Two androgen response elements in the androgen receptor coding region are required for cell-specific up-regulation of receptor messenger RNA.
In most cells and tissues containing androgen receptors (ARs), androgen regulates the levels of AR messenger RNA (mRNA). As the AR concentration is correlated with androgen responsiveness, this autoregulation of AR mRNA may affect cellular sensitivity to androgens. Androgens decrease levels of AR mRNA in many cell lines and tissues; however, in some tissues and possibly also at certain developmental stages, AR mRNA is up-regulated by androgens. Sequences within the 5'-flanking region and AR promoter do not appear to be sufficient for androgen regulation of AR mRNA. We have previously shown that both down- and up-regulation of AR mRNA by androgen can be reproduced in cell lines expressing a transfected human AR complementary DNA (cDNA). Sequences within the AR cDNA confer this autoregulation in transfected cells, suggesting that sequences within the transcribed region of the AR gene are sufficient for autoregulation. In this study we have determined the mechanism of androgenic up-regulation of AR mRNA encoded by the human AR cDNA in the prostate cancer cell line, PC3, and have identified the cis-acting sequences of the AR cDNA that are required. The observations that actinomycin D blocked androgenic up-regulation of AR mRNA but cycloheximide had no effect are consistent with a model in which AR is directly involved in transcriptional up-regulation of AR cDNA expression. Nuclear run-on assays showed that androgen treatment resulted in increased transcription of the AR cDNA. Furthermore, a 350-bp AR cDNA fragment inserted 5' of a thymidine kinase promoter-chloramphenicol acetyltransferase gene conferred androgen induction of chloramphenicol acetyltransferase activity in PC3 cells. This 350-bp fragment, which is located in the AR coding region, contains two putative androgen response elements (AREs) separated by 182 bp. The 5'-most ARE (ARE-1, 5'-TGTCCT-3') resembles a half-site of the palindromic consensus hormone response element, recognized by several steroid receptors, including AR, and the 3'-sequence (ARE-2, 5'-AGTACTCC-3') is identical to a portion of an androgen-responsive region found in the rat probasin gene promoter. Analysis of either ARE-1 or ARE-2 mutants revealed that these elements function synergistically. AR protein binds to the 350-bp fragment, as demonstrated by electrophoretic mobility shift assays using a glutathione-S-transferase-AR fusion protein containing the DNA- and steroid-binding domains of AR. These results indicate that the AR coding region contains an androgen-responsive region that is involved in cell line-specific up-regulation of AR mRNA.


Gap2 promotes the formation of a stable protein complex required for mature Fap1 biogenesis.
Serine-rich repeat glycoproteins (SRRPs) are important bacterial adhesins conserved in streptococci and staphylococci. Fap1, a SRRP identified in Streptococcus parasanguinis, is the major constituent of bacterial fimbriae and is required for adhesion and biofilm formation. An 11-gene cluster is required for Fap1 glycosylation and secretion; however, the exact mechanism of Fap1 biogenesis remains a mystery. Two glycosylation-associated proteins within this cluster--Gap1 and Gap3--function together in Fap1 biogenesis. Here we report the role of the third glycosylation-associated protein, Gap2. A gap2 mutant exhibited the same phenotype as the gap1 and gap3 mutants in terms of Fap1 biogenesis, fimbrial assembly, and bacterial adhesion, suggesting that the three proteins interact. Indeed, all three proteins interacted with each other independently and together to form a stable protein complex. Mechanistically, Gap2 protected Gap3 from degradation by ClpP protease, and Gap2 required the presence of Gap1 for expression at the wild-type level. Gap2 augmented the function of Gap1 in stabilizing Gap3; this function was conserved in Gap homologs from Streptococcus agalactiae. Our studies demonstrate that the three Gap proteins work in concert in Fap1 biogenesis and reveal a new function of Gap2. This insight will help us elucidate the molecular mechanism of SRRP biogenesis in this bacterium and in pathogenic species.


Rickettsialpox in New York City: a persistent urban zoonosis.
Rickettsialpox, a spotted fever rickettsiosis, was first identified in New York City (NYC) in 1946. During the next five years, approximately 540 additional cases were identified in NYC. However, during the subsequent five decades, rickettsialpox received relatively little attention from clinicians and public health professionals, and reporting of the disease diminished markedly. During February 2001 through August 2002, 34 cases of rickettsialpox in NYC were confirmed at CDC from cutaneous biopsy specimens tested by using immunohistochemical (IHC) staining, PCR analysis, and isolation of Rickettsia akari in cell culture, as well as an indirect immunofluorescence assay of serum specimens. Samples were collected from patients with febrile illnesses accompanied by an eschar, a papulovesicular rash, or both. Patients originated predominantly from two boroughs (Manhattan and the Bronx). Only 8 (24%) of the cases were identified prior to the reports of bioterrorism-associated anthrax in the United States during October 2001, and lesions of several patients evaluated during and subsequent to this episode were suspected initially to be cutaneous anthrax. IHC staining of biopsy specimens of eschars and papular lesions were positive for spotted fever group rickettsiae for 32 patients. Of the eleven patients for whom paired serum samples were obtained, all demonstrated fourfold or greater increases in antibody titers reactive with R. akari. The 17-kDa protein gene sequence of R. akari was amplified from eschars of five patients. Four isolates of R. akari were obtained from cutaneous lesions. Possible factors responsible for the increase in clinical samples evaluated for rickettsialpox during this interval include renewed clinical interest in the disease, improved diagnostic methods, epizootiological influences, and factors associated with the recent specter of bioterrorism.


Deep reinforcement learning for the control of microbial co-cultures in bioreactors.
Multi-species microbial communities are widespread in natural ecosystems. When employed for biomanufacturing, engineered synthetic communities have shown increased productivity in comparison with monocultures and allow for the reduction of metabolic load by compartmentalising bioprocesses between multiple sub-populations. Despite these benefits, co-cultures are rarely used in practice because control over the constituent species of an assembled community has proven challenging. Here we demonstrate, in silico, the efficacy of an approach from artificial intelligence-reinforcement learning-for the control of co-cultures within continuous bioreactors. We confirm that feedback via a trained reinforcement learning agent can be used to maintain populations at target levels, and that model-free performance with bang-bang control can outperform a traditional proportional integral controller with continuous control, when faced with infrequent sampling. Further, we demonstrate that a satisfactory control policy can be learned in one twenty-four hour experiment by running five bioreactors in parallel. Finally, we show that reinforcement learning can directly optimise the output of a co-culture bioprocess. Overall, reinforcement learning is a promising technique for the control of microbial communities.


Observations on the effect of immersion in Bath spa water.
Immersion in water in spas has been practised for centuries and has many proponents. Despite fierce debate about its efficacy there has been little scientific evaluation of the effect of immersion in mineral waters. Eight normal subjects were immersed in Bath spa water for two hours and the renal, haematological, and cardiovascular responses were compared with those in the control periods before and after immersion. Significant, twofold diuresis and natriuresis, 5% haemodilution, and a 50% increase in cardiac index were observed in subjects immersed, sitting, in Bath spa water at 35 degrees C. These changes may constitute part of the scientific rationale for spa treatment in many states of disease.


Relationship between antibody susceptibility and lipopolysaccharide O-antigen characteristics of invasive and gastrointestinal nontyphoidal Salmonellae isolates from Kenya.
Nontyphoidal Salmonellae (NTS) cause a large burden of invasive and gastrointestinal disease among young children in sub-Saharan Africa. No vaccine is currently available. Previous reports indicate the importance of the O-antigen of Salmonella lipopolysaccharide for virulence and resistance to antibody-mediated killing. We hypothesised that isolates with more O-antigen have increased resistance to antibody-mediated killing and are more likely to be invasive than gastrointestinal. We studied 192 NTS isolates (114 Typhimurium, 78 Enteritidis) from blood and stools, mostly from paediatric admissions in Kenya 2000-2011. Isolates were tested for susceptibility to antibody-mediated killing, using whole adult serum. O-antigen structural characteristics, including O-acetylation and glucosylation, were investigated. Overall, isolates were susceptible to antibody-mediated killing, but S. Enteritidis were less susceptible and expressed more O-antigen than Typhimurium (p<0.0001 for both comparisons). For S. Typhimurium, but not Enteritidis, O-antigen expression correlated with reduced sensitivity to killing (r = 0.29, 95% CI = 0.10-0.45, p = 0.002). Both serovars expressed O-antigen populations ranging 21-33 kDa average molecular weight. O-antigen from most Typhimurium were O-acetylated on rhamnose and abequose residues, while Enteritidis O-antigen had low or no O-acetylation. Both Typhimurium and Enteritidis O-antigen were approximately 20%-50% glucosylated. Amount of S. Typhimurium O-antigen and O-antigen glucosylation level were inversely related. There was no clear association between clinical presentation and antibody susceptibility, O-antigen level or other O-antigen features. Kenyan S. Typhimurium and Enteritidis clinical isolates are susceptible to antibody-mediated killing, with degree of susceptibility varying with level of O-antigen for S. Typhimurium. This supports the development of an antibody-inducing vaccine against NTS for Africa. No clear differences were found in the phenotype of isolates from blood and stool, suggesting that the same isolates can cause invasive disease and gastroenteritis. Genome studies are required to understand whether invasive and gastrointestinal isolates differ at the genotypic level.


A variable probe pitch micro-Hall effect method.
Hall effect metrology is important for a detailed characterization of the electronic properties of new materials for nanoscale electronics. The micro-Hall effect (MHE) method, based on micro four-point probes, enables a fast characterization of ultrathin films with minimal sample preparation. Here, we study in detail how the analysis of raw measurement data affects the accuracy of extracted key sample parameters, i.e., how the standard deviation on sheet resistance, carrier mobility and Hall sheet carrier density is affected by the data analysis used. We compare two methods, based primarily on either the sheet resistance signals or the Hall resistance signals, by theoretically analysing the effects of electrode position errors and electrical noise on the standard deviations. We verify the findings with a set of experimental data measured on an ultrashallow junction silicon sample. We find that in presence of significant electrical noise, lower standard deviation is always obtained when the geometrical analysis is based on the sheet resistance signals. The situation is more complicated when electrode position errors are dominant; in that case, the better method depends on the experimental conditions, i.e., the distance between the insulating boundary and the electrodes. Improvement to the accuracy of Hall Effect measurement results is crucial for nanoscale metrology, since surface scattering often leads to low carrier mobility.


