Setting the distal and posterior condyle of the femoral component to restore the medial pre-arthritic femoral articular surface results in better outcomes after total knee arthroplasty.
The present study of total knee arthroplasty (TKA) describes an intra-operative method that determines the direction and quantifies the magnitude of deviation of the distal and the posterior medial and lateral (DM, PM, DL, and PL) condyle of the femoral component relative to the pre-arthritic femoral articular surface. For each femoral condyle, the deviations were categorized, and an analysis determined which had better or worse Forgotten Joint Score (FJS), Oxford Knee Score (OKS), and WOMAC scores at 1-year follow-up. Four academic arthroplasty surgeons supervised a cemented primary CR TKA (Triathlon, Stryker) on 120 consecutive patients. 103 that completed patient-reported outcome measures (PROMs) were analyzed. The surgeon determined the direction and the magnitude of deviation of the condyle of the femoral component by intraoperatively measuring the thickness of the femoral resection, adding compensations of 1 mm for the saw kerf and 2 mm for worn cartilage, and then subtracting the thickness of the femoral component's condyle. For each femoral condyle, a Kruskal-Wallis test determined the categories of deviation with clinically important and significantly different 1-year PROMs. A 1 to 2.5 mm and 3 mm or more proximal deviation of the DM condyle of the femoral component worsened the median FJS by 35 and 40 points, OKS by 9 and 14 points, and WOMAC score by 9 and 17 points, respectively, relative to those with a -0.5 to 0.5 mm deviation (p < 0.01). A 1 to 2.5 mm and 3 mm or more anterior deviation of the PM condyle of the femoral component worsened the FJS by 34 and 48 points, OKS by 7 and 13 points, and WOMAC scores by 8 and 16 points, respectively (p < 0.01). Deviations of the DL and PL condyle of the femoral component did not affect PROMs (p ≥ 0.13). Although many factors can affect PROM, such as patient expectations, the surgeon should understand that setting the DM and the PM condyles of the femoral component within 1 mm of the patient's pre-arthritic femoral articular surface can potentially result in better FJS, OKS, and WOMAC scores at 1 year. II, Prospective cohort study.


Increased risk of upstage when combinations of breast lesions of uncertain malignant potential are found on core needle biopsy: The need for surgical excision.
Management of breast lesions of uncertain malignant potential diagnosed at core needle biopsy (CNB) is controversial due to variable upstage rate (UR) with surgical excision (SE). We performed an IRB-approved retrospective analysis of adult women who underwent CNB demonstrating atypical ductal hyperplasia (ADH), flat epithelial atypia, radial scar, or intraductal papilloma then SE between 2010 and 2022. We evaluated CNB pathology for combination diagnoses (CD), defined as multiple primary lesions or primary with lobular neoplasia (LN), and surgical pathology for upstage. 719 patients were included. UR was 12.2% (88/719). CD experienced higher UR than pure (17.7% (45/254) vs. 9.2% (43/465), p = 0.001). ADH/LN had the highest UR of all CD (34.6% (9/26), p = 0.001). Increased size (15.6 vs. 10.5 mm, p < 0.001), distance from nipple (79 vs. 66 mm, p < 0.001), and personal history of breast cancer (p = 0.04) were associated with UR. CD was associated with increased UR. ADH/LN had the highest UR.


Components of the RNAi machinery that mediate long-distance chromosomal associations are dispensable for meiotic and early somatic homolog pairing in Drosophila melanogaster.
Homolog pairing is indispensable for the proper segregation of chromosomes in meiosis but the mechanism by which homologs uniquely pair with each other is poorly understood. In Drosophila, somatic chromosomes also undergo full homolog pairing by an unknown mechanism. It has been recently demonstrated that both insulator function and somatic long-distance interactions between Polycomb response elements (PREs) are stabilized by the RNAi machinery in Drosophila. This suggests the possibility that long-distance pairing interactions between homologs, either during meiosis or in the soma, may be stabilized by a similar mechanism. To test this hypothesis, we have characterized meiotic and early somatic chromosome pairing of homologous chromosomes in flies that are mutant for various components of the RNAi machinery. Despite the identification of a novel role for the piRNA machinery in meiotic progression and synaptonemal complex (SC) assembly, we have found that the components of the RNAi machinery that mediate long-distance chromosomal interactions are dispensable for homologous chromosome pairing. Thus, there appears to be at least two mechanisms that bring homologous sequences together within the nucleus: those that act between dispersed homologous sequences and those that act to align and pair homologous chromosomes.


Bullous and cicatricial pemphigoid. Clinical, histopathologic, and immunopathologic correlations.
A study of the records, biopsies, and immunopathologic data from 84 patients with bullous pemphigoid and 60 patients with cicatricial pemphigoid revealed that patients with bullous pemphigoid and negative or perhaps very low titer of circulating antibasement-membrane antibodies may constitute a distinct subgroup of patients with bullous pemphigoid. This group contained more women than men, had increased mucous membrane involvement, and had higher incidences of hypothyroidism, positive antinuclear antibody tests, and malignancy than did the other patients with bullous pemphigoid. Six of 41 patients with bullous pemphigoid who were given sulfapyridine or dapsone responded to these drugs, and these 6 constitute another group of patients necessitating further study. In nine patients, localized pemphigoid was found. The lesions were of two types: those occurring in sun-exposed areas and those occurring pretibially. Three of 57 patients with cicatricial pemphigoid had circulating antibasement-membrane antibodies. The clinical extent of disease in cicatricial pemphigoid was less extensive in our series than that previously seen at our institution. This was probably due to the earlier and more accurate diagnosis afforded by immunopathologic studies and to wider appreciation of the disease among nondermatologists.


Well-differentiated papillary villoglandular adenocarcinoma of the uterine cervix.
This article presents a rare case of well-differentiated papillary villoglandular adenocarcima of the uterine cervix. This patient had vaginal bleeding and her disease was limited to the cervix. Since 1989, a total of 41 cases have been reported in the literature as a distinct entity. In the past, this tumor was included with other varieties of adenocarcinomas of the cervix and not as a separate entity. Due to its excellent prognosis, papillary villoglandular adenocarcinoma of the cervix, may be treated by a procedure less radical than a hysterectomy when the tumor is superficial with no vascular or lymphatic invasion. Recognition of this entity and separation from other varieties of adenocarcinomas of the uterine cervix are warranted.


[Hungarian Diet and Nutritional Status Survey -- the OTAP2009 study. V. Intake of microelements in the Hungarian population].
For a healthy status the adequate intake of microelements is vital. The Hungarian Diet and Nutritional Status Survey - joining to the European Health Interview Survey - studied the dietary habits of the Hungarian population. The present paper demonstrates the microelement intake. While the intake of iron, copper and zinc was sufficient in males, it was deficient in females according to the Hungarian recommendations. Especially women in their reproductive age ingested iron below the recommendation, thus representing a health risk. In comparison to earlier Hungarian data, zinc and chromium intake decreased unfavorable. Since in Hungary the consumption of the whole grain products with high trace element content is traditionally low, as also reflected in the present study, it would be desirable to increase the contribution of these foods in the diet in order to enhance the intake of microelements.


Survey of inpatient counseling by hospital pharmacists.
A survey was conducted to determine the inpatient-counseling practices of hospital pharmacists. A questionnaire about the frequency of inpatient counseling, barriers to counseling, and suggestions for increasing the level of inpatient counseling was mailed to 667 hospital pharmacists. Recipients were asked to rate six attitudinal statements about inpatient counseling. The response rate was 30%. The largest group of respondents worked in institutions where discharge counseling was provided to specific populations or as needed. Some 67% of respondents reported not counseling any patients. Barriers to counseling most often cited were lack of time and inadequate staff; facilitators most often cited were decentralization and resource availability. The most frequent suggestions for increasing the amount of counseling were making changes that provide more time, having adequate staff to provide counseling, and having a well-designed counseling program in place. Responses about barriers and facilitators varied with practice setting and frequency of counseling. On average, pharmacists reported a belief that they are the health care professionals most qualified to counsel inpatients about medications and that this is their responsibility. More than two thirds of the responding hospital pharmacists reported counseling no patients; the barrier to counseling most frequently reported was lack of time, and the facilitator most often reported was decentralization; on average, pharmacists reported that they believed they should have a role in inpatient counseling.


The human papillomavirus type 16 L1 protein directly interacts with E2 and enhances E2-dependent replication and transcription activation.
The human papillomavirus (HPV) E2 protein is a multifunctional protein essential for the control of virus gene expression, genome replication and persistence. E2 is expressed throughout the differentiation-dependent virus life cycle and is functionally regulated by association with multiple viral and cellular proteins. Here, we show for the first time to our knowledge that HPV16 E2 directly associates with the major capsid protein L1, independently of other viral or cellular proteins. We have mapped the L1 binding region within E2 and show that the α-2 helices within the E2 DNA-binding domain mediate L1 interaction. Using cell-based assays, we show that co-expression of L1 and E2 results in enhanced transcription and virus origin-dependent DNA replication. Upon co-expression in keratinocytes, L1 reduces nucleolar association of E2 protein, and when co-expressed with E1 and E2, L1 is partially recruited to viral replication factories. Furthermore, co-distribution of E2 and L1 was detected in the nuclei of upper suprabasal cells in stratified epithelia of HPV16 genome-containing primary human keratinocytes. Taken together, our findings suggest that the interaction between E2 and L1 is important for the regulation of E2 function during the late events of the HPV life cycle.


