes of anhedonia: CAARMS 'Anhedonia' item 4.3 and BOL 'Introvertive Anhedonia' subscale scores.Results: In comparison with non-FEP, FEP patients showed higher baseline anhedonia scores. After 1-year follow-up period, FEP individuals had a significant decrease in severity of anhedonia scores. In the FEP group, anhedonia showed significant, enduring (over time) correlations with impaired role functioning, negative symptoms, comorbid depression, poorer self-perceived quality of life and specific schizotypal personality traits (i.e. interpersonal deficits).Conclusions: Anhedonia is relevant in the early phase of psychosis and its severity is associated with functioning deterioration and a bad quality of life.


In vivo construction of liver tissue by implantation of a hepatic non-parenchymal/adipose-derived stem cell sheet.
Subcutaneous hepatocyte sheet implantation is an attractive therapeutic option for various liver diseases. However, this technique is limited by the availability of hepatocytes. Thus, the use of hepatic non-parenchymal cells (NPCs) containing small hepatocytes, which have the ability to proliferate more rapidly than mature hepatocytes, for transplantation has been suggested. The aim of our study was to construct liver tissue subcutaneously in rats by implanting NPC sheets co-cultivated with adipose-derived stem cells (ADSCs), which produce certain angiogenic factors. We crafted NPC-ADSC sheets on temperature-responsive culture dishes. NPCs formed functioning bile canaliculi and stored glycogen. In addition, their ability to produce albumin was not inferior to that of hepatocytes. Albumin production increased over time when co-cultivated with ADSCs. We then implanted the co-cultivated cell sheets subcutaneously. The co-cultivated sheets retained glycogen, formed bile canaliculi, showed signs of vascularization and survived subcutaneously without pre-vascularization. These results suggest that NPCs can be a viable option in cell therapy for liver diseases. This technique using co-cultivated cell sheets may be useful in the field of regenerative medicine. Copyright © 2017 John Wiley & Sons, Ltd.


Background in 99Tcm DTPA renography evaluated by the impact of its components on individual kidney glomerular filtration rate.
Following injection for renography, 99Tcm-labelled diethylenetriamine-pentacetic acid (DTPA) rapidly enters the extravascular space. Background therefore comprises two components, a falling intravascular signal and an extravascular signal which initially rises. We estimated the relative magnitudes of these two components in terms of their impact on the calculation of differential renal function and individual kidney glomerular filtration rate (IKGFR) from the second phase of the 99Tcm-labelled DTPA renogram in 56 paediatric kidneys. We expressed each of the two background signals as a GFR equivalent. The GFR equivalent of the intravascular signal recorded from a peri-renal background region of interest (ROI), scaled by a factor equal to the ratio of the pixel numbers in the renal and background ROIs, was -39 (S.D. 14) ml min-1. The GFR equivalent of the extravascular signal was smaller than this and opposite to it at 23 (S.D. 10) ml min-1, giving a median ratio for the two equivalents of -1.68. Because of the opposing effects of the two background components on the second phase of the renogram, techniques recently described for the quantification of IKGFR from the renogram, and which eliminate the intravascular component, offer no theoretical advantage over a method of analysis which uses 'direct' subtraction of the total background signal. In practice, however, these new techniques are superior in their handling of 'noisy' data, consistently giving a lower coefficient of variation in their estimation of IKGFR.


Efficient determination of protocatechuic acid in fruit juices by selective and rapid magnetic molecular imprinted solid phase extraction coupled with HPLC.
Magnetic molecular imprinted polymers (MMIPs) have been prepared as solid phase material to selectively extract protocatechuic acid (PCA) from fruit juices with high capacity and fast binding kinetics. The resulting MMIPs were characterized by TEM, FT-IR, TGA, and VSM. The adsorption process between PCA and MMIPs followed Langumuir adsorption isotherm with maximum adsorption capacity at 7.5 mg/g and pseudo-second-order reaction kinetics with fast binding kinetics (equilibrium time at 40 min). In addition, the prepared MMIPs showed rapid magnetic separation (10 s) and reusability (retained 94.9% after six cycles). Subsequently, MMIPs were successfully applied for selective enrichment and determination of PCA from fruit juices (0.45 μg/mL in grape juice but not detected in apple juice, pineapple juice, orange juice, and peach juice) with satisfactory recoveries (92-107%). The results indicated that synthesized MMIPs can be used for efficient and selective extraction of PCA from complex matrices.