Efficacy, safety, and potential of extended-release lamotrigine in the treatment of epileptic patients.
Epilepsy is a frequent, chronic disease demanding long-term medication with antiepileptic drugs (AEDs). When slow release formulations of AEDs are used the chance of compliance and control of seizures is increased. Lamotrigine (LTG) is a broad spectrum antiepileptic drug (AED), effective against both generalized and partial seizures. Its immediate-release formulation (LTG-IR) requires twice-daily dosing. In contrast, an extended-release formulation (LTG-XR) may be given once daily, providing a flatter dose-concentration curve with apparently lower maximum serum levels. Simplified dosing positively affects compliance and LTG-XR has a similar profile of efficacy and tolerability to LTG-IR. Rashes, including Stevens-Johnson syndrome, are the most serious adverse effect impacting 0.8% of pediatric patients. Thus, LTG-XR should be discontinued upon the appearance of rash.


A Contextual Behavioral Framework for Enhancing Cultural Responsiveness in Behavioral Service Delivery for Latino Families.
In recent years, the field of behavior analysis has shifted its attention to issues of diversity, social justice, and cultural responsiveness. With various cultural groups in the United States, behavior analytic practitioners increasingly find themselves serving clients of diverse cultural backgrounds. One of the populations that continue to face underrepresentation is Latinos. In the current article, a cultural understanding of the Latino culture is provided to support cultural responsiveness in behavioral service delivery. This article explores the Latino identity of individuals receiving behavioral services, systemic barriers faced by Latinos, the use of acceptance and commitment training for Latino families and clients, and Latino cultural values and their role in behavioral service delivery. Most important, a shift in perspective to account for the barriers perceived by practitioners within the context of Latino cultural values is offered through a contextual behavioral framework, the literature, and the authors' personal and professional experiences as Latino behavior analysts. Recommendations in the areas of assessment, treatment design, service delivery, and collaboration when working with Latinos are also discussed.


Prevention of lymphocele by using gelatin-thrombin matrix as a tissue sealant after pelvic lymphadenectomy in patients with gynecologic cancers: a prospective randomized controlled study.
This prospective randomized controlled pilot study aimed to find whether gelatin-thrombin matrix used as a tissue sealant (FloSeal) can prevent the occurrence of pelvic lymphocele in patients with gynecologic cancer who has undergone pelvic lymphadenectomy. Each patient, who undergo a laparotomic pelvic lymph node dissection on both sides, was randomly assigned for FloSeal application on 1 side of the pelvis. The other side of the pelvis without any product application being the control side. The amount of lymph drainage at each side of the pelvis was measured for 3 days, and computed tomography scans were obtained 7 days and 6 months after surgery for detection of pelvic lymphocele. Among 37 cases, the median amount of lymph drainage was significantly decreased in the hemi-pelvis treated with FloSeal compared to the control hemi-pelvis (p=0.025). The occurrence of lymphocele was considerably reduced in treated hemi-pelvis (8/37, 21.6%) compared with control hemi-pelvis (12/37, 32.4%) after 7 post-operative days (p=0.219), and more decreased in the treated hemi-pelvis (5/37, 13.5%) compared with control hemi-pelvis (9/37, 24.3%) after postoperative 6 months (p=0.344). The application of FloSeal as a tissue sealant in lymph nodes resected tissues can reduce the incidence of pelvic lymphocele in gynecologic cancer patients. A large randomized controlled study could confirm these preliminary results.


Lowered cortistatin expression is an early event in the human diabetic retina and is associated with apoptosis and glial activation.
Cortistatin (CST), a neuropeptide with strong structural and functional similarities to somatostatin, is abundant in the vitreous fluid, and it is decreased in patients with proliferative diabetic retinopathy. The aims of the present study were to explore whether the retina produces CST, and to compare its expression between diabetic and nondiabetic donors. Retinal neurodegeneration was assessed by measuring glial fibrilar acidic protein (GFAP) by confocal laser microscopy and counting the apoptotic TUNEL positive cells in which nuclear fragmentation as well as condensation were present. Human postmortem eyes (10) from five diabetic donors were compared with 10 eyes from five nondiabetic donors, matched by age. CST mRNA (RT-PCR) and CST (confocal laser microscopy) were measured separately in both the neuroretina and retinal pigment epithelium (RPE). Retinal neurodegeneration was assessed by measuring glial fibrillar acidic protein (GFAP) by confocal laser microscopy and counting the apoptotic cells by TUNEL. CST was found to be produced by the human retina, and higher levels of CST mRNA were found in RPE than in the neuroretina. CST mRNA levels in diabetic donors were significantly lower in both the RPE (p=0.001) and the neuroretina (p=0.03) in comparison with nondiabetic donors. CST immunofluorescence was in agreement with mRNA expression, but the differences were only significant when comparing neuroretinas (p=0.03). Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas in comparison with nondiabetic retinas. These changes were inversely related with CST levels. CST is expressed in the human retina. There is more CST in the RPE than in the neuroretina. A lower expression of CST exists in diabetic retinas and it is associated with retinal neurodegeneration.


The prevalence of alpha-antitrypsin heterozygotes (Pi MZ) in patients with obstructive pulmonary disease.
An increased incidence of intermediate deficiency of serum alpha1-antitrypsin resulting from Pi phenotype MZ has been reported in patients with chronic obstructive pulmonary disease (COPD) by some laboratories but not confirmed by others. Prevalence of Pi MZ was determined in patients with COPD among 502 subjects referred to a pulmonary function testing laboratory in a region with low concentrations of air pollutants. Control prevalences were obtained from 930 randomly selected subjects in the same community as well as from patients without COPD referred to the laboratory. Depending on criteria used to define COPD, 155 to 306 subjects had COPD. Pi MZ prevalence in subjects with COPD varied from 1.5 to 4 times the prevalence in the community control group and in the patients without COPD. This difference approached significance or was significant. Because Pi MZ was present in only 3.5 to 4.5 per cent of patients with COPD, Pi MZ is not a major factor in the etiology of COPD in this community. The higher incidence of Pi MZ inpatients with COPD reported by other investigators may be explained by small sample size, bias in selection of study or control population groups, or the development of COPD from interaction between Pi MZ and air pollutants or other factors not present in this community.


Ictal characteristics of pseudoseizures.
The spontaneous pseudoseizures resembling tonic-clonic seizures in 25 patients were recorded on simultaneous videotape and electroencephalograms and were compared with the seizures recorded from 25 patients with true tonic-clonic epileptic events. The goal of the comparison was to identify bedside clinical criteria to assist in differentiating between the two groups. The variables of age, sex, and selected physical manifestations of the events were compared for the two groups by appropriate statistical methods, including a multivariate step-wise discriminate analysis. Significant differences between the two groups of seizures were identified for several variables, and most strikingly for the character of upper and lower extremity movements, the time of vocalization during the event, the character of pelvic movements, and the nature of body tone during the events. Useful bedside criteria for distinguishing a pseudoseizure from a tonic-clonic seizure were identified.


Structure and chemical ordering in CoPt nanoalloys.
The structure and chemical ordering of CoPt nanoclusters in the size range of 1 to 3 nm are investigated by global optimization methods and Monte Carlo simulations using a many body potential derived from the tight binding model. For the smaller systems (number of atoms N < 100), the optimized clusters display a polyicosahedral-like atomic structure with a little core-shell chemical ordering characterized by a particular surface chemical configuration: some pentagonal or hexagonal Pt rings centered, respectively on a Co atom or a Co dimer. A transition to the decahedral symmetry occurs at about N = 100 atoms, with a pseudo L1(0) ordered phase in each tetrahedral unit. For larger cluster sizes, 201 < N < 1289, the L1(0)-ordered/disordered transition on the face centered cubic truncated octahedron is studied by canonical Monte Carlo simulations showing that the critical disordering temperature decreases with the cluster size. We also notice a Co surface segregation especially at edges and, possibly, (100) facets, depending on the cluster size, on both cubic and fivefold symmetry structures.


[Clinical implications of DNA-topoisomerases examination in renal biopsies from patients with nephritis].
To study expression of topoisomerases (TI) I and II alpha (DNA-bound enzymes involved in transcription and replication) in renal tissue as markers of activity and prognosis of glomerulonephritis (GN) decisive for choice of immunodepressive therapy. TI expression was studied immunohistochemically in renal biopsies from 177 patients with different morphological variants of GN and in the samples of unaffected kidney tissue removed in 12 patients for local tumors. There are definite differences between proliferative and non-proliferative GN variants--elevation of TI levels and monocytic infiltration in proliferative GN. Focal-segmental glomerulosclerosis is characterized by a high TI II alpha level in mesangial cells and monocytic infiltration of the glomeruli which are typical for inflammation. A statistical relationship between TI levels in mesangial cells and glomerular epithelium suggests a pathogenetic relation between these links of the pathological process. Molecular markers of activation and proliferation of cells and direct inductors of the inflammatory process (cells of monocytic infiltrate) closely correlated with the activity index--an integral indicator of inflammatory activity, as well as with the integral indicator of sclerotic processes in renal tissue--sclerosis index. Monocytic infiltration in the interstitium correlated both with morphological manifestations of activity, progression of nephritis and their clinical equivalents. In high TI expression GN resistance to immunodepressive therapy rose. To overcome the resistance, immunodepressive therapy must be more active--large doses and duration of treatment. In patients with lupus nephritis and mesangiocapillary GN renal prognosis was worse in the presence of high TI expression in mesangial cells and epithelium of the renal canaliculi. The authors are the first to demonstrate TI expression in renal tissue of GN patients, correlation of its level with activity of renal process as well as its role in prediction of response to treatment and the rate of renal failure progression. It is suggested that high TI expression entails a progressive course of GN.