Urinary metabolomics of bronchopulmonary dysplasia (BPD): preliminary data at birth suggest it is a congenital disease.
Bronchopulmonary dysplasia (BPD) or chronic lung disease is one of the principal causes of mortality and morbidity in preterm infants. Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications. The trigger cause of the disease comprehends the impairment of the alveolar development and the increased angiogenesis. Nevertheless, the molecular pathways characterizing the disease are still unclear. Therefore, the use of the metabolomics technique, due to the capability of identifying instantaneous metabolic perturbation, might help to recognize metabolic patterns associated with the condition. The purpose of this study is to compare urinary metabolomics at birth in 36 newborns with a gestational age below 29 weeks and birth weight <1500 g (very low birth weight - VLBW), admitted in Neonatal Intensive Care Unit (NICU) divided into two groups: the first group (18 cases) consisting of newborns who have not yet developed the disease, but who will subsequently develop it and the second group (18 controls) consisting of newborns not affected by BPD. Urine samples were collected within 24-36 h of life and immediately frozen at -80 °C. The (1)H-NMR spectra were analyzed using a partial least squares discriminant analysis (PLS-DA) model coupled with orthogonal Signal Correction. Using this approach it was possible with urine at birth to discriminate newborns that will be later have a diagnosis of BPD with a high statistics power. In particular, we found five important discriminant metabolites in urine in BPD newborns: lactate, taurine, TMAO, myoinositol (which increased) and gluconate (which decreased). These preliminary results seem to be promising for the identification of predictor's biomarkers characterizing the BPD condition. These data may suggest that BPD is probably the result of an abnormal development (respiratory bud, vascular tree, hypodysplasia of pneumocytes) and could be considered a congenital disease (genetics plus intrauterine epigenetics). Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications.


Behavioural addictions in adolescents and young adults: results from a prevalence study.
Our study aims to assess the prevalence of behavioural addictions in an adolescent population, evaluating the effects of gender and age, and to assess the correlations among different behavioural addictions. 2853 high school students were assessed in order to evaluate the prevalence of behavioural addictions such as Pathological Gambling (PG), Compulsive Buying (CB), Exercise Addiction (EA), Internet Addiction (IA), and Work Addiction (WA), in a population of Italian adolescents. The South Oaks Gambling Screen-Revised Adolescent (SOGS-RA), the Compulsive Buying Scale (CBS), the Exercise Addiction Inventory (EAI), the Internet Addiction Test (IAT), and the Work Addiction Risk Test (WART), were compiled anonymously by the students. Overall prevalence was 7.0% for PG, 11.3% for CB, 1.2% for IA, 7.6% for WA, 8.5% for EA. PG and EA were more common among boys, while gender had no effect on the other conditions. CB was more common among younger (<18 years old) students. The scores of all of these scales were significantly correlated. The strong correlation among different addictive behaviours is in line with the hypothesis of a common psychopathological dimension underlying these phenomena. Further studies are needed to assess personality traits and other clinical disorders associated with these problems behaviours.


[Use of the basophil degranulation test and the leukocyte migration inhibition test to characterize mycogenic sensitization].
The results of experiments in using the basophil degranulation test and the leukocyte migration inhibition test for the characterization of mycogenous sensitization are presented. The model of mycogenous sensitization was created in guinea pigs by 3 injections of homogenized Candida albicans cells. Immediate allergic reaction is shown to develop earlier, as indicated by the results of the determination of homocytotropic antibody tites in passive skin anaphylaxis and by the results of the basophil degranulation test, than the appearance of delayed hypersensitivity detected by the leukocyte migration inhibition test.


The structure of Photosystem I acclimated to far-red light illuminates an ecologically important acclimation process in photosynthesis.
Phototrophic organisms are superbly adapted to different light environments but often must acclimate to challenging competition for visible light wavelengths in their niches. Some cyanobacteria overcome this challenge by expressing paralogous photosynthetic proteins and by synthesizing and incorporating ~8% chlorophyll f into their Photosystem I (PSI) complexes, enabling them to grow under far-red light (FRL). We solved the structure of FRL-acclimated PSI from the cyanobacterium Fischerella thermalis PCC 7521 by single-particle, cryo-electron microscopy to understand its structural and functional differences. Four binding sites occupied by chlorophyll f are proposed. Subtle structural changes enable FRL-adapted PSI to extend light utilization for oxygenic photosynthesis to nearly 800 nm. This structure provides a platform for understanding FRL-driven photosynthesis and illustrates the robustness of adaptive and acclimation mechanisms in nature.


Methane emission, metabolism, and performance of Holstein dairy cows with low, medium, and high lymphocyte proliferation during transition.
This study aimed to identify interactions between state of lactation (dry or early lactating) and immune responder group (low, medium, or high) for energy metabolism traits as well as metabolic and immunological traits in dairy cows. In early lactation, when the energy priority of cows shifts toward the mammary gland, the energy available to be partitioned toward the immune system may differ among individuals. The equilibrium between energy supply from feed, digestion, and body reserve mobilization and energy expenditure with milk, immune system, methane, and heat production is delicate in this stage. Seventeen Holstein cows entering their second to fifth lactation were kept under comparable feeding, housing, and management conditions and were studied from 14 ± 6 d before calving to 11 ± 3 d after calving. Feed intake, milk yield, body condition, blood metabolites, and cortisol as well as gaseous exchange in respiration chambers were measured. The latter was used to quantify methane emission and to calculate resting metabolic rate and heat production. Subsets of blood leukocytes and peripheral blood mononuclear cells (PBMC) were monitored. Activation and proliferation of the PBMC in response to the mitogen phytohemagglutinin ante- and postpartum were assessed using the oxygen consumption rate (24-h cell culture assay) and the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay (72-h cell culture assay). Cows were classified based on the in vitro proliferative response of the PBMC measured postpartum in low (n = 6), medium (n = 5), and high (n = 6) responders. We found no interaction of state of lactation with responder group for feed intake, milk yield, efficiency, metabolic traits, and immune cell activation ante- and postpartum. However, after calving, low-responder cows produced less methane per unit of body weight and per unit of energy-corrected milk compared with the other cows. This might be indicative of a low rumen fermentation intensity. Low responders might therefore suffer from a lower availability of digestible energy in early lactation and not be able to sustain the shift from immune cell activation to proliferation. If so, the selection of environmentally friendly low-methane emitters could promote phenotypes with a compromised immune response in the critical early lactation.


Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma.
The endothelin-1 (ET-1) receptors were recently found to mediate pro-survival functions in multiple myeloma (MM) cells in response to autocrine ET-1. This study investigated the effectiveness of macitentan, a dual ET-1 receptor antagonist, in MM treatment, and the mechanisms underlying its activities. Macitentan affected significantly MM cell (RPMI-8226, U266, KMS-12-PE) survival and pro-angiogenic cytokine release by down-modulating ET-1-activated MAPK/ERK and HIF-1α pathways, respectively. HIF-1α silencing abrogated the ET-1 mediated induction of genes encoding for pro-angiogenic cytokines such as VEGF-A, IL-8, Adrenomedullin, and ET-1 itself. Upon exposure to macitentan, MM cells cultured in the presence of the hypoxia-mimetic agent CoCl2, exogenous ET-1, or CoCl2 plus ET-1, down-regulated HIF-1α and the transcription and release of downstream pro-angiogenic cytokines. Consistently, macitentan limited significantly the basal pro-angiogenic activity of RPMI-8226 cells in chorioallantoic membrane assay. In xenograft mouse models, established by injecting NOG mice either via intra-caudal vein with U266 or subcutaneously with RPMI-8226 cells, macitentan reduced effectively the number of MM cells infiltrating bone marrow, and the size and microvascular density of subcutaneous MM tumors. ET-1 receptors targeting by macitentan represents an effective anti-proliferative and anti-angiogenic therapeutic approach in preclinical settings of MM.


The intact CFTR protein mediates ATPase rather than adenylate kinase activity.
The two NBDs (nucleotide-binding domains) of ABC (ATP-binding-cassette) proteins function in a complex to mediate ATPase activity and this activity has been linked to their regulated transport activity. A similar model has been proposed for CFTR (cystic fibrosis transmembrane conductance regulator), the chloride channel defective in cystic fibrosis, wherein ATP binding and hydrolysis regulate the channel gate. Recently, it was shown that the individual NBDs isolated from CFTR primarily mediate adenylate kinase activity, raising the possibility that this activity may also contribute to gating of the CFTR channel. However, this present study shows that whereas the isolated NBDs exhibit adenylate kinase activity, the full-length purified and reconstituted CFTR protein functions as an ATPase, arguing that the enzymatic activity of the NBDs is dependent on their molecular context and appropriate domain-domain assembly. As expected, the disease-causing mutant bearing a mutation in the ABC signature motif, CFTR-G551D, exhibited a markedly reduced ATPase activity. Furthermore, mutation of the putative catalytic base in CFTR caused a reduction in ATPase activity, with the CFTR-E1371Q mutant supporting a low level of residual activity. Neither of these mutants exhibited detectable adenylate kinase activity. Together, these findings support the concept that the molecular mechanism of action of CFTR is dependent on ATP binding and hydrolysis, and that the structure of prokaryotic ABC ATPases provide a useful template for understanding their mechanism of action.


[Gorham-Stout syndrome of the spine. Case report and review of the literature].
Two female patients with Gorham-Stout syndrome (GSS) of the spine are described. One 25 year old patient developed progressive osteolysis of the upper cervical spine over a period of several years but despite gross extent of the disease had no neurological complications. Some bone implanted in order to stabilise the spine was absorbed after only a few weeks. A six year old girl with progressive osteolysis of the thoracic spine developed a reversible trans-section syndrome on several occasions. During an active episode, the spine was stabilised by a titanium implant. In both patients the condition arrested spontaneously. A review of the world literature (175 cases) has indicated that, including our two patients, there were only 15 patients with primary involvement of the spine and 27 patients with secondary involvement. The relatively good prognosis of the condition (mortality 13.3%), which often shows spontaneous arrest, becomes much worse if there is involvement of the spine or thorax because of neurological complications or a chylothorax. Involvement of the spine increases mortality to 33.3%, and to 52% if the thorax is involved. Early diagnosis and the institution of appropriate treatment is therefore essential. For involvement of the spine, a combination of radiotherapy and surgical stabilisation with a titanium implant should be performed since in nearly all patients bone transplants are reabsorbed. For this treatment the patient should be transferred to a neuro-orthopaedic centre.