Cytogenetics of the land snails Cantareus aspersus and C. mazzullii (Mollusca: Gastropoda: Pulmonata).
A cytogenetic study was carried out on the chromosomes and nuclear DNA contents of the land snails Cantareus aspersus and C. mazzullii (Gastropoda: Pulmonata). Chromosomes were studied using Giemsa staining, banding methods and fluorescent in situ hybridization (FISH) with three repetitive DNA probes [18S rDNA, (GATA)(n) and (TTAGGG)(n)]. Results were very similar in the two species both showing (1) 54 bi-armed chromosomes [submetacentrics (SM) + metacentrics (M) + subtelocentrics (ST)]; (2) 10 terminal NORs after sequential application of rDNA FISH and silver staining; (3) uniform DNA fluorescence with CMA(3) and DAPI staining and (4) genomic composition considerably enriched both in highly- and moderately-repeated DNAs. The telomeric (TTAGGG)(n) sequence hybridized with the termini of all of the chromosomes in the two species. In spite of their apparent karyological uniformity, flow cytometry DNA assays showed that C. aspersus and C. mazzullii are characterized by different nuclear DNA content (C values are 3.58 and 3.08 pg, respectively) and slightly different base composition in their genomes. Present data on GS and AT% in C. mazzullii and C. aspersus confirm the trend toward high GS values and GC percentages among land snails.


Evolutionary transitions in learning and cognition.
We define a cognitive system as a system that can learn, and adopt an evolutionary-transition-oriented framework for analysing different types of neural cognition. This enables us to classify types of cognition and point to the continuities and discontinuities among them. The framework we use for studying evolutionary transitions in learning capacities focuses on qualitative changes in the integration, storage and use of neurally processed information. Although there are always grey areas around evolutionary transitions, we recognize five major neural transitions, the first two of which involve animals at the base of the phylogenetic tree: (i) the evolutionary transition from learning in non-neural animals to learning in the first neural animals; (ii) the transition to animals showing limited, elemental associative learning, entailing neural centralization and primary brain differentiation; (iii) the transition to animals capable of unlimited associative learning, which, on our account, constitutes sentience and entails hierarchical brain organization and dedicated memory and value networks; (iv) the transition to imaginative animals that can plan and learn through selection among virtual events; and (v) the transition to human symbol-based cognition and cultural learning. The focus on learning provides a unifying framework for experimental and theoretical studies of cognition in the living world. This article is part of the theme issue 'Basal cognition: multicellularity, neurons and the cognitive lens'.


Subtyping of European foot-and-mouth disease virus strains by nucleotide sequence determination.
The VP1-coding regions of foot-and-mouth disease virus strains from 18 recent European outbreaks and of 9 strains isolated more than 20 years ago and used in part as vaccines were determined by direct cDNA sequencing. Comparison of the sequences revealed that most of the isolated outbreak viruses are closely related to the vaccine strains used. Isolates from the Italian epizootic of 1984 to 1985 correspond, for example, to the vaccine strain A5 Parma 62; the outbreak in 1984 in Bernbeuren, Federal Republic of Germany, was induced by A5 Allier 60; outbreaks in 1982 in Funen, Denmark, and in Murchin, German Democratic Republic, were caused by O1 Lausanne 65. Viruses isolated during the 1983 Iberian epizootic show a close relationship to the vaccine strain A5 Allier 60 but were probably derived from another not yet identified vaccine strain from Spain. Only two minor outbreaks in the Federal Republic of Germany, A Aachen in 1976 and O Wuppertal in 1982, did not correspond to the classical European strains but were obviously introduced from outside. We suggest that nucleotide sequence analysis should be used as a standard method of diagnosis, because when compared with other techniques it more clearly reveals the origin and course of epizootics and offers the possibility of preventing further outbreaks.


Utilisation of pharmacy-based sexual and reproductive health services: a quantitative retrospective study.
To explore the utilisation of pharmacy-based sexual and reproductive health services (SRHS) in order to optimise delivery and identify barriers to access. The health provider Umbrella offers six SRHS from over 120 pharmacies in Birmingham (England). In this retrospective study, data collected between August 2015 and August 2018 were used to analyse uptake, user characteristics and attendance patterns according to day of the week. A total of 60 498 requests for a pharmacy service were included in the analysis. Emergency contraception (50.4%), condoms (33.1%) and STI self-sampling kits (9.6%) accounted for more than 90% of all requests. A lower uptake of services was observed for the contraceptive injection (0.6%), oral contraception (5.4%) and chlamydia treatment (1.0%). Services were most likely to be requested by those self-identifying as female (85.6%), and those aged 16-24 years (53.8%). Based on available ethnicity data (n=54 668), most requests for a service were made by White/White British individuals (43.4%) and Asian/Asian British people (23.1%). The largest number of services were delivered on Mondays (20.9%) and the lowest on Sundays (5.0%). A high proportion of requests for services on Saturdays (57.0%), Sundays (67.6%) and Mondays (54.4%) were made by females presenting for emergency contraception. The evaluation of healthcare utilisation is important to help refine and optimise the delivery of services. However, information relating to pharmacy-based SRHS is scarce and often limited to a single type of service provision. Overall, a wide range of pharmacy-based services were accessed by a diverse range of people, suggesting that pharmacies are a suitable provider of many SRHS. However, the routinely collected data analysed in the study had several limitations restricting the analysis. Sexual health providers should ensure they collect data which are as comprehensive as is possible in order to help understand the utilisation of services.