[Immediate and late results of combined treatment of dilatated cardiomyopathy in children].
Effects of combined treatment of chronic heart failure on the clinical course and outcome of dilatated cardiomyopathy was evaluated in 151 children followed up for 6 months-14 years (4.0 +/- 0.5 yr). It was shown that the use of ACE inhibitors and beta-adrenoblockers in combined therapy of this pathology improved survival and quality of life of the children


Comparison of Methods for Measuring Cyclodeviation.
To compare the double-Maddox rod test with other methods of measuring cyclodeviation DESIGN: Retrospective cohort study. We retrospectively identified 153 adults in a clinical practice with cyclodeviation assessed using double-Maddox rods, of whom 105 were also assessed using fusible synoptophore targets, 73 using nonfusible synoptophore targets, 118 using single-Maddox rod, and 43 using fundus photography. Relationships between double-Maddox rod and other tests were evaluated by calculating mean differences with 95% confidence intervals (CI), intraclass correlation coefficients (ICC), and Bland-Altman plots with linear regression. Synoptophore cross-in-circle targets and the largest (of right or left) single-Maddox rod values were similar to double-Maddox values (mean differences: -1.2° and 0.1°, respectively; ICC: 0.79 and 0.82, respectively). Synoptophore house targets measured less excyclodeviation (mean difference: -2.7°; ICC: 0.71). Mean summed single-Maddox rod values were somewhat similar to double-Maddox values (mean difference: 1.5°; ICC: 0.85), but differences increased with greater cyclodeviation (r2 = 0.2678; P < .001). Fundus photographs showed large, uncorrelated differences compared with double-Maddox rod test, when summing right and left eyes and when using the largest of right or left (mean differences: 12.2° and 6.2°; ICC: -0.02 and 0.21, respectively), and differences increased with greater cyclodeviation (r2 = 0.4094; P < .001 and r2 = .1143; P= .03, respectively). There was good agreement between double-Maddox and the largest single- Maddox test values and synoptophore cross-in-circle targets but poorer agreement with other tests. Further study is needed to understand which measurements best reflect true cyclodeviation and relationships with symptoms.


[Oxidation of alpha-methylstyrene by Pseudomonas cultures].
The work was aimed at studying alpha-methylstyrene oxidation by three active Pseudomonas cultures. P. acidovorans 9 oxidized alpha-methylstyrene only to acetophenone whereas two P. aeruginosa cultures assimilated the compound entirely. Analysis of the intermediate products and enzymes catalyzing the aromatic ring cleavage suggests that these strains oxidize alpha-methylstyrene via a new unknown pathway.


New luminescent solids in the Ln-W(Mo)-Te-O-(Cl) systems.
Solid-state reactions of lanthanide(III) oxide (and/or lanthanide(III) oxychloride), MoO3 (or WO3), and TeO2 at high temperature lead to eight new luminescent compounds with four different types of structures, namely, Ln2(MoO4)(Te4O10) (Ln = Pr, Nd), La2(WO4)(Te3O7)2, Nd2W2Te2O13, and Ln5(MO4)(Te5O13)(TeO3)2Cl3 (Ln = Pr, Nd; M = Mo, W). The structures of Ln2(MoO4)(Te4O10) (Ln = Pr, Nd) feature a 3D network in which the MoO4 tetrahedra serve as bridges between two lanthanide(III) tellurite layers. La2(WO4)(Te3O7)2 features a triple-layer structure built of a [La2WO4]4+ layer sandwiched between two Te3O72- anionic layers. The structure of Nd2W2Te2O13 is a 3D network in which the W2O108- dimers were inserted in the large tunnels of the neodymium(III) tellurites. The structures of Ln5(MO4)(Te5O13)(TeO3)2Cl3 (Ln = Pr, Nd; M = Mo, W) feature a 3D network structure built of lanthanide(III) ions interconnected by bridging TeO32-, Te5O136-, and Cl- anions with the MO4 (M = Mo, W) tetrahedra capping on both sides of the Ln4 (Ln = Pr, Nd) clusters and the isolated Cl- anions occupying the large apertures of the structure. Luminescent studies indicate that Pr2(MoO4)(Te4O10) and Pr5(MO4)(Te5O13)(TeO3)2Cl3 (M = Mo, W) are able to emit blue, green, and red light, whereas Nd2(MoO4)(Te4O10), Nd2W2Te2O13, and Nd5(MO4)(Te5O13)(TeO3)2Cl3 (M = Mo, W) exhibit strong emission bands in the near-IR region.


Assessment of conceptual tempo in the type A (coronary prone) behavior pattern.
Previous research has documented an association between a particular behavioral complex termed Type A, and increased incidence of coronary heart disease. In an effort to define further some of the behavioral characteristics that distinguish Type A subjects from their noncoronary-prone (Type B) counterparts, subjects were administered a test of conceptual impulsivity-reflection. While there were clear sex differences in performance, the results of the present study offered only qualified support for the notion that Type A individuals are more impulsive than Type B individuals. One component of Type A, Speed and Impatience, was shown to be related to increased impulsivity in women, but not in men. The findings suggest the importance of considering the interaction of gender with behavioral subcomponents of the Type A behavior pattern.


Prognostic implications of ploidy and proliferative activity in diffuse large cell lymphomas.
Paraffin-embedded surgical biopsies from 50 patients with newly diagnosed diffuse large cell lymphoma (DLCL) were examined for proliferative activity and DNA aneuploidy by flow cytometry. These results were correlated with the clinical characteristics of these patients and the course of their disease. High proliferative activity, defined as less than 80% of cells in G0 or G1, was found to be the single most important pretreatment adverse prognostic factor in these patients. This relationship remained significant after correcting for poor performance status and advanced Ann Arbor stage, the other factors found to be associated with a shortened survival. DLCLs with high proliferative activity were more probable to present with extranodal involvement than those with lower proliferative activity. The mitotic count as determined by light microscopy did not correlate with flow cytometry-defined proliferative activity and may be a less accurate method for assessing this important biological characteristic in DLCL. DNA aneuploidy was detected in 62% of cases but did not appear to have any prognostic significance. Biopsies from patients who presented with lymphomatous bone marrow involvement, however, invariably demonstrated an aneuploid stemline. These results suggest that differences in proliferative activity may be an important biological basis for the variable prognosis seen in DLCL.


Strategic modeling of the pediatric nurse practitioner workforce.
To assess the current pediatric nurse practitioner (PNP) workforce and to investigate the impact of potential policy changes to address forecasted shortages. We modeled the admission of students into nursing bachelor's programs and followed them through advanced clinical programs. Prediction models were combined with optimal decision-making to determine best-case scenario admission levels. We computed 2 measures: (1) the absolute shortage and (2) the expected number of years until the PNP workforce will be able to fully satisfy PNP demand (ie, self-sufficiency). There is a forecasted shortage of PNPs in the workforce over the next 13 years. Under the best-case scenario, it would take at least 13 years for the workforce to fully satisfy demand. Our analysis of potential policy changes revealed that increasing the specialization rate for PNPs by 4% would decrease the number of years required until there are enough PNPs from 13 years to 5 years. Increasing the certification examination passing rate to 96% from the current average of 86.9% would lead to self-sufficiency in 11 years. In addition, increasing the annual growth rate of master's programs to 36% from the current maximum of 10.7% would result in self-sufficiency in 5 years. Current forecasts of demand for PNPs indicate that the current workforce will be incapable of satisfying the growing demand. Policy changes can result in a reduction in the expected shortage and potentially improve access to care for pediatric patients.


A review of health-related workplace productivity loss instruments.
The objective of this review was to identify health-related workplace productivity loss survey instruments, with particular emphasis on those that capture a metric suitable for direct translation into a monetary figure. A literature search using Medline, HealthSTAR, PsycINFO and Econlit databases between 1966 and 2002, and a telephone-administered survey of business leaders and researchers, were conducted to identify health-related workplace productivity measurement survey instruments. This review was conducted from the societal perspective. Each identified instrument was reviewed for the following: (i). reliability; (ii). content validity; (iii). construct validity; (iv). criterion validity; (v). productivity metric(s); (vi). instrument scoring technique; (vii). suitability for direct translation into a monetary figure; (viii). number of items; (ix). mode(s) of administration; and (x). disease state(s) in which it had been tested. Reliability and validity testing have been performed for 8 of the 11 identified surveys. Of the 11 instruments identified, six captured metrics that are suitable for direct translation into a monetary figure. Of those six, one instrument measured absenteeism, while the other five measured both absenteeism and presenteeism. All of the identified instruments except for one were available as paper, self-administered questionnaires and many were available in languages other than English. This review provides a comprehensive overview of the published, peer-reviewed survey instruments available to measure health-related workplace productivity loss. As the field of productivity measurement matures, tools may be developed that will allow researchers to accurately calculate lost productivity costs when performing cost-effectiveness and cost-benefit analyses. Using data captured by these instruments, society and healthcare decision makers will be able to make better informed decisions concerning the value of the medications, disease management and health promotion programmes that individuals receive.


RPE cell surface proteins in normal and dystrophic rats.
Membrane-bound proteins in plasma membrane enriched fractions from cultured rat RPE were analyzed by two-dimensional gel electrophoresis. Membrane proteins were characterized on three increasingly specific levels. Total protein was visualized by silver staining. A maximum of 102 separate proteins were counted in silver-stained gels. Glycoproteins were labeled with 3H-glucosamine or 3H-fucose and detected by autoradiography. Thirty-eight fucose-labeled and 61-71 glucosamine-labeled proteins were identified. All of the fucose-labeled proteins were labeled with glucosamine-derived radioactivity. Proteins exposed at the cell surface were labeled by lactoperoxidase-catalyzed radioiodination prior to preparation of membranes for two-dimensional analysis. Forty separate 125I-labeled surface proteins were resolved by two-dimensional electrophoresis/autoradiography. Comparison with the glycoprotein map showed that a number of these surface labeled proteins were glycoproteins. Two-dimensional maps of total protein, fucose-labeled, and glucosamine-labeled glycoproteins, and 125I-labeled surface proteins of membranes from dystrophic (RCS rdy-p+) and normal (Long Evans or RCS rdy+p+) RPE were compared. No differences in the total protein or surface-labeled proteins were observed. However, the results suggest that a 183K glycoprotein is more heavily glycosylated with glucosamine and fucose in normal RPE membranes as compared to membranes from dystrophic RPE.