Role of Bladder Hydrodistention and Intravesical Sodium Hyaluronate in the Treatment of Interstitial Cystitis.
To evaluate the clinical efficacy of bladder hydrodistention and intravesical sodium hyaluronate in the treatment of interstitial cystitis (IC). Twenty-one patients with IC received intravesical sodium hyaluronate therapy under nerve block or intravenous anesthesia. Bladders were perfused with 100 cmH2O perfusion pressure and expanded for 10 min and were later injected with 40 mg/50 mL sodium hyaluronate through the catheter. After 1 h, the perfusion fluid was released. Perfusion was applied once per week, 4 to 6 times as a course of treatment. Under anesthesia, the average bladder capacity was 191.62 ± 88.67 mL, and after bladder expansion, the bladder capacity reached 425.33 ± 79.83 mL (P = .000). There were 2 suspected bladder ruptures after bladder expansion at 6.5 min and 7.2 min. After 10 min of bladder expansion, there were 19 cases of significantly gross hematuria. After treatment, the catheters of 17 patients were removed at 24 h; for the 2 cases of hematuria, catheters were removed at 72 h and for the 2 cases of suspected bladder rupture, catheters were removed after 4 days. After catheter removal, the pain threshold significantly decreased, and the maximum urinary output increased slightly. Compared with values before treatment, the day before the second injection of sodium hyaluronate, the frequency of urination decreased significantly (32.8 vs. 18.5 times/24 h), the maximum urinary output increased significantly (86.7 vs. 151.9 mL), the pain decreased significantly (8.7 vs. 3.0), and the O'Leary-Sant IC score and quality of life score were significantly decreased (30.0 vs. 17.0 and 5.9 vs. 2.4, respectively) (P = .000). Bladder hydrodistention under anesthesia for patients with severe intractable IC produces immediate effectiveness; sodium hyaluronic infusion can alleviate frequent urination and pain, and the efficacy was positively correlated with the duration of treatment.


'Not men enough to rule!': politicization of ethnicities and forcible circumcision of Luo men during the postelection violence in Kenya.
As a contribution to ongoing research addressing sexual violence in war and conflict situations in the Democratic Republic of Congo, Kenya and Rwanda, this paper argues that the way sexual violence intersects with other markers of identity, including ethnicity and class, is not clearly articulated. Male circumcision has been popularized, as a public health strategy for prevention of HIV transmission, although evidence of its efficacy is disputable and insufficient attention has been given to the social and cultural implications of male circumcision. This paper draws from media reporting and the material supporting the prosecutor at the International Criminal Court case against four Kenyans accused of crimes against humanity, to explore the postelection violence, especially forcible male circumcision. During the postelection violence in Kenya, women were, as in other conflict situations, raped. In addition, men largely from the Luo ethnic group were forcibly circumcised. Male circumcision among the Gikuyu people is a rite of passage, but when forced upon the Luo men, it was also associated with cases of castration and other forms of genital mutilation. The aim appears to have been to humiliate and terrorize not just the individual men, but their entire communities. The paper examines male circumcision and questions why a ritual that has marked a life-course transition for inculcating ethical analysis of the self and others, became a tool of violence against men from an ethnic group where male circumcision is not a cultural practice. The paper then reviews the persistence and change in the ritual and more specifically, how male circumcision has become, not just a sexual health risk, but, contrary to the emerging health discourse and more significantly, a politicized ethnic tool and a status symbol among the Gikuyu elite. In the view of the way male circumcision was perpetrated in Kenya, we argue it should be considered as sexual violence, with far-reaching consequences for men's physical and mental health.


Social anxiety and interpersonal risk for suicidal ideation: A longitudinal daily diary analysis.
Social anxiety is associated with elevated suicidal ideation (SI). One potential explanation is that socially anxious persons experience frequent interpersonal stressors that elicit SI. Longitudinal designs with temporal ordering are needed to adequately test this hypothesis. Therefore, this study leveraged a longitudinal design combining trait and daily reports. Two hundred eleven community adult participants with elevated levels of depression and/or social anxiety completed social anxiety and SI measures at baseline and again at a 1.5-month follow-up. Between these assessments, participants completed a 14-day diary study that assessed three forms of interpersonal distress: unfavorable social comparisons, perceived barriers to seeking social support, and loneliness. As predicted, simple mediation models revealed that baseline social anxiety had a significant indirect effect on SI severity at 1.5 months postbaseline via unfavorable social comparisons (indirect effect: β = 0.07, p < 0.05) and barriers to seeking support (indirect effect: β = 0.08, p < 0.05); however, social anxiety did not have a significant indirect effect on SI severity through loneliness. Study results are consistent with the proposition that increases in interpersonal distress may explain socially anxious persons' vulnerability to SI. Implications of these findings for the research, assessment, and treatment of suicidality in social anxiety are discussed.


Improved statistical signal detection in pharmacovigilance by combining multiple strength-of-evidence aspects in vigiRank.
Detection of unknown risks with marketed medicines is key to securing the optimal care of individual patients and to reducing the societal burden from adverse drug reactions. Large collections of individual case reports remain the primary source of information and require effective analytics to guide clinical assessors towards likely drug safety signals. Disproportionality analysis is based solely on aggregate numbers of reports and naively disregards report quality and content. However, these latter features are the very fundament of the ensuing clinical assessment. Our objective was to develop and evaluate a data-driven screening algorithm for emerging drug safety signals that accounts for report quality and content. vigiRank is a predictive model for emerging safety signals, here implemented with shrinkage logistic regression to identify predictive variables and estimate their respective contributions. The variables considered for inclusion capture different aspects of strength of evidence, including quality and clinical content of individual reports, as well as trends in time and geographic spread. A reference set of 264 positive controls (historical safety signals from 2003 to 2007) and 5,280 negative controls (pairs of drugs and adverse events not listed in the Summary of Product Characteristics of that drug in 2012) was used for model fitting and evaluation; the latter used fivefold cross-validation to protect against over-fitting. All analyses were performed on a reconstructed version of VigiBase(®) as of 31 December 2004, at around which time most safety signals in our reference set were emerging. The following aspects of strength of evidence were selected for inclusion into vigiRank: the numbers of informative and recent reports, respectively; disproportional reporting; the number of reports with free-text descriptions of the case; and the geographic spread of reporting. vigiRank offered a statistically significant improvement in area under the receiver operating characteristics curve (AUC) over screening based on the Information Component (IC) and raw numbers of reports, respectively (0.775 vs. 0.736 and 0.707, cross-validated). Accounting for multiple aspects of strength of evidence has clear conceptual and empirical advantages over disproportionality analysis. vigiRank is a first-of-its-kind predictive model to factor in report quality and content in first-pass screening to better meet tomorrow's post-marketing drug safety surveillance needs.


Investigations of metal-coordinated peptides as supramolecular synthons.
This article describes the synthesis and controlled assembly of four model biological-hybrid scaffolds via coordination of a metal complex to four new tripeptides. Each model tripeptide investigated has either a central pyridyl glycyl or a pyridyl alanyl residue between two terminally protected glycines. All tripeptides were coordinated to their complementary recognition unit, a p-methoxy SCS-Pd pincer complex. The assembly events were fully characterized and investigated by 1H NMR, ES-MS, and isothermal titration calorimetry (ITC) to elucidate how the substitution and spatial distance of the pyridyl moiety to the peptide backbone affects the metal coordination. Using these characterization techniques, we have shown that the metal-coordination events in all cases are fast and quantitative and that the peptide backbones do not interfere with the self-assembly. The ITC analyses showed that the 4-pyridyl tripeptides are the tightest binding ligands toward the palladated pincer complexes with the alanyl derivative being the strongest overall, demonstrating the superiority of the 4-pyridyl peptides over their 3-pyridyl analogues. The measured association constants are comparable to other pincer-pyridine systems in DMSO suggesting that the controlled coordination of the metalated pincer/pyridine interaction is an interesting biological synthon and will allow for the future development of important noncovalent peptide-based hybrid materials.


[Present day diagnosis of voice disorders in children].
Videoendostroboscopy (VESS) was employed for diagnosis of vocal dysfunction in 369 children aged 6 to 16 years. Effects of flexible and hard endoscopes were compared. Vibratory cycle was analyzed in 55 healthy children of different age. Diagnosis and differential diagnosis of soft and hard nodules, physiological and long-term mutation, chronic laryngitis are described as well as a videoendostroboscopic picture in functional dysphonias, vocal grooves and polyps. VESS is a modern, informative and safe diagnostic procedure.


Desorption/ionization on silicon time-of-flight/time-of-flight mass spectrometry.
Desorption/ionization on silicon (DIOS) tandem time-of-flight (TOF/TOF) mass spectrometry (MS) provides high accuracy and significant fragmentation information, particularly in the characterization of biomolecules. DIOS TOF/TOF offers a high-throughput surface-based ionization platform as well as complete fragmentation through high collision energies. The absence of matrix interference in DIOS allows for the MS and MS/MS analysis of small molecules well below m/z 300. In addition, sample preparation is minimal, and the DIOS chips can be stored and reanalyzed for fragmentation information or accurate mass measurements. The combined benefits of robustness, minimal sample preparation, good sensitivity, high throughput, and sequencing capability make DIOS TOF/TOF a powerful tool for small molecule characterization and protein identification.


Antimicrobial activity of silver sulfide quantum dots functionalized with highly conjugated Schiff bases in a one-step synthesis.
In the present paper, low-dimensional Ag2S QDs were fabricated for the first time, with four different dithiocarbazate derivative Schiff bases (SB) as capping agents in a one-pot synthesis. These SB-capped Ag2S QDs were almost spherical with an average size range of 4.0 to 5.6 nm, which is slightly smaller than conventional thioglycolic acid (TGA)-capped Ag2S QDs. We demonstrate that the growth of Gram-positive bacteria (Bacillus subtillus and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and a prevalent fungal pathogen (Candida albicans) are inhibited more when the bacterial and fungal cells were nurtured with the synthesized SB-Ag2S QDs, compared with TGA-Ag2S QDs or free unbound Schiff bases. The minimum inhibitory concentration (MIC) results confirmed that even low concentrations of SB-Ag2S QDs were able to inhibit bacterial (MIC 5-75 μg mL-1) and fungal growth (MIC 80-310 μg mL-1), and in some cases they performed better than streptomycin (8-25 μg mL-1). Lethality bioassay results confirmed that SB-Ag2S QDs were not toxic to brine shrimp (Artemia salina). The results show that capping agents are essential in the design of functional Ag2S QDs, and highlight that Schiff bases provide an excellent opportunity to optimize the biological activities of silver based QDs.