Copayments for medication in 2014. Final rule.
This document adopts as a final rule, without change, an interim final rule amending the Department of Veterans Affairs (VA) medical regulations to freeze the copayments required for certain medications provided by VA until December 31, 2014. Under that rule, the copayment amounts for all veterans were maintained at the same rates as they were in 2013, which were $8 for veterans in priority groups 2-6 and $9 for veterans in priority groups 7 and 8. On January 1, 2015, the copayment amounts may increase based on the prescription drug component of the Medical Consumer Price Index (CPI-P).


Plasmodium falciparum Maf1 Confers Survival upon Amino Acid Starvation.
The target of rapamycin complex 1 (TORC1) pathway is a highly conserved signaling pathway across eukaryotes that integrates nutrient and stress signals to regulate the cellular growth rate and the transition into and maintenance of dormancy. The majority of the pathway's components, including the central TOR kinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence. Plasmodium falciparum encodes a putative ortholog of the RNA polymerase (Pol) III repressor Maf1, which has been demonstrated to modulate Pol III transcription in a TOR-dependent manner in a number of organisms. Here, we investigate the role of P. falciparum Maf1 (PfMaf1) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an altered Maf1 expression profile, we demonstrated that proper Maf1 expression is necessary for survival of the dormancy-like state induced by prolonged amino acid starvation and is needed for full recovery from other stresses that slow or stall the parasite cell cycle. This Maf1 mutant is defective in the downregulation of pre-tRNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stress-responsive regulator of structural RNA transcription is conserved in P. falciparum Recent work has demonstrated that parasites carrying artemisinin-resistant K13 alleles display an enhanced ability to recover from drug-induced growth retardation. We show that one such artemisinin-resistant line displays greater regulation of pre-tRNA expression and higher survival upon prolonged amino acid starvation, suggesting that overlapping, PfMaf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation.IMPORTANCE Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The TOR pathway is a well-studied signaling pathway found throughout eukaryotes that is known to integrate a variety of signals to regulate organismal growth in response to starvation and other stresses. The human malaria parasite Plasmodium falciparum appears to have lost the TOR pathway over the course of evolution, and it is unclear how the parasite modulates its growth in response to starvation and drug treatment. Here, we show that Maf1, a protein regulated by TOR in other eukaryotes, plays an important role in maintaining the parasite's viability in the face of starvation and other forms of stress. This suggests that PfMaf1 is a component of a yet-to-be-described nutrient and stress response pathway.


Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas.
Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL. We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL. Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value. We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL. [Media: see text].


Mycotic aneurysm complicating staphylococcal endocarditis.
To emphasize the role of noninvasive diagnostic investigative methods and their importance in early detection of mycotic aneurysm related to staphylococcal endocarditis, and of monitoring therapy or identifying complications. Two patients with mycotic aneurysm that developed as complications of staphylococcal endocarditis are presented. The first patient had mesenteric artery mycotic aneurysm and presented with sudden rupture one month after initial diagnosis of mitral valve infective endocarditis and completion of a full course of antimicrobial therapy. The second patient had multiple cerebral mycotic microaneurysms and presented with hemorrhagic cerebral embolization from aortic valve infective endocarditis. The first patient died because of ischemic cerebral edema 48 h after rupture of the mesenteric artery mycotic aneurysm and massive hemoperitoneum, which was treated surgically with distal ileal resection and ileostomy. The second patient was alive two years after prolonged antimicrobial therapy and aortic replacement to treat moderate aortic regurgitation and progressive left ventricular enlargement. Mycotic aneurysm is a rare complication of infective endocarditis but has a high mortality rate because of its early or late potential catastrophic rupture. Diagnosis by noninvasive diagnostic imaging techniques of mycotic aneurysm before rupture would be beneficial for its treatment.