Expression of novel antioxidant thioredoxin-2 in the rat brain.
Thioredoxins are a class of small redox-regulating proteins that have been implicated in the control of various aspects of cellular functions and seem to be one of the key regulators of signalling in the cellular responses to various stresses. Thioredoxin-2 (Trx2) is a novel mammalian thioredoxin which, in contrast to previously known cytosolic thioredoxin (Trx1), has been localized to the mitochondria. Trx2 is abundantly expressed in skeletal muscle, heart and adrenal gland, as well as in some other peripheral tissues with high metabolic activity. Using in situ hybridization and immunohistochemistry, we have studied the distribution and regulation of Trx2 expression in the rat brain. Trx2 mRNA and protein are highly expressed in the neurons in several brain regions, including the olfactory bulb, frontal cortex, hippocampus, some hypothalamic and thalamic nuclei, cerebellum and numerous brainstem nuclei. In addition, the Trx2 mRNA expression in paraventricular hypothalamic nucleus and reticular thalamic nucleus was found to be sensitive to peripheral glucocorticoids, as dexamethasone treatment caused significant elevation of Trx2 mRNA level in this area. No changes in other brain areas were observed after dexamethasone treatment. These findings implicate a significant regulatory and/or protective function of Trx2 in the nervous system.


Comparison of approaches to quantify SARS-CoV-2 in wastewater using RT-qPCR: Results and implications from a collaborative inter-laboratory study in Canada.
Detection of SARS-CoV-2 RNA in wastewater is a promising tool for informing public health decisions during the COVID-19 pandemic. However, approaches for its analysis by use of reverse transcription quantitative polymerase chain reaction (RT-qPCR) are still far from standardized globally. To characterize inter- and intra-laboratory variability among results when using various methods deployed across Canada, aliquots from a real wastewater sample were spiked with surrogates of SARS-CoV-2 (gamma-radiation inactivated SARS-CoV-2 and human coronavirus strain 229E [HCoV-229E]) at low and high levels then provided "blind" to eight laboratories. Concentration estimates reported by individual laboratories were consistently within a 1.0-log10 range for aliquots of the same spiked condition. All laboratories distinguished between low- and high-spikes for both surrogates. As expected, greater variability was observed in the results amongst laboratories than within individual laboratories, but SARS-CoV-2 RNA concentration estimates for each spiked condition remained mostly within 1.0-log10 ranges. The no-spike wastewater aliquots provided yielded non-detects or trace levels (<20 gene copies/mL) of SARS-CoV-2 RNA. Detections appear linked to methods that included or focused on the solids fraction of the wastewater matrix and might represent in-situ SARS-CoV-2 to the wastewater sample. HCoV-229E RNA was not detected in the no-spike aliquots. Overall, all methods yielded comparable results at the conditions tested. Partitioning behavior of SARS-CoV-2 and spiked surrogates in wastewater should be considered to evaluate method effectiveness. A consistent method and laboratory to explore wastewater SARS-CoV-2 temporal trends for a given system, with appropriate quality control protocols and documented in adequate detail should succeed.


[ Hoigne reaction and its modifications].
The author analyzes 114 works published lately dealing with methodical improvement of Hoigne's reaction and its application both in experimental studies and in clinical practice. The great majority of the works (over 90) were referred to the use of modification of this reaction suggested by Klemparskaya and Raeva for detection of autoantibodies to the lysate of autoerythrocytes and organ extracts. This reaction was found to be useful for studying the autosensitization process in man and animals; its prognostic significance at the clinic was of importance since its intensity corresponded to the severity of the process and promptly decreased with effective treatment.


Actin-regulating activities in cultured BHK cells.
A large proportion (60-85%) of the actin present in lysates of cultured baby hamster kidney (BHK) cells is monomeric at low temperature. All this G-actin is accounted for in the fractions obtained by high-speed centrifugation of the lysate in the presence or absence of non-ionic detergent; 98 (+/- 7)% of its reacts as monomer in the deoxyribonuclease assay. The fractions nevertheless possess actin polymerization nucleating activity, as assayed by the fluorescence of extraneous pyrene-conjugated actin, reflecting the presence of capping proteins and their complexes with oligomeric actin, which dissociate during the deoxyribonuclease assay. Despite the enhanced nucleation, the total proportion of actin polymerized at equilibrium is reduced, relative to that of actin in the absence of cell extract, presumably because of the presence of 'barbed'-end capping protein(s). With increasing concentrations of the supernatant material, the proportion of polymerized actin was progressively reduced and the presence of inhibitory activity against polymerization became apparent. On addition of micromolar concentrations of free calcium, nucleation by the supernatant fractions is greatly accelerated, but the extent of polymerization undergoes a further reduction, due to the elevated critical monomer concentration resulting from capping. Inhibition of polymerization by the supernatant fraction in the presence of calcium is much greater than by saturating concentrations of cytochalasin E. These observations are most simply interpreted as showing that the cytoplasm additionally contains a 'pointed'-end capping protein. The plasma membranes were found to have nucleating activity largely residing in the Triton-insoluble fractions. Actin cross-linking activity was assayed by adding small proportions of either the supernatant or membrane fractions to a large excess of F-actin and analysing the pellet resulting from a low-speed centrifugation. Supernatant fraction, containing Triton-soluble membrane-derived material, possessed much greater cross-linking capacity than the membrane-free supernatant prepared in the absence of detergent. The membrane fractions had practically no cross-linking activity on their own. Nevertheless, a non-ionic detergent extract of the membrane enhanced the cross-linking activity of the supernatant, indicating the participation of more than one species in a cross-linking process.


SEMIPARAMETRIC EFFICIENT ESTIMATION FOR SHARED-FRAILTY MODELS WITH DOUBLY-CENSORED CLUSTERED DATA.
In this paper, we investigate frailty models for clustered survival data that are subject to both left- and right-censoring, termed "doubly-censored data". This model extends current survival literature by broadening the application of frailty models from right-censoring to a more complicated situation with additional left censoring. Our approach is motivated by a recent Hepatitis B study where the sample consists of families. We adopt a likelihood approach that aims at the nonparametric maximum likelihood estimators (NPMLE). A new algorithm is proposed, which not only works well for clustered data but also improve over existing algorithm for independent and doubly-censored data, a special case when the frailty variable is a constant equal to one. This special case is well known to be a computational challenge due to the left censoring feature of the data. The new algorithm not only resolves this challenge but also accommodate the additional frailty variable effectively. Asymptotic properties of the NPMLE are established along with semi-parametric efficiency of the NPMLE for the finite-dimensional parameters. The consistency of Bootstrap estimators for the standard errors of the NPMLE is also discussed. We conducted some simulations to illustrate the numerical performance and robustness of the proposed algorithm, which is also applied to the Hepatitis B data.


[Features of the course of retrobulbar neuritis in alcoholic intoxication].
The authors analyzed the course of bilateral retrobulbar neuritis (RN) in 39 patients with alcoholic intoxication. In almost one-third of those studied RN was first the only sign of the disease (24 patients suffered from chronic alcoholism of different stages). They were followed up for 1 to 3 years. Characteristics of disorders of the central and peripheral vision and of the status of the ocular fundus were found to correlate with general signs of intoxication. The data obtained my be of a definite significance for the timely specification of the diagnosis and aetiology of the process in patients with syndromes of bilateral RN.


The impact of an online Facebook support group for people with multiple sclerosis on non-active users.
Multiple sclerosis (MS) is a debilitating disease and there is little research on support networks for people with MS (PwMS). More specifically, most studies on online support groups focus on those who actively participate in the group, whereas the majority of those who utilise online support groups do so in a passive way. This study therefore aimed to explore the experiences of non-active users of an online Facebook support group for PwMS. Emphasis was placed on the facilitators and the barriers that were associated with membership to this group. An exploratory qualitative research design was implemented, whereby thematic analysis was utilised to examine the ten semi-structured interviews that were conducted. Several facilitators were acquired through the online support group; namely emotional support (constant source of support, exposure to negative aspects of the disease), informational support (group as a source of knowledge, quality of information) and social companionship (place of belonging). Some barriers were also identified; namely emotional support (emotions lost online, response to messages, exposure to negative aspects of the disease), informational support (information posted on the group, misuse of group) and social companionship (non-active status). These findings demonstrate that the non-active members of the online support group for PwMS have valid reasons for their non-active membership status. More important, the findings suggest that the online Facebook support group provided the group members with an important support network in the form of emotional support, informational support and social companionship, despite their non-active membership status or the barriers that have been identified.


The Costs of Living Together: Immune Responses to the Microbiota and Chronic Gut Inflammation.
While the vertebrate microbiota is critical to the normal function of many host traits, hosts may expend a large amount of energy to constrain and interface with their microbiota via their immune system to avoid the high fitness costs associated with gut dysbiosis, pathobionts, and opportunistic pathogens. All jawed vertebrates share mucosal immunity dedicated to isolating the microbiota, and a breakdown of this system can result in chronic gut inflammation. In humans, chronic gut inflammation negatively affects growth and development. There is little information available on the prevalence of chronic gut inflammation in wild animals, but given that animals with different life histories emphasize different immune responses, it follows that wild animals may vary in their susceptibility to chronic gut inflammation, and most animals will experience signaling that can lead to this state. These can be top-down signals originating from sources like the central nervous system or bottom-up signals originating from changes in the gut microbiota. The sources of these signals might include stress, developmental transitions, food restriction, and dietary shifts. Here, we briefly discuss host-microbiota interactions from the perspective of life history theory and ecoimmunology, focusing on the mucosal immune system and chronic gut inflammation. We also include future directions for research and the tools necessary to investigate them.