Plasma cyclic AMP responses to adrenaline administration in patients with spinocerebellar degeneration, bronchial asthma, and diabetes mellitus--a preliminary report of a clinical test for detecting beta-adrenergic dysfunctions.
Plasma cyclic AMP responses to adrenaline administration in normal volunteers, patients with spinocerebellar degeneration, bronchial asthma, pulmonary emphysema, and diabetes mellitus were studied. Intramuscular administration of low doses (0.1--0.4 mg/person) of adrenaline caused a dose-dependent increase in plasma cyclic AMP. The increase in cyclic AMP was completely prevented by propranolol, while it was not affected by phentolamine or atropine. In patients with spinocerebellar degeneration, the concentrations of plasma cyclic AMP both before and after adrenaline administration were lower than in normal subjects. In asthmatic patients, the plasma cyclic AMP increase after adrenaline administration was smaller than that of the healthy controls. The plasma concentration of cyclic AMP in patients with insulin-dependent diabetes reached the peak level more slowly than in diabetic patients with dietary control alone. Examining changes in the plasma cyclic AMP level after adrenaline administration appears to be a useful means for assessing the degree of beta-adrenergic dysfunction.


The intersection between geriatrics and palliative care: a call for a new research agenda.
Palliative care is interdisciplinary treatment focused on the relief of suffering and achieving the best possible quality of life for patients and their caregivers. It differs for geriatric patients from what is usually appropriate in a younger population because of the nature and duration of chronic illness during old age. In spite of the fact that death occurs far more commonly in older people than in any age group, the evidence base for palliative care in older adults is sparse. Over the coming years, the research foci in the field of geriatrics and palliative care that must be addressed include establishing the prevalence of symptoms in patients with chronic disease; evaluating the association between treatment of symptoms and outcomes; increasing the evidence base for treatment of symptoms; understanding psychological well-being, spiritual well-being, and quality of life of patients and elucidating and alleviating sources of caregiver burden; reevaluating service delivery; adapting research methodologies specifically for geriatric palliative care; and increasing the number of geriatricians trained as investigators in palliative care research. This article discusses specific methods to improve the current situation within each of these seven areas.


Quantitative analysis of the growth of Salmonella stanley during alfalfa sprouting and evaluation of Enterobacter aerogenes as its surrogate.
Raw seed sprouts have been implicated in several food poisoning outbreaks in the last 10 years. Few studies have included investigations of factors influencing the effectiveness of testing spent irrigation water, and in no studies to date has a nonpathogenic surrogate been identified as suitable for large-scale irrigation water testing trials. Alfalfa seeds were inoculated with Salmonella Stanley or its presumptive surrogate (nalidixic acid-resistant Enterobacter aerogenes) at three concentrations (-3, -30, and -300 CFU/g) and were then transferred into either flasks or a bench top-scale sprouting chamber. Microbial concentrations were determined in seeds, sprouts, and irrigation water at various times during a 4-day sprouting process. Data were fit to logistic regression models, and growth rates and maximum concentrations were compared using the generalized linear model procedure of SAS. No significant differences in growth rates were observed among samples taken from flasks or the chamber. Microbial concentrations in irrigation water were not significantly different from concentrations in sprout samples obtaihed at the same time. E. aerogenes concentrations were similar to those of Salmonella Stanley at corresponding time points for all three inoculum concentrations. Growth rates were also constant regardless of inoculum concentration or strain, except that lower inoculum concentrations resulted in lower final concentrations proportional to their initial concentrations. This research demonstrated that a nonpathogenic easy-to-isolate surrogate (nalidixic acid-resistant E. aerogenes) provides results similar to those obtained with Salmonella Stanley, supporting the use of this surrogate in future large-scale experiments.


Protective effect of genistein on nonalcoholic fatty liver disease (NAFLD).
NAFLD is a vital health problem worldwide; however, no effective treatment is currently available for NAFLD. Intensive studies have indicated the efficacy of genistein (GE), a bioactive isoflavone extracted from soy, in treating NAFLD. In addition to its oestrogen-like effects, GE is known to have multiple molecular effects, for instance, lipid and glucose metabolism-promoting effects and activities against lipid peroxidation, inflammation, fibrosis, and NAFLD-related tumours. Here, this review summarizes the potential role of GE in the treatment and prevention of NAFLD and some of the currently known targets and signalling pathways of GE in NAFLD.


Moving stereotactic fiducial system to obtain a respiratory signal: proof of principle.
The purpose of this study was to obtain a respiratory signal with the use of an add-on device to a specific stereotactic body frame and evaluate precision and accuracy of the method, with the use of a dynamic phantom. The authors designed and constructed a simple add-on device which, attached to a stereotactic body frame, provides information of the patient's respiratory signal in every CT axial image acquired. To assess the approach, 12 CT studies were acquired, on a phantom that simulates respiratory motion, which was placed inside the frame with the add-on device. Images of the phantom with sinusoidal and shark-fin motion patterns were acquired, with different amplitude in the movement of the external surrogate and the target. Cycle time was 6 s. Images were retrospectively processed to obtain a respiratory signal from the vertical movement of the "abdomen." The obtained signal was adjusted to a sinusoidal function; the resultant amplitude and cycle time were compared with the preset function in the phantom. The cycle amplitude and time obtained with the method agreed with the preset values within 0.4 mm and 0.29 s, respectively. In the cases of sinusoidal movements the maximal discrepancy was less than 1 mm. A respiratory signal was obtained in all cine CT sequence studies with this method that consistently coincides with the preset motion of the phantom. The authors proposed a tool to obtain a respiratory signal based on information contained into the CT axial images.


First cannabis use: does onset shift to younger ages? Findings from 1988 to 2003 from the Dutch National School Survey on Substance Use.
To investigate the hypothesis that changes in cannabis prevalence among Dutch secondary school students (aged 12-17 years) were paralleled by shifts in the age of first cannabis use. Data were derived from five waves (1988, 1992, 1996, 1999 and 2003) of the Dutch National School Survey on Substance Use, a nationally representative cross-sectional study, with a total of 32,777 respondents. Written questionnaires on cannabis, tobacco, alcohol, other drug use and socio-demographic and behavioural variables were administered in classroom settings. Survival analysis showed a strong increase in cumulative incidences by age of first cannabis use from 1988 to 1992, a further increase in 1996 and stabilization in 1999, continuing into 2003. From 1992 to 1996, age of onset shifted towards younger ages. Onset peaked at age 15 in 1992 and age 14 in 1996. The proportion of life-time cannabis users starting at age 13 or younger increased from 26% in 1992 to 41% in 1996. The overall trend was similar for boys and girls. The study largely confirmed the expectation that the increase in cannabis use from 1988 to 1996 was paralleled by a decrease in the age of first cannabis use. From 1996 to 2003 age of first cannabis use and prevalence stabilized, possibly occasioned by a change in cannabis policy in the mid-1990s.


New formats of polymeric stationary phases for HPLC separations: molded macroporous disks and rods.
A molding process has been used for the preparation of separation media in different shapes such as rods and flat membrane-like disks. The polymerization is carried out using a mixture of monomers, porogenic solvent and free-radical initiator under conditions that afford macroporous materials with through-pores or channels large enough to provide the high flow characteristics required for applications in chromatography. In contrast to classical suspension polymerization, the solubility of monomers in water does not restrict their use. The versatility of the preparation technique is demonstrated in polymerizations involving both hydrophobic and hydrophilic monomers such as styrene, chloromethylstyrene, glycidyl methacrylate, alkyl methacrylates and acrylamide. Techniques have been developed that allow fine control of the porous properties of the polymers. These, in turn, determine the hydrodynamic properties of the separation devices that contain the molded media. Since all the mobile phase must flow through the separation medium, the mass transport within the molded media is accelerated considerably by convection. Therefore, the separations can be performed at much higher flow rates than in packed columns. This is particularly important for separations of large molecules such as proteins for which diffusion is a serious problem that significantly slows down the separation processes. The molded separation media have been used for the separation of biological compounds using gentle chromatographic modes such as hydrophobic interaction, ion-exchange and affinity chromatography during which the biological activity of the separated compounds is completely retained.


Mobile Compression Reduces Bleeding-related Readmissions and Wound Complications After THA and TKA.
The use of chemoprophylaxis to prevent thromboembolic disease after primary THA and TKA can be associated with postoperative bleeding complications. Mechanical prophylaxis has been studied as an alternative to chemoprophylaxis with greater safety in patients undergoing THA, but no data have been published comparing the safety of chemoprophylaxis versus mechanical methods for patients undergoing TKA. The risk of readmission resulting from bleeding and venous thromboembolism (VTE) has also not been determined for patients undergoing THA or TKA when treated with low-molecular-weight heparin (LMWH) alone compared with mechanical prophylaxis plus aspirin (ASA). We sought to answer four questions: For the THA and TKA cohorts, respectively, (1) was the incidence of readmission resulting from VTE and bleeding complications higher with LMWH than mobile compression plus ASA; and (2) was the incidence of wound bleeding complications higher with LMWH than mechanical compression plus ASA? For the TKA cohort specifically, (3) was the frequency of systemic bleeding events and complications related to chemical prophylaxis higher with LMWH compared with mechanical compression plus ASA? (4) Was there a difference in symptomatic VTEs between LMWH and mechanical compression plus ASA? Between November 2008 and April 2011, 632 patients underwent primary THA and TKA. Seventy-two patients (11%) were identified before surgery as being at high risk for VTE (31 patients) or bleeding (41 patients) and were excluded from the study. Five hundred sixty patients (89%) were considered to be at standard risk for VTE and bleeding and comprise the study cohort. Between November 2008 and November 2009, 252 patients (76 THAs, 176 TKAs) underwent THA and TKA and were treated with LMWH (5 mg dalteparin given subcutaneously daily for 14 days) and in-hospital nonmobile mechanical compression. Between November 2009 and April 2011, a total of 308 patients undergoing THA and TKA (108 THAs, 200 TKAs) were treated using a mobile compression device plus oral aspirin once daily for 2 weeks after surgery. All complications and readmissions that occurred within 6 weeks of surgery were noted. There were no differences between the VTE treatment groups with regard to age, sex, or body mass index. For the THA cohort, there was no difference in the frequency of readmission for a bleeding complication (wound or systemic) between the two groups (2.6% for LMWH versus 0.9% for mobile compression; p = 0.57; odds ratio [OR], 2.9). Patients undergoing TKA treated with LMWH had higher readmission rates within 6 weeks of surgery because of a bleeding complication, a wound infection, or the development of a VTE (6.8% for LMWH versus 1.5% for mobile compression; p = 0.015; OR, 4.8). For the THA cohort, there was higher wound bleeding complication frequency with LMWH (9.2% for LMWH versus 0.9% for mechanical compression; p = 0.009; OR, 10.9). Patients undergoing TKA treated with LMWH had a higher frequency of wound bleeding complications or infection (3.9% for LMWH versus 0.5% for mobile compression; p = 0.028; OR, 8.2). Patients undergoing TKA treated with LMWH had higher rates of systemic bleeding or a complication secondary to LMWH administration (2.8% for LMWH versus 0% for mobile compression; p = 0.022; OR, 12.8). No difference was noted in the rate of symptomatic VTEs between either group (for THA: 2.6% for the LMWH group versus 1.9% for the mechanical compression group; p = 1; for TKA: 1.1% versus 0%, respectively; p = 0.22). Based on these results, we advocate for routine use of mobile mechanical compression devices in the prevention of VTEs and complications associated with more potent chemical anticoagulants. However, more focused randomized clinical trials are needed to validate these findings. Level III, therapeutic study.


[The small-intestine-stasis syndrome following side-to-side anastomosis].
This review describes the small intestine stasis syndrome after side-to-side anastomosis. Symptoms of intermittent abdominal pains with steatorrhea and loss of weight are caused by disturbance of passage with a rise in bacterial concentrations. Of 27 patients observed 15 had no disorders, while 12 had gastrointestinal symptoms which had been misinterpreted and given conservative treatment for a long time (3--22 years). Treatment is either by antibiotics or by excision of the lateral anastomosis followed by end-to-end anastomosis of the normal intestine. Special attention must be paid to the consequences of side-to-side anastomosis in childhood.


A review of musculoskeletal modelling of human locomotion.
Locomotion through the environment is important because movement provides access to key resources, including food, shelter and mates. Central to many locomotion-focused questions is the need to understand internal forces, particularly muscle forces and joint reactions. Musculoskeletal modelling, which typically harnesses the power of inverse dynamics, unites experimental data that are collected on living subjects with virtual models of their morphology. The inputs required for producing good musculoskeletal models include body geometry, muscle parameters, motion variables and ground reaction forces. This methodological approach is critically informed by both biological anthropology, with its focus on variation in human form and function, and mechanical engineering, with a focus on the application of Newtonian mechanics to current problems. Here, we demonstrate the application of a musculoskeletal modelling approach to human walking using the data of a single male subject. Furthermore, we discuss the decisions required to build the model, including how to customize the musculoskeletal model, and suggest cautions that both biological anthropologists and engineers who are interested in this topic should consider.


Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice.
Several β cell antigens recognized by T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D) are also T cell targets in the human disease. While numerous antigen-specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen (HLA)-transgenic mouse model incorporating human β cell-specific T cells might provide a better platform for evaluating antigen-specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet-infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to 'reprogram' primary human CD8 T cells to express three T cell receptors (TCRs) specific for a peptide derived from the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP265-273 ) and recognized in the context of the human class I major histocompatibility complex (MHC) molecule HLA-A2. The TCRs bound peptide/MHC multimers with a range of avidities, but all bound with at least 10-fold lower avidity than the anti-viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The β cell-specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon (IFN)-γ in response to antigen and exhibited cytotoxic activity against peptide-pulsed target cells. The cells engrafted in HLA-A2-transgenic NOD-scid IL2rγ(null) mice and could be detected in the blood, spleen and pancreas up to 5 weeks post-transfer, suggesting the utility of this approach for the evaluation of T cell-modulatory therapies for T1D and other T cell-mediated autoimmune diseases.


Infant HIV type 1 gp120 vaccination elicits robust and durable anti-V1V2 immunoglobulin G responses and only rare envelope-specific immunoglobulin A responses.
Infant responses to vaccines can be impeded by maternal antibodies and immune system immaturity. It is therefore unclear whether human immunodeficiency virus type 1 (HIV-1) vaccination would elicit similar responses in adults and infants. HIV-1 Env-specific antibody responses were evaluated in 2 completed pediatric vaccine trials. In the Pediatric AIDS Clinical Trials Group (PACTG) 230 protocol, infants were vaccinated with 4 doses of Chiron rgp120 with MF59 (n=48), VaxGen rgp120 with aluminum hydroxide (alum; n=49), or placebo (n=19) between 0 and 20 weeks of age. In PACTG 326, infants received 4 doses of ALVAC-HIV-1/AIDSVAX B/B with alum (n=9) or placebo (n=13) between 0 and 12 weeks of age. By 52 weeks of age, the majority of maternally acquired antibodies had waned and vaccine Env-specific immunoglobulin G (IgG) responses in vaccinees were higher than in placebo recipients. Chiron vaccine recipients had higher and more-durable IgG responses than VaxGen vaccine recipients or ALVAC/AIDSVAX vaccinees, with vaccine-elicited IgG responses still detectable in 56% of recipients at 2 years of age. Remarkably, at peak immunogenicity, the concentration of anti-V1V2 IgG, a response associated with a reduced risk of HIV-1 acquisition in the RV144 adult vaccine trial, was 22-fold higher in Chiron vaccine recipients, compared with RV144 vaccinees. As exemplified by the Chiron vaccine regimen, vaccination of infants against HIV-1 can induce robust, durable Env-specific IgG responses, including anti-V1V2 IgG.


Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells: the role of MGMT in protection against the genotoxic effects of alkylating agents.
O6-Methylguanine-DNA methyltransferase (MGMT) is responsible for removal of O6-alkylguanine from DNA induced by alkylating mutagens/carcinogens. To analyze the involvement of O6-alkylguanine in the generation and MGMT in avoidance of various genotoxic effects of alkylating agents, we transfected Chinese hamster ovary (CHO) cells that lack MGMT activity with human MGMT cDNA cloned into a mammalian expression vector (pSV2MGMT). A high proportion (60-80%) of transfectants selected for a cotransfected neo gene survived treatment with high doses of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-hydroxyethyl-N-chloroethylnitrosourea (HeCNU). Parallel transfections with an expression vector containing the bacterial ada gene (pSV2ada) showed the human MGMT to be more effective than the ada expression vector in mediating alkylation resistance. Various clonal CHO cell lines have been established stably transfected with the human MGMT cDNA. The transfectants expressed human MGMT at levels ranging from 8600 to 210,000 molecules per cell. The high MGMT expressors became strongly resistant to the killing effects of MNNG, HeCNU, N-methyl-N-nitrosourea (MNU) and, to a significant lesser degree, methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS). No killing resistance was observed to N-ethyl-N-nitrosourea (ENU), though the MGMT and ada transfectants showed reduction in mutation frequency induced by this agent. Protection from mutation induction by MGMT (and ada) expression was also demonstrated for MNNG. The transfectants were also protected from the sister chromatid exchange (SCE) inducing and, to a lesser degree, clastogenic effect of MNNG and MNU, and slightly to EMS and MMS. Again no protection was observed towards ENU. Correlations between MGMT activity and resistance to a given end point suggest that, for MNNG, O6-methylguanine is the preponderant toxic, mutagenic and SCE inducing lesion. About 90% of MNNG (and MNU) induced SCEs and nearly all of the MNNG-induced gene mutations seem to be due to this adduct. For alkylation-induced chromosomal aberrations, however, and for cell killing and SCEs induced by MMS, EMS and ENU, other lesions than O6-alkylguanine appear to be of major importance. The data strongly support the view that O6-methylguanine is a genotoxic lesion and MGMT a function decisively involved in avoidance of genotoxic effects in cells exposed to MNNG and related compounds. They indicate also that it is important to take into account the property and mode of action of any given alkylating agent in assessing the protective role of MGMT against alkylation-induced genotoxicity.


Update on intracerebral hemorrhage.
This article provides an update on the latest diagnostic and therapeutic trials relating to the management of intracerebral hemorrhage (ICH). Early hematoma expansion and worsening cerebral edema may account for delayed neurologic deterioration after ICH. Despite advances in other areas of stroke, there has been no significant improvement in the morbidity and mortality after ICH. The cause of ICH has been shifting from chronic hypertension to other etiologies. Current understanding of the pathophysiologic processes involved with hematoma expansion and the development of secondary injury after ICH has focused the treatment strategies on prevention of these potential complications. Care for the patient after ICH includes basic medical care, prevention of hematoma expansion, and treatment of potential secondary complications. Trials are underway to evaluate the effect of acute blood pressure control on hematoma expansion and the development of cerebral edema. Similarly, new surgical techniques are being explored for clot removal, and medical therapies are being developed to prevent secondary neurotoxic damage.