Myopic regression after photorefractive keratectomy: a retrospective cohort study.
Myopic regression is a major complication of photorefractive keratectomy (PRK). The rates and causes vary considerably among different studies. This study aimed to investigate myopic regression at six months after myopic PRK. In this retrospective cohort study, we included all eligible patients with myopia ranging from - 0.75 to - 9 D, aged 18 to 50 years, who underwent PRK by a single surgeon with the availability of preoperative and postoperative data at six months after the initial procedure. All participants underwent comprehensive ophthalmic examinations preoperatively and at six months post-PRK. Overcorrection was planned based on the participant's age range to achieve the desired refractive result after PRK. All patients received the same postoperative antibiotic and steroid eye drops in a similar dosage regimen, and the contact lenses were removed after complete corneal epithelial healing. Based on the spherical equivalent of refraction six months after PRK, eyes without and with myopic regression were allocated into groups 1 and 2, respectively. We included 254 eyes of 132 patients who underwent myopic PRK with a mean (standard deviation) age of 30.12 (7.48) years; 82 (62.12%) were women and 50 (37.88%) were men. The frequency of myopic regression was significantly lower in patients with younger age, lower preoperative cylindrical refraction, and lower ablation depth (all P < 0.05). Overcorrection was more successful in eyes with low myopia than in eyes with high myopia (P < 0.05). The highest frequency of myopic regression occurred in eyes with moderate myopia (25.68%), followed by eyes with high myopia (20.0%) and low myopia (6.54%). Among different age groups, patients aged ≤ 30 years had a lower frequency of myopic regression. The frequency of myopic regression in the different age groups was 5.0% at 18 - 20 years, 7.46% at 26 - 30 years, 12.28% at 21 - 25 years, 21.31% at 31 - 35 years, and 26.53% at 36 - 50 years. Overcorrection was more successful in eyes with low myopia than in eyes with high myopia. The success rate was higher in younger patients with lower astigmatism and ablation depths. Myopic regression was most frequent in eyes with moderate myopia, followed by those with high and low myopia. Further studies should replicate our findings over a longer follow-up period with a larger sample size before generalization is warranted.


Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation: early clinical experience.
Thromboembolism due to atrial fibrillation (AF) is a frequent cause of stroke. More than 90% of thrombi in AF form in the left atrial appendage (LAA). Obliteration of the appendage may prevent embolic complications. We evaluated the feasibility and safety of implanting a novel device for percutaneous left atrial appendage transcatheter occlusion (PLAATO). LAA occlusion using the PLAATO system was attempted in 15 patients with chronic AF at high risk for stroke, who are poor candidates for long-term warfarin therapy. The implant consists of a self-expanding nitinol cage covered with a polymeric membrane (ePTFE). The LAA was successfully occluded in 15/15 patients (100%). Angiography and transesophageal echocardiography (TEE) during the procedure showed that the device was well-seated in all patients and that there was no evidence of perforation, device embolization, or interference with surrounding structures. In 1 patient, the first procedure was complicated by a hemopericardium, which occurred during LAA access. A second attempt 30 days later was successful with no untoward sequela. No other complications occurred. At 1-month follow-up, chest fluoroscopy and TEE revealed continued stable implant position with smooth atrial-facing surface and no evidence of thrombus. Thus, transcatheter closure of the LAA is feasible in humans. This novel implant technology may be appropriate for patients with AF who are not suitable candidates for anticoagulation therapy. Further trials are needed to show the long-term safety and its efficacy in reducing stroke.


Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer.
Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression correlated inversely with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test, p = 0.0075). In a multivariate disease-free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p = 0.0014), along with grade and progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2 mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. Using immunohistology, the cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases in both the murine model and human tissues. We conclude that Stefin A expression reduces distant metastasis in breast cancer and propose that this may be due to the inhibition of cysteine cathepsins, such as cathepsin B.


(Coarse coding of shape fragments) + (retinotopy) approximately = representation of structure.
The ability to deal with object structure--to determine what is where in a given object, rather than merely to categorize or identify it--has been hitherto considered the prerogative of 'structural description' approaches, which represent shapes as categorical compositions of generic parts taken from a small alphabet. In this note, we propose a simple extension to a theoretically motivated and extensively tested appearance-based model of recognition and categorization, which should make it capable of representing object structure. We describe a pilot implementation of the extended model, survey independent evidence supporting its modus operandi, and outline a research program focused on achieving a range of object processing capabilities, including reasoning about structure, within a unified appearance-based framework.


Uridine kinase, adenylate kinase, and guanase in human lung tumors.
In pulmonary neoplasms, the uridine kinase concentration was higher (2- to 20-fold) than in the noninvolved lung portions of each of the 12 subjects studied. The extent of elevation of uridine kinase in the different tumors showed a significant positive correlation with the rises (1.5- to 30-fold) in thymidine kinase, suggesting that neoplastic transformation in human lung involved coordinated increases in the capacity for the reutilization of different nucleoside phosphates. Adenylate kinase was always at lower levels in neoplasms compared to noninvolved areas of the same lung, and the extent of this loss in the different tumors correlated inversely with the gain in uridine kinase and thymidine kinase. Normal fetal human lung was also deficient in adenylate kinase, while its uridine kinase and thymidine kinase (and also guanase) activities were above the adult levels. The guanase activities of the different neoplasms, unrelated to their uridine kinase or thymidine kinase content, correlated with the activities in the subjects' noninvolved lung. These individual differences were much more striking than those between the neoplastic and control samples. Variations in guanase activity thus appear to be "random," whereas observations on the three other enzymes attest to the orderly nature of biochemical differences among individual tumors and between normal and neoplastic lung.


The dorsal neural tube: a dynamic setting for cell fate decisions.
The dorsal neural tube first generates neural crest cells that exit the neural primordium following an epithelial-to-mesenchymal conversion to become sympathetic ganglia, Schwann cells, dorsal root sensory ganglia, and melanocytes of the skin. Following the end of crest emigration, the dorsal midline of the neural tube becomes the roof plate, a signaling center for the organization of dorsal neuronal cell types. Recent lineage analysis performed before the onset of crest delamination revealed that the dorsal tube is a highly dynamic region sequentially traversed by fate-restricted crest progenitors. Furthermore, prospective roof plate cells were shown to originate ventral to presumptive crest and to progressively relocate dorsalward to occupy their definitive midline position following crest delamination. These data raise important questions regarding the mechanisms of cell emigration in relation to fate acquisition, and suggest the possibility that spatial and/or temporal information in the dorsal neural tube determines initial segregation of neural crest cells into their derivatives. In addition, they emphasize the need to address what controls the end of neural crest production and consequent roof plate formation, a fundamental issue for understanding the separation between central and peripheral lineages during development of the nervous system.


[Evoked potentials and spike activity of cortical neurons at the moment of conditioned reflex realization].
Experiments on alert rabbits have revealed a definite but dissimilar correspondence of amplitude-temporal dynamics of evoked potentials, neuroronal spike activity in the visual (VC) and the sensorimotor (SC) areas of the cerebral cortex and movements appearing in response to photic flashes, the conditioned signal (CS) of a defensive reflex. VC reaction to the CS sets in in 15 to 20 msec. During the subsequent 20 to 40 msec, there is intensive VC activation and involvement in the reaction of most of the responding elements in the SC. Subsequently, the activation in VC weakens and increases in the SC. Against this background, movements in response to the CS appear with a latency of 60 to 120 msec. The probability of movements in response to photic flashes decreases in the case of distinct phasic reactions to the CS in the period of deep inhibition and intensive postinhibitory activation of VC units. The data obtained imply that the SC neurones play a decisive role in the achievements of the defensive movement to the CS. As to the detection of the very fact of visual stimulation and to the modulation function and correction of the movement, they are provided for both by SC and VC neurones.


Bactericidal effect of hydrogen peroxide on Salmonella typhimurium in liquid whole egg.
The effect of hydrogen peroxide on Salmonella typhimurium in whole egg was evaluated. The bactericidal effects observed on the test organism at 5 degrees and 20 degrees C were found to be similar. There was a 99% kill in the presence of 0.5% and 1.0% H2O2. Addition of the test organism and H2O2 after pre-heating the egg material at 40 degrees C for 15 min caused a rapid kill which was 10,000-fold greater than that produced by H2O2 alone.


Huntingtin is critical both pre- and postsynaptically for long-term learning-related synaptic plasticity in Aplysia.
Patients with Huntington's disease exhibit memory and cognitive deficits many years before manifesting motor disturbances. Similarly, several studies have shown that deficits in long-term synaptic plasticity, a cellular basis of memory formation and storage, occur well before motor disturbances in the hippocampus of the transgenic mouse models of Huntington's disease. The autosomal dominant inheritance pattern of Huntington's disease suggests the importance of the mutant protein, huntingtin, in pathogenesis of Huntington's disease, but wild type huntingtin also has been shown to be important for neuronal functions such as axonal transport. Yet, the role of wild type huntingtin in long-term synaptic plasticity has not been investigated in detail. We identified a huntingtin homolog in the marine snail Aplysia, and find that similar to the expression pattern in mammalian brain, huntingtin is widely expressed in neurons and glial cells. Importantly the expression of mRNAs of huntingtin is upregulated by repeated applications of serotonin, a modulatory transmitter released during learning in Aplysia. Furthermore, we find that huntingtin expression levels are critical, not only in presynaptic sensory neurons, but also in the postsynaptic motor neurons for serotonin-induced long-term facilitation at the sensory-to-motor neuron synapse of the Aplysia gill-withdrawal reflex. These results suggest a key role for huntingtin in long-term memory storage.