Modeling segmentation of a visual scene via neural oscillators: fragmentation, discovery of details and attention.
The present study analyses the problem of binding and segmentation of a visual scene by means of a network of neural oscillators, laying emphasis on the problems of fragmentation, perception of details at different scales and spatial attention. The work is based on a two-layer model: a second layer of Wilson-Cowan oscillators is inhibited by information from the first layer. Moreover, the model uses a global inhibitor (GI) to segment objects. Spatial attention consists of an excitatory input, surrounded by an inhibitory annulus. A single object is identified by synchronous oscillatory activity of neural groups. The main idea of this work is that segmentation of objects at different detail levels can be achieved by linking parameters of the GI (i.e. the threshold and the inhibition strength) with the dimension of the zone selected by attention and with the dimension of the smaller objects to be detected. Simulations show that three possible kinds of behavior can be attained with the model, through proper choice of the GI parameters and attention input: (i) large objects in the visual scene are perceived, while small details are suppressed; (ii) large objects are perceived, while details are assembled together to constitute a single 'noise term'; (iii) if attention is focused on a smaller area and the GI parameters modulated accordingly (i.e. the threshold and attention strength are reduced) details are individually perceived as separate objects. These results suggest that the GI and attention may represent two concurrent aspects of the same attentive mechanism, i.e. they should work together to provide flexible management of a visual scene at different levels of detail.


Fortification of pork loins with docosahexaenoic acid (DHA) and its effect on flavour.
Pork is traditionally low in docosahexanoic acid (DHA, C22:6n-3) and deficient in omega-3 fats for a balanced human diet. DHA as triglycerides was commercially prepared from the microalgae Schizochytrium and injected into fresh pork loins. Treatments of a mixed brine control (CON), 3.1% sunflower oil in mixed brine (SF) and a 3.1% DHA oil in mixed brine (DHA) were injected into pork loins at 10 mL/100 g and grilled at 205°C. After cooking, the CON and SF pork loins contained 0.03 to 0.05 mg DHA/g of pork and the DHA injected loins contained approximately 1.46 mg DHA/g. This also changed the fatty acid profile of omega-6: omega-3 from, 5 to 1 in the CON pork, to a ratio of 1.7 to 1 in DHA pork. The appearance, odor, oxidation rates and sensory taste, as judged by a trained panel, determined the DHA injected meat to be, 'slightly desirable' and gave lower 'off flavour' scores, relative to the CON and SF injected pork. Pork can be fortified with DHA oil to 146 mg/100 g serving, which would meet half the recommended daily omega 3 fatty acid requirements for adult humans and would be desirable in taste.


Hyperlipoproteinemia, atherosclerosis risk, and dietary management.
There is new impetus for dietary intervention in response to the recent data relating levels of circulating lipids and lipoproteins to atherosclerosis risk. Certain levels of cholesterol, stratified for age and sex, are associated with "moderate" and "high" risk of atherosclerosis. Knowing the relationship of diet to lipid levels and lipid transport by the various lipoproteins enables the appropriate diagnosis and management. Dietary measures include attention to the level of calories and fat, the type of fat, cholesterol content, source of protein, the type of carbohydrate and fiber, and the level of alcohol intake. Lipid (cholesterol) screening at intervals is recommended for all adults and for children at special risk of hyperlipidemia.


Procurement of total human face graft for allotransplantation: a preclinical study and the first clinical case.
The authors report the technical difficulties involved in the procurement of a total human face graft for allotransplantation. After completing a preclinical study that involved 13 fresh cadavers, the authors harvested a total face graft for allotransplantation onto a patient in April of 2009. The harvested tissue specimen included the entire face along with the scalp and the auricles. The authors then removed the unnecessary parts, specifically, the lips and the skin overlying the chin. The preclinical study and clinical results confirmed that complete revascularization of a total face graft, complete with the scalp and auricles, from a single external carotid vascular pedicle was possible. All dissections were completed in less than 6 hours during the preclinical study. Graft procurement for the clinical case took 11 hours. Facial soft tissues were harvested en bloc to decrease graft harvest time and prevent tissue injury. A resin mask that covered the entire face of the donor provided excellent cosmetic results. All nerves and eyelid structures were easily reattached. One month after transplantation, skin necrosis necessitated several stages of excision. Biopsy specimens from the transplanted tissue were negative for immune-mediated rejection. Unfortunately, the patient experienced a cardiac arrest during follow-up surgery and died 2 months after the transplant procedure. A composite tissue allotransplantation of the total face along with the scalp and the auricles is technically feasible. The authors' flap provided reliable vascularization and was obtained in a standardized fashion in less than 11 hours. The graft contained all of the perioral muscles, branches of the facial nerve, eyelid structures, and major salivary glands.


Prescribed fires, smoke exposure, and hospital utilization among heart failure patients.
Prescribed fires often have ecological benefits, but their environmental health risks have been infrequently studied. We investigated associations between residing near a prescribed fire, wildfire smoke exposure, and heart failure (HF) patients' hospital utilization. We used electronic health records from January 2014 to December 2016 in a North Carolina hospital-based cohort to determine HF diagnoses, primary residence, and hospital utilization. Using a cross-sectional study design, we associated the prescribed fire occurrences within 1, 2, and 5 km of the patients' primary residence with the number of hospital visits and 7- and 30-day readmissions. To compare prescribed fire associations with those observed for wildfire smoke, we also associated zip code-level smoke density data designed to capture wildfire smoke emissions with hospital utilization amongst HF patients. Quasi-Poisson regression models were used for the number of hospital visits, while zero-inflated Poisson regression models were used for readmissions. All models were adjusted for age, sex, race, and neighborhood socioeconomic status and included an offset for follow-up time. The results are the percent change and the 95% confidence interval (CI). Associations between prescribed fire occurrences and hospital visits were generally null, with the few associations observed being with prescribed fires within 5 and 2 km of the primary residence in the negative direction but not the more restrictive 1 km radius. However, exposure to medium or heavy smoke (primarily from wildfires) at the zip code level was associated with both 7-day (8.5% increase; 95% CI = 1.5%, 16.0%) and 30-day readmissions (5.4%; 95% CI = 2.3%, 8.5%), and to a lesser degree, hospital visits (1.5%; 95% CI: 0.0%, 3.0%) matching previous studies. Area-level smoke exposure driven by wildfires is positively associated with hospital utilization but not proximity to prescribed fires.


Ethnic-specific prevalence rates of intimate partner violence against women in New Zealand.
This study presents age-standardised ethnic-specific prevalence rates of intimate partner violence against women in New Zealand, by physical and/or sexual intimate partner violence, psychological intimate partner violence, controlling behaviours and economic abuse. Data are from 1,431 ever-partnered women in the representative and cross-sectional He Koiora Matapopore, the 2019 New Zealand Family Violence Study. High lifetime prevalence of intimate partner violence is present across all ethnic groups in NZ, with over half of all women reporting any intimate partner violence (55.8%). Substantial ethnic disparities exist in intimate partner violence rates, with Māori women reporting the highest prevalence of intimate partner violence (64.6%), followed by NZ European women (61.6%). Intimate partner violence prevention and intervention services are needed at the population-level, and services must be culturally responsive and attuned to the needs of communities that bear the greatest burden. Ethnic differences in intimate partner violence prevalence likely contribute to health disparities at the population-level, reinforcing calls for prevention and necessitating healthcare systems to be culturally informed and mobilised to address intimate partner violence as a priority health issue.


Antiangiogenic effect of soluble vascular endothelial growth factor receptor-1 in placental angiogenesis.
Differential splicing of the flt-1 mRNA generates soluble variant of vascular endothelial growth factor (VEGF) receptor-1 (sVEGFR-1, also known as sFlt-1). The action of VEGF is antagonized by sVEGFR-1. Soluble VEGFR-1 binds to VEGF with a high affinity and therefore works to modulate VEGF and VEGF signaling pathway. In this study, the authors tested the hypothesis that VEGF-mediated endothelial cell angiogenesis is tightly modulated by the release of sVEGFR-1 and placental expression of sVEGFR-1 is upregulated by hypoxia. Immunolocalization studies showed progressively intense staining for sVEGFR-1 and VEGF in the trophoblast of placental villous explants throughout gestation. Endothelial cell migration studies using a modified Boyden's chamber showed a significant increase in cell migration in response to VEGF that was significantly attenuated in the presence of exogenous sVEGFR-1. Furthermore, stimulation of endothelial cells with VEGF led to a dose-dependent increase in the release of sVEGFR-1 as determined by enzyme-linked immunosorbent assay (ELISA). Exposure of normal placental villous explants to hypoxia (1% pO2) increased trophoblast expression of sVEGFR-1 when compared with tissue normoxia (5% pO2). In addition, conditioned media from hypoxia treated placental villous explants induced a significant increase in endothelial cell migration that was significantly reduced in presence of sVEGFR-1. Our study demonstrates that hypoxia positively regulates sVEGFR-1 protein expression in ex vivo trophoblasts, which control VEGF-driven angiogenesis.


Evaluation of the discriminatory power of spoligotyping and 19-locus mycobacterial interspersed repetitive unit-variable number of tandem repeat analysis (MIRU-VNTR) of Mycobacterium bovis strains isolated from cattle in Algeria.
Bovine tuberculosis (bTB) caused by Mycobacterium (M.) bovis and M. caprae is a transmissible disease of livestock, notifiable to the World Organization for Animal Health (OIE). BTB particularly affects cattle and small ruminants and can be transmitted to humans thereby posing a significant threat to veterinary and public health worldwide. M. bovis is the principal cause of bTB in Algeria. In order to better understand the route of spreading and elaborate an eradication program, isolation and characterization of mycobacteria from Algerian cattle was performed. Sixty strains belonging to the M. tuberculosis complex were analyzed by spoligotyping, thereof 42 by 19-locus-MIRU-VNTR-typing. Spoligotyping revealed 16 distinguishable patterns (Hunter-Gaston discriminatory index [HGDI] of 0.8294), with types SB0120 (n = 20) and SB0121 (n = 13) being the most frequent patterns, representing 55% of the strains. Analyses based on 19-locus-MIRU-VNTR yielded 32 different profiles, five clusters and one orphan pattern, showing higher discriminatory power (HGDI = 0.9779) than spoligotyping. Seven VNTR-loci [VNTR 577 (alias ETR C), 2163b (QU11b), 2165 (ETR A), 2461 (ETR B), 3007 (MIRU 27), 2163a (QUB11a) and 3232 (QUB 3232)] were the most discriminative loci (HGDI ˃ 0.50). In conclusion, 19-locus-MIRU-VNTR yielded more information than spoligotyping concerning molecular differentiation of strains and better supports the elucidation of transmission routes of M. bovis between Algerian cattle herds.