Age differences in orbitofrontal activation: an fMRI investigation of delayed match and nonmatch to sample.
Several investigations have suggested that the orbitofrontal cortex (OFC) may be particularly vulnerable to the effects of age-related changes. We recently reported behavioral data indicating greater age differences in orbitofrontal tasks when directly compared to tasks tapping dorsolateral prefrontal functions. The present study was designed to investigate the neural underpinnings of age differences in OFC functioning. Event-related functional magnetic resonance imaging (fMRI) was performed during delayed match and nonmatch to sample tasks, previously shown to differentially activate medial and lateral OFC in young adults. Sixteen healthy younger [age = 26.7(5.6)] and 16 healthy older individuals [age = 69.1 + 5.6] with similar levels of education and general cognitive functioning participated in the experiment. Participants chose the stimulus from a pair of stimuli matching a previously viewed target (match to sample) or chose the nontarget item (nonmatch to sample) depending upon a trial-specific instruction word. Consistent with previous studies, SPM99 analyses of the younger age group revealed activation for medial OFC regions during the match task compared to the nonmatch task and lateral OFC activation during the nonmatch task compared to the match task. In contrast, older adults showed prefrontal activation only during the match relative to the nonmatch task and posterior temporal and limbic involvement during the nonmatch relative to the match task. Between-group analyses confirmed within-group results suggesting differential age-related recruitment of prefrontal regions when performing match and nonmatch tasks. Results suggest that OFC recruitment during these cognitive tasks changes with age and should be evaluated within the context of other prefrontal subregions to further define differential age effects on frontal functions.


Periplasmic cleavage and modification of the 1-phosphate group of Helicobacter pylori lipid A.
Pathogenic bacteria modify the lipid A portion of their lipopolysaccharide to help evade the host innate immune response. Modification of the negatively charged phosphate groups of lipid A aids in resistance to cationic antimicrobial peptides targeting the bacterial cell surface. The lipid A of Helicobacter pylori contains a phosphoethanolamine (pEtN) unit directly linked to the 1-position of the disaccharide backbone. This is in contrast to the pEtN units found in other pathogenic Gram-negative bacteria, which are attached to the lipid A phosphate group to form a pyrophosphate linkage. This study describes two enzymes involved in the periplasmic modification of the 1-phosphate group of H. pylori lipid A. By using an in vitro assay system, we demonstrate the presence of lipid A 1-phosphatase activity in membranes of H. pylori. In an attempt to identify genes encoding possible lipid A phosphatases, we cloned four putative orthologs of Escherichia coli pgpB, the phosphatidylglycerol-phosphate phosphatase, from H. pylori 26695. One of these orthologs, Hp0021, is the structural gene for the lipid A 1-phosphatase and is required for removal of the 1-phosphate group from mature lipid A in an in vitro assay system. Heterologous expression of Hp0021 in E. coli resulted in the highly selective removal of the 1-phosphate group from E. coli lipid A, as demonstrated by mass spectrometry. We also identified the structural gene for the H. pylori lipid A pEtN transferase (Hp0022). Mass spectrometric analysis of the lipid A isolated from E. coli expressing Hp0021 and Hp0022 shows the addition of a single pEtN group at the 1-position, confirming that Hp0022 is responsible for the addition of a pEtN unit at the 1-position in H. pylori lipid A. In summary, we demonstrate that modification of the 1-phosphate group of H. pylori lipid A requires two enzymatic steps.


Small fiber neuropathies.
This article reviews the clinical, neurophysiologic, and neuropathologic findings in patients presenting with small fiber neuropathies. Emphasis is placed on recent updates to the literature, but also on understanding the differential diagnosis and initial evaluation of patients with small fiber neuropathy. There have been several updates in the literature about diseases associated with small fiber neuropathy. First, treatment-induced neuropathy in diabetes mellitus is an iatrogenic small fiber neuropathy linked to overly rapid correction in blood glucose levels in the setting of chronic hyperglycemia. Second, several novel mutations to sodium channels have been identified in patients presenting with idiopathic small fiber neuropathy that may significantly alter our understanding and future treatment of small fiber neuropathy. Third, antibodies against voltage-gated potassium channels appear to be associated with a much higher incidence of pain than would be expected, although the mechanism has not been established. Fourth, the link between glucose dysregulation, metabolic syndrome, and neuropathy continues to grow. Finally, several other disorders, including postural orthostatic tachycardia syndrome, have been postulated to be associated with small fiber neuropathies. Small fiber neuropathies are a heterogeneous group of disorders that may present with a variety of sensory or autonomic symptoms. Recent reports highlight a number of new causes of small fiber neuropathy that continue to reduce the number of remaining idiopathic cases.


Genomic Origin and Diversification of the Glucosinolate MAM Locus.
Glucosinolates are a diverse group of plant metabolites that characterize the order Brassicales. The MAM locus is one of the most significant QTLs for glucosinolate diversity. However, most of what we understand about evolution at the locus is focused on only a few species and not within a phylogenetic context. In this study, we utilize a micro-synteny network and phylogenetic inference to investigate the origin and diversification of the MAM/IPMS gene family. We uncover unique MAM-like genes found at the orthologous locus in the Cleomaceae that shed light on the transition from IPMS to MAM. In the Brassicaceae, we identify six distinct MAM clades across Lineages I, II, and III. We characterize the evolutionary impact and consequences of local duplications, transpositions, whole genome duplications, and gene fusion events, generating several new hypothesizes on the function and diversity of the MAM locus.


Grandparenting and life satisfaction among Chinese elderlies: a study of possible mechanisms.
This study examines the impact of caregiving on older people's life satisfaction, focusing on the role of caring for grandchildren. The study considers individual characteristics (aging attitudes) and situational factors (intergenerational support) and aims to identify the mediating roles of aging attitudes and intergenerational support in the relationship between caregiving and life satisfaction. The study analyzed data from the 2014 China Longitudinal Aging Social Survey (CLASS), focusing on 5363 grandparents who reported providing care for their grandchildren in the 12 months before the survey. Life satisfaction was subjectively measured. The data was analyzed using multiple linear regression, propensity score matching, and mediation analysis. The study found that grandparents who cared for their grandchildren have higher levels of life satisfaction. Self-aging attitudes, general aging attitudes, intergenerational economic support, intergenerational instrumental support, and intergenerational emotional support fully mediated the relationship between grandchild care and life satisfaction. This study demonstrates that caring for grandchildren is a vital activity for older people that helps them develop positive aging attitudes and strengthens intergenerational support, thereby improving their quality of life. Hence, the government, society, families, and communities should provide more social support to older adults caring for grandchildren. This would not only benefit the health of the older people themselves but also promote intergenerational harmony and family development.


Social stimuli increase activity of adult-born cells in the telencephalon of zebrafish (Danio rerio).
Fish have particularly high levels of adult neurogenesis, and this high neurogenic capacity may contribute to behavioural plasticity. While it is known that adult-born cells can differentiate into neurons and incorporate into neural circuits, it is unclear whether they are responsive to external stimuli and are thereby capable of contributing to behavioural change. We tested whether cells born in the telencephalon of adult zebrafish are activated by social stimuli. We marked cell birth with BrdU and, 40 days later, exposed fish to brief (15 min) visual social stimuli and assayed cellular activity through immunolocalization of phospho-S6-ribosomal protein (pS6). BrdU+/pS6+ co-labelled cells were found in six brain regions, and, in four regions [dorsal (D), dorsomedial (Dm) and dorsolateral (Dl) zones of the dorsal telencephalon and pre-optic area (POA)], the number of co-labelled cells and fraction of BrdU+ cells that labelled positive for pS6 increased during social stimulation. These results are consistent with the hypothesis that adult-born neurons play a role in regulating social behaviour.


Pinpointing genes underlying the quantitative trait loci for root-knot nematode resistance in palaeopolyploid soybean by whole genome resequencing.
The objective of this study was to use next-generation sequencing technologies to dissect quantitative trait loci (QTL) for southern root-knot nematode (RKN) resistance into individual genes in soybean. Two hundred forty-six recombinant inbred lines (RIL) derived from a cross between Magellan (susceptible) and PI 438489B (resistant) were evaluated for RKN resistance in a greenhouse and sequenced at an average of 0.19× depth. A sequence analysis pipeline was developed to identify and validate single-nucleotide polymorphisms (SNPs), infer the parental source of each SNP allele, and genotype the RIL population. Based on 109,273 phased SNPs, recombination events in RILs were identified, and a total of 3,509 bins and 3,489 recombination intervals were defined. About 50.8% of bins contain 1 to 10 genes. A linkage map was subsequently constructed by using bins as molecular markers. Three QTL for RKN resistance were identified. Of these, one major QTL was mapped to bin 10 of chromosome 10, which is 29.7 kb in size and harbors three true genes and two pseudogenes. Based on sequence variations and gene-expression analysis, the candidate genes underlying the major QTL for RKN resistance were pinpointed. They are Glyma10g02150 and Glyma10g02160, encoding a pectin methylesterase inhibitor and a pectin methylesterase inhibitor -pectin methylesterase, respectively. This QTL mapping approach not only combines SNP discovery, SNP validation, and genotyping, but also solves the issues caused by genome duplication and repetitive sequences. Hence, it can be widely used in crops with a reference genome to enhance QTL mapping accuracy.


[Computer analysis of erythrocyte catalase activity in diagnosis of mild brain trauma and concussion].
A complex investigation of catalase activity in erythrocytes was conducted basing on the results of computer quantitative morphometry of histochemical examination of blood samples from persons with mild craniocerebral trauma. It was found that erythrocytic catalase activity correlates with severity of brain trauma. A novel technique of objective histochemical diagnosis of trauma is described. It provides objective grounds for expert conclusions. Differential features of erythrocytic shape were defined in a small series of micropreparations vs the rest blood samples.


Clinical Data Warehouse: An Effective Tool to Create Intelligence in Disease Management.
Clinical business intelligence tools such as clinical data warehouse enable health care organizations to objectively assess the disease management programs that affect the quality of patients' life and well-being in public. The purpose of these programs is to reduce disease occurrence, improve patient care, and decrease health care costs. Therefore, applying clinical data warehouse can be effective in generating useful information about aspects of patient care to facilitate budgeting, planning, research, process improvement, external reporting, benchmarking, and trend analysis, as well as to enable the decisions needed to prevent the progression or appearance of the illness aligning with maintaining the health of the population. The aim of this review article is to describe the benefits of clinical data warehouse applications in creating intelligence for disease management programs.


Antiretroviral prescription, retention in care and viral suppression by place of birth among adults with diagnosed HIV in the United States-2015-2017, medical monitoring project.
HIV clinical outcomes have not been fully assessed by place of birth at the national level. We analyzed the Medical Monitoring Project data, an annual cross-sectional survey designed to produce nationally representative estimates on adults with diagnosed HIV in the United States, collected during 2015-2017 (n = 7617). We compared sociodemographic, behavioral, and clinical outcomes by place of birth using Rao-Scott chi-square tests (P < .05). Overall, 13.6% of adults with diagnosed HIV were non-US-born. During the past 12 months, a higher percentage of non-US-born than US-born adults, respectively, were prescribed ART (89.4% vs. 84.1%), retained in care (87.1% vs. 80.0%), virally suppressed at the last test (77.2% vs. 70.9%), and had sustained viral suppression (70.9% vs. 63.3%). A lower percentage of non-US-born adults reported binge drinking (13.0% vs. 16.1%), using non-injection drugs (15.3% vs. 31.7%), and suffering from depression (15.9% vs. 23.3%) or anxiety (10.0% vs. 20.2%). A significantly higher percentage of non-US-born adults had Ryan White HIV/AIDS Program (RWHAP) coverage (54.4% vs. 43.1%) and attended a RWHAP-funded health care facility (73.9% vs. 66.6%). Factors contributing to better HIV clinical outcomes among non-US-born persons may include access to RWHAP coverage, lower levels of substance use, and better mental health.


Tug of war: A bimanual technique for anterior circumferential proliferative vitreoretinopathy in recurrent retinal detachment.
To describe a bimanual technique, "tug of war" for managing anterior circumferential proliferative vitreoretinopathy (PVR) in eyes with recurrent retinal detachment (RRD). We retrospectively analyzed outcomes from eyes with RRD that underwent reattachment surgery using this maneuver and had a minimum of 6 months follow-up. A chandelier light was inserted for endo-illumination and the circumferential anterior PVR was tackled with two 25-gauge forceps stretching circumferential tractional membranes in opposite direction (tug of war) till they snapped. Eleven eyes of 11 patients with a mean age of 38.2 ± 19.7 years underwent surgery. All eyes had advanced PVR of Grade C A Type 4 (Circumferential). The median duration of RD from the time of first surgery was 6 months (interquartile range = 3-8 months). The tug of war maneuver was successful in relieving the anterior retinal traction leading to retinal reattachment in all eyes without the need for relaxing retinotomies or retinectomies. Small iatrogenic retina tears occurred at the time of tug of war maneuver in 3 (27%) eyes at the site of maximum traction. The mean best-corrected visual acuity (BCVA) improved from 1.87 ± 0.2 logarithm of minimum angle of resolution (logMAR) to 1.3 ± 0.4 logMAR at 6-months follow-up (P = 0.04). The 'tug of war' maneuver is useful for relieving circumferential anterior traction and reattaching the retina in eyes with RRD without having to resort to large relaxing retinotomies or retinectomies.


Sleep and circadian disruption and incident breast cancer risk: An evidence-based and theoretical review.
Opportunities for restorative sleep and optimal sleep-wake schedules are becoming luxuries in industrialized cultures, yet accumulating research has revealed multiple adverse health effects of disruptions in sleep and circadian rhythms, including increased risk of breast cancer. The literature on breast cancer risk has focused largely on adverse effects of night shift work and exposure to light at night (LAN), without considering potential effects of associated sleep disruptions. As it stands, studies on breast cancer risk have not considered the impact of both sleep and circadian disruption, and the possible interaction of the two through bidirectional pathways, on breast cancer risk in the population at large. We review and synthesize this literature, including: 1) studies of circadian disruption and incident breast cancer; 2) evidence for bidirectional interactions between sleep and circadian systems; 3) studies of sleep and incident breast cancer; and 4) potential mechanistic pathways by which interrelated sleep and circadian disruption may contribute to the etiology of breast cancer.


Intraductal cisplatin treatment in a BRCA-associated breast cancer mouse model attenuates tumor development but leads to systemic tumors in aged female mice.
BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1-associated breast cancer may be local prophylactic treatment via the nipple. Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer. We show that ID cisplatin and PARP-inhibition can successfully ablate mammary epithelial cells, and this approach attenuated tumor onset in a mouse model of Brca1-associated breast cancer from 153 to 239 days. Long-term carcinogenicity studies in 150 syngeneic wild-type mice demonstrated that tumor incidence was increased in the ID treated mammary glands by 6.3% due to systemic exposure to cisplatin. Although this was only evident in aged mice (median age = 649 days), we conclude that ID cisplatin treatment only presents a safe and feasible local prevention option if systemic exposure to the chemotherapy used can be avoided.


The New Stealth Drug on the Street: A Narrative Review of Xylazine as a Street Drug.
Xylazine is an alpha-adrenergic receptor agonist approved for use only in animals with a prescription from a veterinarian. It is a powerful sedative that is slowly infiltrating the recreational street drug scene and is often used by polysubstance abusers. Known as "tranq," it can be fatal, and xylazine-induced toxicity cannot be reversed with naloxone or nalmefene. Due to its vasoconstrictive effects, chronic use of xylazine is associated with necrotic skin lesions and general deterioration of health. Since xylazine is not approved for human use and is not scheduled as a controlled substance, there are no human studies to provide evidence of drug-drug interactions, lethal doses, or reversal protocols. Xylazine is available online without a prescription. Street drug users may take xylazine knowingly or unknowingly, as it is often combined with other illicit substances such as fentanyl. There are no rapid tests for xylazine, although there are specialty tests that can be ordered. Xylazine represents a major threat to street drug users and another challenge to emergency healthcare workers, first responders, and others who care for those who have taken this "new" street drug.


Do personality disorders predict negative treatment outcome in obsessive-compulsive disorders? A prospective 6-month follow-up study.
Comorbid personality disorders (PDs) are discussed as risk factors for a negative treatment outcome in obsessive-compulsive disorder (OCD). However, studies published so far have produced conflicting results. The present study examined whether PDs affect treatment outcome in patients with OCD. The treatment sample consisted of 55 patients with OCD who were consecutively referred to a Behaviour Therapy Unit for an in-patient or day-clinic treatment. Treatment consisted of an individualised and multimodal cognitive behaviour therapy (CBT, with or without antidepressive medication). Measurements were taken prior and after treatment and 6-month after admission. A large percentage of patients benefited from treatment irrespective of the presence of a PD and were able to maintain their improvement at follow-up. Duration of treatment was not prolonged in OCD patients with concomitant Axis II disorders. However, some specific personality traits (schizotypal, passive-aggressive) were baseline determinants for later treatment failure at trend level. Results are encouraging for therapists working with patients co-diagnosed with Axis II disorders since these patients are not necessarily non-responders. The results stress the importance of a specifically tailored treatment approach based on an individual case formulation in OCD patients with complex symptomatology and comorbid Axis II disorders.


Parental Supervision: Predictive Variables of Positive Involvement in Cyberbullying Prevention.
From an increasingly early age, parents face the challenge of educating their sons and daughters to act in the world of offline and online relationships. If for professional educators it is not proving easy, the involvement and guidance of parents in their children's use of the internet seems to be a complex and unexplored challenge. This work aims to analyse the variables that influence digital education and determine a predictive model of positive parental involvement. This study was done with a representative sample consisting of five hundred and ninety-six families (596), representing the parents of children from schools with similar socio-cultural indexes. To do this, and using self-report instruments convertible into independent scales, four predictor variables were analysed: (1) parental knowledge of cyberbullying; (2) perception of parental competence in this regard; (3) parental perception of online risks; and (4) the attribution of parental responsibility in digital education. A structural equations model (SEM) examined the predictive value of these variables with respect to positive parental involvement. The structural equations model confirmed direct and mediated relationships between the independent and mediating variables on the dependent variable: parental supervision. The results indicate that positive parental involvement can be predicted from higher scores in parental knowledge of cyberbullying, perception of parental competence, risk adjustment, and attribution of parental responsibility.


Antivirals and influenza: frequency of resistance.
Antivirals are effective in prophylaxis and therapy for influenza and are likely to be active against a new pandemic variant. They can be divided into the M2 inhibitors, adamantane and rimantadine, and the neuraminidase inhibitors (NAIs), zanamivir and oseltamivir. The former are limited in activity to type A viruses, whereas the latter are also active against type B viruses. Both classes of drugs appear similarly efficacious in prophylaxis at approximately 70-90%. However, use of M2 inhibitors (adamantanes) in therapy is limited by side effects, more common with amantadine, and also by production of antiviral resistance and lack of demonstrated prevention of complications. The NAIs prevent both types of seasonal influenza, shorten duration of illness, and reduce complications. As such, their use for seasonal influenza treatment has been increasing. They are active against A(H5N1) but oseltamivir has been most extensively stockpiled because the infection in humans may be disseminated. Resistance does emerge, but not at the same frequency as with the M2 inhibitors. Resistant viruses also appear less fit and thus less able to spread. However, as use increases, resistance needs to be carefully monitored.


Identification of a gene that affects the efficiency of host cell infection by Legionella pneumophila in a temperature-dependent fashion.
The ability to infect host cells is critical for the survival and replication of intracellular pathogens in humans. We previously found that many genes involved in the ability of Legionella pneumophila to infect macrophages are not expressed efficiently under standard laboratory growth conditions. We have developed an approach using expression of L. pneumophila genes from an exogenous constitutive promoter on a low-copy-number vector that allows identification of genes involved in host cell infection. Through the use of this strategy, we found that expression of a gene, lvhB2, enhances the efficiency of L. pneumophila infection of mammalian cells. The putative protein encoded by lvhB2 has similarity to structural pilin subunits of type IV secretion systems. We confirmed that this gene plays a role in host cell infection by the construction of an in-frame deletion in the L. pneumophila lvhB2 gene and complementation of this mutant with the wild-type gene. The lvhB2 mutant does not display a very obvious defect in interactions with host cells when the bacteria are grown at 37 degrees C, but it has an approximately 100-fold effect on entry and intracellular replication when grown at 30 degrees C. These data suggest that lvhB2 plays an important role in the efficiency of host cell infection by L. pneumophila grown at lower temperatures.