Searching for an inhibitory action of blood-borne beta-endorphin on LH release.
Concentrations of beta-endorphin were quantified in peripheral blood plasma of sheep by a radioimmunoassay that cross-reacted with beta-lipotrophin. Plasma concentrations of beta-endorphin increased abruptly after physical confinement, bacteraemia, and electroacupuncture treatment for induction of analgesia. In these experimental situations in which plasma concentrations of beta-endorphin increased, plasma concentrations of LH often decreased. To test the hypothesis that increases in blood-borne beta-endorphin actually caused the decrease in LH release, naloxone was administered to antagonize the opioid receptors at which blood-borne beta-endorphin might act. In no case did administration of naloxone disrupt the temporal correlation between experimentally induced increases in plasma beta-endorphin and decreases in plasma LH. It was concluded that the increases in blood-borne beta-endorphin did not cause the decrease in LH release. Other research investigated whether beta-endorphin might be delivered via blood from pituitary to hypothalamus in locally enriched concentrations. Even when pituitary release of beta-endorphin was acutely stimulated, it was not possible to demonstrate retrograde delivery of beta-endorphin to the hypothalamus without dilution in the systemic circulation. In conclusion, it is unlikely that blood-borne beta-endorphin inhibits the release of LH, and beta-endorphin should not be classified as a hormone until blood concentrations of the peptide can be shown to exert some effect at a location distant from its site of secretion.


Friend or foe? A parasitic wasp shifts the cost/benefit ratio in a nursery pollination system impacting plant fitness.
Nursery pollination systems are species interactions where pollinators also act as fruit/seed herbivores of the plant partner. While the plants depend on associated insects for pollination, the insects depend on the plants' reproductive structures for larval development. The outcome of these interactions is thus placed on a gradient between mutualism and antagonism. Less specialized interactions may fluctuate along this gradient with the ecological context, where natural enemies can play an important role. We studied whether a natural enemy may impact the level of seed consumption of a nursery pollinator and how this in turn may influence individual plant fitness. We used the plant Silene latifolia, its herbivore Hadena bicruris, and its ectoparasitoid Bracon variator as a model plant-herbivore-natural enemy system. We investigated seed output, germination, survival, and flower production as proxies for individual plant fitness. We show that B. variator decreases the level of seed consumption by H. bicruris larvae which in turn increased seed output in S. latifolia plants, suggesting that parasitism by B. variator may act as a regulator in the system. However, our results also show that plant survival and flower production decrease with higher seed densities, and therefore, an increase in seed output may be less beneficial for plant fitness than estimated from seed output alone. Our study should add another layer to the complex discussion of whether parasitoids contribute to plant fitness, as we show that taking simple proxies such as seed output is insufficient to determine the net effect of multitrophic interactions.


MicroRNAs in stress signaling and human disease.
Disease is often the result of an aberrant or inadequate response to physiologic and pathophysiologic stress. Studies over the last 10 years have uncovered a recurring paradigm in which microRNAs (miRNAs) regulate cellular behavior under these conditions, suggesting an especially significant role for these small RNAs in pathologic settings. Here, we review emerging principles of miRNA regulation of stress signaling pathways and apply these concepts to our understanding of the roles of miRNAs in disease. These discussions further highlight the unique challenges and opportunities associated with the mechanistic dissection of miRNA functions and the development of miRNA-based therapeutics.


[The difficulties encountered in diagnostics of malignant neoplasms of the middle ear in the children].
The objective of the present work was to estimate the potential of CT and MRI diagnostics of malignant neoplasms of the middle ear in the children. Diagnostics of these tumours encounters great difficulties. We analysed the main subjective and objective causes underlying these difficulties and accounting for the late detection of the pathology being considered. Special attention is given to the possibilities of using CT and MRI techniques for diagnostics of malignant neoplasms of the middle ear in the children. The differential radiodiagnostic criteria for malignant tumours are proposed.


Market survey of Mondia whytei (mulondo) roots in Kampala City, Uganda.
This study explored the consumers' and vendors' perceptions about Mondia whitei roots, in Kampala city, Uganda; determined the marketing margins and the market flow of the roots in the city; documented demand and supply opportunities as well as challenges to marketing of the roots by the vendors. Seventy vendors and 70 consumers of the roots were administered with semi-structured questionnaires. Results showed that M. whytei roots are largely perceived as sexual stimulant, appetiser, flavours for food and drinks, and stimulant for milk production in lactating mothers. Majority of the vendors (74%) and consumers (85%) perceived the trade in the roots as worthwhile. Men and adolescent boys were reported to be the main consumers. Retailers who buy the roots directly from collectors and later sell to consumers dominate the trade. The average price charged per piece and a kilogram of roots increases from collectors, middlemen and to the retailers. The average retail price was US $0.12 per piece of the root and US $1.50 per kg of the roots. Collectors charged the lowest price (US $0.06 and US $0.60 per piece and a kilogram of the roots respectively) though their profit margins remained the highest (50%). Several demand and supply opportunities exist for M. whytei roots and these included few sexual stimulant accepted alternatives to M. whytei roots in Kampala city; consumers' willingness to pay high prices when the roots are scarce, and a large number of M. whytei roots gatherers that could promote the cultivation of this plant for the market. Challenges, such as seasonal low supply of the roots, and unorganised market structure, hamper the trade in M. whytei roots. There is a need for experimental research on efficacies of the perceived uses of the roots reported in this study. The possibility of value addition to the roots sold should be investigated.


Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy.
Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.


Enantioselective catalysis of hetero Diels-Alder reaction and diethylzinc addition using a single catalyst.
[reaction: see text] Integration of two asymmetric reactions in one pot with the promotion of a single catalyst has been achieved in high efficiency and excellent stereoselectivity for hetero Diels-Alder reaction of Danishefsky's diene and diethylzinc addition to aldehydes. The strategy described in the present work demonstrated the ability of a single catalyst to promote two distinct enantioselective reactions in one pot.


Resistance to fludioxonil in Botrytis cinerea isolates from blackberry and strawberry.
Site-specific fungicides, including the phenylpyrrole fludioxonil, are frequently used for gray mold control but are at risk for the development of resistance. In this study, field isolates that were low-resistant (LR) and moderately resistant (MR) to fludioxonil from blackberry and strawberry fields of North Carolina, South Carolina, and Virginia were characterized. Genes involved in osmoregulation, including bcsak1, BcOS4, bos5, and BRRG-1, were cloned and sequenced to detect potential target gene alterations; however, none were found. A previously described mutation (R632I) in transcription factor Mrr1, which is known to increase the expression of ATP-binding cassette transporter AtrB, was found in MR but not in sensitive (S) or LR isolates. Expression of atrB in MR isolates was ≈200-fold increased compared with an S isolate; however, 30- to 100-fold overexpression was also detected in LR isolates. Both MR isolates exhibited increased sensitivity to salt stress in the form of mycelial growth inhibition at 4% NaCl, indicating a disruption of osmoregulatory processes in those strains. However, the glycerol content was indistinguishable between S, LR, and MR isolates with and without exposure to fludioxonil, suggesting that the glycerol synthesis pathway may not be a part of the resistance mechanism in LR or MR strains. An investigation into the origin of LR and MR isolates from blackberry revealed two insertions in the mrr1 gene consistent with those found in the Botrytis clade group S. The emergence of strains overexpressing atrB in European and now in North American strawberry fields underscores the importance of this resistance mechanism for development of resistance to fludioxonil in Botrytis cinerea.


Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma.
The process of alternative splicing is widely misregulated in cancer, but the contribution of splicing regulators to cancer development is largely unknown. In this study, we found that the splicing factor hnRNP A2/B1 is overexpressed in glioblastomas and is correlated with poor prognosis. Conversely, patients who harbor deletions of the HNRNPA2B1 gene show better prognosis than average. Knockdown of hnRNP A2/B1 in glioblastoma cells inhibited tumor formation in mice. In contrast, overexpression of hnRNP A2/B1 in immortal cells led to malignant transformation, suggesting that HNRNPA2B1 is a putative proto-oncogene. We then identified several tumor suppressors and oncogenes that are regulated by HNRNPA2B1, among them are c-FLIP, BIN1, and WWOX, and the proto-oncogene RON. Knockdown of RON inhibited hnRNP A2/B1 mediated transformation, which implied that RON is one of the mediators of HNRNPA2B1 oncogenic activity. Together, our results indicate that HNRNPA2B1 is a novel oncogene in glioblastoma and a potential new target for glioblastoma therapy.


Classical and controlled auditory mismatch responses to multiple physical deviances in anaesthetised and conscious mice.
Human mismatch negativity (MMN) is modelled in rodents and other non-human species to examine its underlying neurological mechanisms, primarily described in terms of deviance-detection and adaptation. Using the mouse model, we aim to elucidate subtle dependencies between the mismatch response (MMR) and different physical properties of sound. Epidural field potentials were recorded from urethane-anaesthetised and conscious mice during oddball and many-standards control paradigms with stimuli varying in duration, frequency, intensity and inter-stimulus interval. Resulting auditory evoked potentials, classical MMR (oddball - standard), and controlled MMR (oddball - control) waveforms were analysed. Stimulus duration correlated with stimulus-off response peak latency, whereas frequency, intensity and inter-stimulus interval correlated with stimulus-on N1 and P1 (conscious only) peak amplitudes. These relationships were instrumental in shaping classical MMR morphology in both anaesthetised and conscious animals, suggesting these waveforms reflect modification of normal auditory processing by different physical properties of sound. Controlled MMR waveforms appeared to exhibit habituation to auditory stimulation over time, which was equally observed in response to oddball and standard stimuli. These findings are inconsistent with the mechanisms thought to underlie human MMN, which currently do not address differences due to specific physical features of sound. Thus, no evidence was found to objectively support the deviance-detection or adaptation hypotheses of MMN in relation to anaesthetised or conscious mice. These findings highlight the potential risk of mischaracterising difference waveform components that are principally influenced by physical sensitivities and habituation of the auditory system.


The clinical significance of esophagogastric junction outflow obstruction and hypercontractile esophagus in high resolution esophageal manometry.
Although major manometric abnormalities, the significance of esophagogastric junction outflow obstruction (EGJOO) and hypercontractile esophagus (HE) is poorly understood. We sought to determine long term outcomes for EGJOO and HE. High-resolution impedance manometry (HRIM) studies conducted from 5/30/2012 to 8/1/2014 consistent with EGJOO and HE and normal studies from 5/30/12 to 11/1/12 were identified. Standardized follow up was conducted with a phone survey utilizing the impact dysphagia questionnaire (IDQ-10). 56 EGJOO, 40 HE patients and 33 controls were identified. Structural evaluation with EGD and esophagram did not differ among groups. Use of opiates in EGJOO (P<.05) and of anticholinergics in EGJOO and HE patients was more prevalent than in controls (P<.005). Dysphagia was more common in EGJOO (P<.05) and chest pain more common in HE (P<.005) at presentation. While HE patients were more likely to be symptomatic (P<.05), the majority of EGJOO and HE patients overall were asymptomatic at a mean 2.8 years follow up without medical or procedural intervention in the majority (72.5%). Symptom persistence at follow up was predicted by maximum distal contractile integral (DCI) and IRP in both EGJOO and HE (P<.05). The majority of patients with EGJOO and HE appear to have a benign clinical course similar to controls in the absence of specific treatment. However, the combination of abnormal IRP and DCI in both HE and EGJOO appears to discriminate an important subset of patients who may benefit from treatment. Further refinement of manometric criteria may therefore provide more useful clinical definitions of EGJOO and HE.


A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor.
9-Nitrocamptothecin (9NC) is a water-insoluble topoisomerase I inhibitor with a broad antitumor activity in animal models. To determine the maximum tolerated oral dose (MTD), a phase I study was performed in patients with advanced cancer refractory to conventional chemotherapy. 9NC was administered orally with escalating doses to cohorts of five patients beginning at 1 mg/m2/day for five consecutive days every week for 4 weeks. Increments were 0.5 mg/m2/day for each cohort. Toxicity was evaluated in 28 patients diagnosed with various malignancies. Seven patients received 1 mg/m2/day for 28 weeks; 10 patients, 1.5 mg/m2/day for 68 weeks; and 26 patients, 2 mg/m2/day for 159 weeks. At 1.5 mg/m2/day or higher, the dose-limiting toxicity was hematologic, with grade 4 anemia in eight (29%); neutropenia in seven (25%) and thrombocytopenia in five (18%). Grade 2 or higher toxic effects occurred at each dose level: nausea and vomiting in 15 (54%), diarrhea in nine (32%), chemical cystitis in seven (25%), neutropenic sepsis in six (21%) and weight loss in five (18%) (N=28). Responses were observed after 2-8 weeks of therapy in five patients with pancreatic, breast, ovarian and hematologic tumors. Fourteen patients had a disease stabilization and one patient received treatment up to 18 months. The MTD of 9NC given orally has been estimated at 1.5 mg/m2/day for five consecutive days weekly. 9NC may be tolerated for sustained periods of time, but has the potential for significant hematologic, gastrointestinal and urinary bladder toxicity. Significant antitumor activity was observed, warranting further clinical investigations.


Sub-nanoradiant beam pointing monitoring and stabilization system for controlling input beam jitter in gravitational wave interferometers.
In this paper, a simple and effective control system to monitor and suppress the beam jitter noise at the input of an optical system, called a beam pointing control (BPC) system, will be described, showing the theoretical principle and an experimental demonstration for the application of large-scale gravitational wave (GW) interferometers (ITFs), in particular for the Advanced Virgo detector. For this purpose, the requirements for the control accuracy and the sensing noise will be computed by taking into account the Advanced Virgo optical configuration, and the outcomes will be compared with the experimental measurement obtained in the laboratory. The system has shown unprecedented performance in terms of control accuracy and sensing noise. The BPC system has achieved a control accuracy of ~10⁻⁸ rad for the tilt and ~10⁻⁷ m for the shift and a sensing noise of less than 1 n rad/√Hz, which is compliant with the Advanced Virgo GW ITF requirements.


The endocannabinoid N-arachidonoyl glycine (NAGly) inhibits store-operated Ca2+ entry by preventing STIM1-Orai1 interaction.
The endocannabiniod anandamide (AEA) and its derivate N-arachidonoyl glycine (NAGly) have a broad spectrum of physiological effects, which are induced by both binding to receptors and receptor-independent modulations of ion channels and transporters. The impact of AEA and NAGly on store-operated Ca(2+) entry (SOCE), a ubiquitous Ca(2+) entry pathway regulating many cellular functions, is unknown. Here we show that NAGly, but not AEA reversibly hinders SOCE in a time- and concentration-dependent manner. The inhibitory effect of NAGly on SOCE was found in the human endothelial cell line EA.hy926, the rat pancreatic β-cell line INS-1 832/13, and the rat basophilic leukemia cell line RBL-2H3. NAGly diminished SOCE independently from the mode of Ca(2+) depletion of the endoplasmic reticulum, whereas it had no effect on Ca(2+) entry through L-type voltage-gated Ca(2+) channels. Enhanced Ca(2+) entry was effectively hampered by NAGly in cells overexpressing the key molecular constituents of SOCE, stromal interacting molecule 1 (STIM1) and the pore-forming subunit of SOCE channels, Orai1. Fluorescence microscopy revealed that NAGly did not affect STIM1 oligomerization, STIM1 clustering, or the colocalization of STIM1 with Orai1, which were induced by Ca(2+) depletion of the endoplasmic reticulum. In contrast, independently from its slow depolarizing effect on mitochondria, NAGly instantly and strongly diminished the interaction of STIM1 with Orai1, indicating that NAGly inhibits SOCE primarily by uncoupling STIM1 from Orai1. In summary, our findings revealed the STIM1-Orai1-mediated SOCE machinery as a molecular target of NAGly, which might have many implications in cell physiology.


Effects of smoking, gender and occupational exposure on the risk of severe pulmonary fibrosis: a population-based case-control study.
To estimate the effects of smoking, gender and occupational exposure on the risk of developing severe pulmonary fibrosis (PF), including dose-response and interaction effects. National case-control study of 171 patients (cases) who had started a long-term oxygen therapy for PF in Sweden between February 1997 and April 2000, and 719 random control participants from the general population. Of these cases, 137 had probable idiopathic PF (IPF). The ORs for smoking, gender and occupational exposure were estimated using Mantel-Haenszel analysis and conditional logistic regression, controlling for age and year of diagnosis. The adverse effect of smoking was amplified by male gender and occupational exposure, OR 4.6 (95% CI 2.1 to 10.3) for PF, and OR 3.0 (1.3 to 6.5) for IPF, compared with in non-exposed women. Higher cumulative smoking exposure was linearly associated with increased risks. Compared with smoking less than 10 pack-years, smoking ≥20 pack-years was associated with increased risk of PF and IPF, OR 2.6 (1.4 to 4.9) and OR 2.5 (1.3 to 5.0), respectively. Smoking has a dose-related association with increased risk of severe PF. Men with a history of smoking and occupational exposure is a particular risk group for developing severe PF.


Microinstability of the hip-it does exist: etiology, diagnosis and treatment.
Symptomatic hip microinstability is now recognized as a potential cause of pain and disability in young patients. Causes of hip microinstability include underlying bony or soft tissue abnormalities and iatrogenic injuries of the hip capsule; however, many patients lack a clear underlying etiology. Treatment usually begins with an extensive course of non-operative management with an emphasis on activity modification and physical therapy. Surgical intervention should focus on treatment of the underlying cause as well as any associated intra-articular pathology. In many cases, arthroscopic suture plication can be considered when bony deficiency is not the cause. In this article, we will review the spectrum of symptomatic hip microinstability with a focus on the relevant anatomy, etiology, diagnosis and various treatment options.


Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression.
To disclose detailed genetic mechanisms in hepatocellular carcinoma (HCC) with a view toward development of novel therapeutic targets, we analyzed expression profiles of 20 primary HCCs and their corresponding noncancerous tissues by means of cDNA microarrays consisting of 23,040 genes. Up-regulation of mitosis-promoting genes was observed in the majority of the tumors examined. Some genes showed expression patterns in hepatitis B virus-positive HCCs that were different from those in hepatitis C virus-positive HCCs; most of them encoded enzymes that metabolize carcinogens and/or anticancer agents. Furthermore, we identified a number of genes associated with malignant histological type or invasive phenotype. Accumulation of such data will make it possible to define the nature of individual tumors, to provide clues for identifying new therapeutic targets, and ultimately to optimize treatment of each patient.


Inhibitory effects of four isoabrins on the growth of sarcoma 180 cells.
The four isoabrins were shown to be capable of inhibiting the growth of tumor cells in vivo when one-fifth of their median lethal dose was used. From the in vitro experiments, the doses required for 50% inhibition of protein biosynthesis are 3.2 pg, 45 ng, 32 ng, and 10 ng/ml for abrin-a, -b, -3, and -d, respectively. Except for abrin-b, a good correlation between the inhibitory effects of abrins on the tumor growth and protein biosynthesis was observed. These isoabrins show a moderate inhibitory effect on DNA biosynthesis.


A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis.
Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.