[Changing factors of the activity of angiotensin converting enzyme of renal brush border in rats].
In the kidney, angiotensin I-converting enzyme (ACE) is present in the vascular endothelial cells and in the brush border of epithelial cells of the proximal tubule. In spite of this well-known distribution of ACE, little is known of its regulation. In order to elucidate the possible mechanisms of control for brush border ACE, the effects of dexamethasone (DM), (40 micrograms s.c. per day, for 7 days) and triiodothyronine (T3) 0.5 mg/kg s.c. per day, for 10 days) were investigated in male Wistar rats. Plasma and brush border ACE activities were measured by fluorimetry in the presence of an artificial substrate Cbz-Phe-His-Leu and brush border ACE was characterized with a binding assay using 3H-ramiprilat, a specific radiolabelled ACE inhibitor. DM elicited a significant decrease in plasma ACE activity (from 0.46 +/- 0.03 to 0.28 +/- 0.02 nmol His-Leu/min/mg protein) but did not alter enzyme activity in the brush border: 47.12 +/- 5.12 nmol His-Leu/min/mg protein (control, n = 6) and 47.78 +/- 5.63 (DM, n = 6). Administering T3 produced a marked increase in the brush border ACE activity (from 42.87 +/- 4.9 to 81.41 +/- 11.7 nmol His-Leu/min/mg protein). Similarly, the maximum number of 3H-ramiprilat-binding sites increased in the brush border, indicating a good correlation between ACE activity and the quantity of 3H-ramiprilat bound. Thus, the variation in tissue ACE activity corresponded to a change in the enzyme concentration.(ABSTRACT TRUNCATED AT 250 WORDS)


Overexpression of human hepatic lipase and ApoE in transgenic rabbits attenuates response to dietary cholesterol and alters lipoprotein subclass distributions.
The effect of the expression of human hepatic lipase (HL) or human apoE on plasma lipoproteins in transgenic rabbits in response to dietary cholesterol was compared with the response of nontransgenic control rabbits. Supplementation of a chow diet with 0.3% cholesterol and 3.0% soybean oil for 10 weeks resulted in markedly increased levels of plasma cholesterol and VLDL and IDL in control rabbits as expected. Expression of either HL or apoE reduced plasma cholesterol response by 75% and 60%, respectively. The HL transgenic rabbits had substantial reductions in medium and small VLDL and IDL fractions but not in larger VLDL. LDL levels were also reduced, with a shift from larger, more buoyant to smaller, denser particles. In contrast, apoE transgenic rabbits had a marked reduction in the levels of large VLDLs, with a selective accumulation of IDLs and large buoyant LDLs. Combined expression of apoE and HL led to dramatic reductions of total cholesterol (85% versus controls) and of total VLDL+IDL+LDL (87% versus controls). HDL subclasses were remodeled by the expression of either transgene and accompanied by a decrease in HDL cholesterol compared with controls. HL expression reduced all subclasses except for HDL2b and HDL2a, and expression of apoE reduced large HDL1 and HDL2b. Extreme HDL reductions (92% versus controls) were observed in the combined HL+apoE transgenic rabbits. These results demonstrate that human HL and apoE have complementary and synergistic functions in plasma cholesterol and lipoprotein metabolism.


Urea-based anticancer agents. Exploring 100-years of research with an eye to the future.
Suramin was the first urea-based drug to be approved in clinic, and in the following century a number of milestone drugs based on this scaffold were developed. Indeed, urea soon became a privileged scaffold in medicinal chemistry for its capability to establish a peculiar network of drug-target interactions, for its physicochemical properties that are useful for tuning the druggability of the new chemical entities, and for its structural and synthetic versatility that opened the door to numerous drug design possibilities. In this review, we highlight the relevance of the urea moiety in the medicinal chemistry scenario of anticancer drugs with a special focus on the kinase inhibitors for which this scaffold represented and still represents a pivotal pharmacophoric feature. A general outlook on the approved drugs, recent patents, and current research in this field is herein provided, and the role of the urea moiety in the drug discovery process is discussed form a medicinal chemistry standpoint. We believe that the present review can benefit both academia and pharmaceutical companies' medicinal chemists to prompt research towards new urea derivatives as anticancer agents.


Vancomycin administration into the cerebrospinal fluid: a review.
To discuss administering vancomycin directly into the cerebrospinal fluid (CSF) to treat serious central nervous system (CNS) infections. References were obtained through an online search of MEDLINE, limited to material published in English. In addition, information was extracted from clinical trials, review articles, abstracts, and textbooks. Systematic evaluation of this topic in humans has not been done in a prospective manner. Related research articles describing the pathophysiology of CNS infections, intrathecal drug administration, and case reports of CSF vancomycin administration were reviewed. Case reports regarding CSF vancomycin dosing were evaluated and included: drug dosing, infecting organism, infectious disease state, infectious outcome, CSF dynamics/flow abnormalities, methods of drug administration, drug monitoring, and toxicities. The results of this review are based on qualitative evaluations of anecdotal case reports and a basic understanding of intrathecal and intraventricular drug dosing principles. CSF administration of vancomycin is an effective means of bypassing the blood-brain barrier to achieve greater drug concentrations within the CSF. Current limitations to the CSF administration of vancomycin include a lack of data describing its safety, efficacy, and pharmacokinetics. CNS infections may require the CSF administration of vancomycin for successful eradication. Recommendations for dosing in the literature vary. Because of the potential toxicities associated with elevated CSF concentrations of vancomycin, dosing should be conservative.


Corneal Biomechanical Measures for Glaucoma: A Clinical Approach.
Over the last two decades, there has been growing interest in assessing corneal biomechanics in different diseases, such as keratoconus, glaucoma, and corneal disorders. Given the interaction and structural continuity between the cornea and sclera, evaluating corneal biomechanics may give us further insights into the pathogenesis, diagnosis, progression, and management of glaucoma. Therefore, some authorities have recommended baseline evaluations of corneal biomechanics in all glaucoma and glaucoma suspects patients. Currently, two devices (Ocular Response Analyzer and Corneal Visualization Schiempflug Technology) are commercially available for evaluating corneal biomechanics; however, each device reports different parameters, and there is a weak to moderate agreement between the reported parameters. Studies are further limited by the inclusion of glaucoma subjects taking topical prostaglandin analogues, which may alter corneal biomechanics and contribute to contradicting results, lack of proper stratification of patients, and misinterpretation of the results based on factors that are confounded by intraocular pressure changes. This review aims to summarize the recent evidence on corneal biomechanics in glaucoma patients and insights for future studies to address the current limitations of the literature studying corneal biomechanics.


Predicting total global species richness using rates of species description and estimates of taxonomic effort.
We found that trends in the rate of description of 580,000 marine and terrestrial species, in the taxonomically authoritative World Register of Marine Species and Catalogue of Life databases, were similar until the 1950s. Since then, the relative number of marine to terrestrial species described per year has increased, reflecting the less explored nature of the oceans. From the mid-19th century, the cumulative number of species described has been linear, with the highest number of species described in the decade of 1900, and fewer species described and fewer authors active during the World Wars. There were more authors describing species since the 1960s, indicating greater taxonomic effort. There were fewer species described per author since the 1920s, suggesting it has become more difficult to discover new species. There was no evidence of any change in individual effort by taxonomists. Using a nonhomogeneous renewal process model we predicted that 24-31% to 21-29% more marine and terrestrial species remain to be discovered, respectively. We discuss why we consider that marine species comprise only 16% of all species on Earth although the oceans contain a greater phylogenetic diversity than occurs on land. We predict that there may be 1.8-2.0 million species on Earth, of which about 0.3 million are marine, significantly less than some previous estimates.


Typologies of child sexual abuse: An analysis of multiple abuse acts among a large sample of Danish treatment-seeking survivors of childhood sexual abuse.
The deleterious psychological effects of childhood sexual abuse (CSA) have been extensively documented in the research literature. A limitation of this research, however, has been a reliance on overly restrictive and limiting measurements of CSA. Researchers have most commonly referred to discrete instances of rape and molestation; however, evidence suggests that sexual abuse in childhood can include a wide array of acts and that individual survivors can endure many of these. This study employed latent class analysis to identify homogeneous groups of adult CSA survivors characterized by similar typologies of sexual trauma within a large sample of Danish, treatment-seeking survivors of CSA and incest (N = 454). In total, 18 separate contact and noncontact abuse acts were modeled. Furthermore, the association between abuse-related variables (victim gender, the age at which the abuse started, duration of abuse, and perpetrator of abuse) and the resultant CSA groups, or classes, was estimated. Four homogeneous CSA groups were identified: an intercourse group, a high-verbal/low-contact group, a high-sexual-contact group, and a sexual-touch group. Some of the groups were distinguishable from others in terms of the frequency of the abuse and the type of perpetrator identified. The results show that "typologies" of CSA may provide a useful way to describe complex patterns of abuse while also facilitating future investigations of CSA outcome and treatment need. (PsycINFO Database Record


Evaluation of the inactivation of infectious Herpes simplex virus by host-defense peptides.
A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide microplate assay was adapted to screen for the ability of 20 host-defense peptides to inactivate herpes simplex virus type 1 and type 2. The procedure required minimal amounts of material, was reproducible, and was confirmed with standard antiviral testing techniques. In screening tests, with the exception of melittin, a highly cytotoxic and hemolytic peptide found in bee venom, the alpha-helical peptides in our test panel (magainins, cecropins, clavanins, and LL-37) caused little viral inactivation. Several beta-sheet peptides (defensins, tachyplesin, and protegrins) inactivated one or both viruses, sometimes with remarkable selectivity. Two peptides were identified as having antiviral activity against both viruses, indolicidin (a tryptophan-rich peptide from bovine neutrophils) and brevinin-1 (a peptide found in frog skin). The antiviral activity of these two peptides was confirmed with standard antiviral assays. Interestingly, the antiviral activity of brevinin-1 was maintained after reduction and carboxamidomethylation, procedures that abolished its otherwise prominent hemolytic and cytotoxic effects.