bluuebunny/crossref_metadata_2025 huggingface dataset:
Napsins: new human aspartic proteinases
Authors: Tatnell Peter J , Powell David J , Hill Jeffrey , Smith Trudi S , Tew David G , Kay John
Published: July 2002

cDNA sequences were elucidated for two closely related human genes which encode the precursors of two hitherto unknown aspartic proteinases. The (pro)napsin A gene is expressed predominantly in lung and kidney and its translation product is predicted to be a fully functional, glycosylated aspartic proteinase (precursor) containing an RGD motif and an additional 18 residues at its C‐terminus. The (pro)napsin B gene is transcribed exclusively in cells related to the immune system but lacks an in‐frame stop codon and contains a number of polymorphisms, one of which replaces a catalytically crucial Gly residue with an Arg. Consideration is given to whether (pro)napsin B may be a transcribed pseudogene or whether its putative protein product undergoes rapid intracellular degradation.
Identification and structural characterization of two genes encoding glutamate transporter homologues differently expressed in the nervous system of Drosophila melanogaster
Authors: Besson Marie Thérèse , Soustelle Laurent , Birman Serge
Published: July 2002

In vertebrates, excitatory amino acid transporters (EAATs) are believed to mediate the removal of glutamate released at excitatory synapses and to maintain extracellular concentrations of this neurotransmitter below excitotoxic levels. Glutamate is also used in insects as an excitatory neurotransmitter at the neuromuscular junction and probably in the central nervous system where its role remains to be established. We report the molecular characterization and developmental expression pattern of two Drosophila cDNAs: dEAAT1, which has recently been identified as a high affinity glutamate transporter [1], and dEAAT2, a novel protein sharing strong homology to dEAAT1 and to the mammalian EAAT protein family. The developmental expression pattern of the two Drosophila EAAT genes has been compared by Northern blot analysis and whole‐mount in situ hybridizations. The two transporters are transcribed in distinct cell types of the nervous system and are strongly expressed in the adult visual system.
Second form of gonadotropin‐releasing hormone in mouse: immunocytochemistry reveals hippocampal and periventricular distribution
Authors: Gestrin Emily D , White Richard B , Fernald Russell D
Published: July 2002

Hypothalamic GnRH (GnRH‐I) is known and named for its role in regulating reproductive function in vertebrates by controlling release of gonadotropins from the pituitary. However, another form of GnRH of unknown function (pGlu‐His‐Trp‐Ser‐His‐Gly‐Trp‐Tyr‐Pro‐Gly; GnRH‐II) is expressed in the mesencephalon of all vertebrate classes except jawless fish. Here we show with immunocytochemical staining that the GnRH‐II peptide is localized to the mouse midbrain as in other vertebrates, as well as in cells surrounding the ventricles and in cells adjacent to the hippocampus. Staining of adjacent sections using GnRH‐I antibody revealed that the distribution of GnRH‐I does not overlap with that of GnRH‐II.
Cell cycle arrest mediated by hepatitis delta antigen
Authors: Hwang Soon B , Park Kyu-Jin
Published: July 2002

Hepatitis delta antigen (HDAg) is the only viral‐encoded protein of the hepatitis delta virus (HDV). This protein has been extensively characterized with respect to its biochemical and functional properties. However, the molecular mechanism responsible for persistent HDV infection is not yet clear. Previously, we reported that overexpression of HDAg protects insect cells from baculovirus‐induced cytolysis [Hwang, S.B. Park, K.‐J. and Kim, Y.S. (1998) Biochem. Biophys. Res. Commun. 244, 652–658]. Here we report that HDAg mediates cell cycle arrest when overexpressed in recombinant baculovirus‐infected insect cells. Flow cytometry analysis has shown that HDAg expression in Spodoptera frugiperda cells causes an accumulation of substantial amounts of polyploid DNA in the absence of cell division. This phenomenon may be partly responsible for the persistent infection of chronic HDV patients.
Addressing substrate glutamine requirements for tissue transglutaminase using substance P analogues
Authors: Pastor María Teresa , Diez Antonio , Pérez-Payá Enrique , Abad Concepción
Published: July 2002

We have investigated the effect on the substrate requirements for guinea pig liver (tissue) transglutaminase of a set of 11 synthetic glutamine substitution analogues making up the full sequence of the naturally occurring tissue transglutaminase substrate substance P. While a number of peptide sequences derived from proteins that are well‐recognized as tissue transglutaminase substrates have been studied, the enzyme activity using substitution analogues of full‐length natural substrates has not been investigated as thoroughly. Thus, our set of substance P analogues only differs from one to other by one amino acid mutation while the length (of the peptide) is maintained as in the natural parent peptide. Our results indicate that a glutamine residue is not recognized as substrate by the enzyme whether it is placed at the N‐ or C‐terminal or between two positively charged residues or between two proline residues. To further address the effect on enzyme activity of charged amino acids in the vicinity of the reactive glutamine residue, a new set of synthetic charge replacement analogues of substance P has been also studied. Together, the results have identified new minimal requirements for modification of a particular glutamine residue in a polypeptide chain. It would be of interest to set up a full set of such requirements in order to highlight potential glutamine residues as enzyme targets in the growing list of proteins that are being described as transglutaminase substrates.
In vivo synthesis of complexN‐glycans by expression of humanN‐acetylglucosaminyltransferase I in the filamentous fungusTrichoderma reesei
Authors: Maras Marleen , De Bruyn André , Vervecken Wouter , Uusitalo Jaana , Penttilä Merja , Busson Roger , Herdewijn Piet , Contreras Roland
Published: July 2002

The humanN‐acetylglucosaminyltransferase I gene was introduced in the genome ofTrichoderma reeseistrain VTT‐D‐80133. Expression was studied after induction from the cellobiohydrolase I promoter. Successful in vivo transfer of GlcNAc was demonstrated by analyzing the neutralN‐glycans which were synthesized on cellobiohydrolase I. Final proof of the formation of GlcNAcMan5GlcNAc2was obtained by NMR analysis.
Molecular cloning and functional expression of a human peptide methionine sulfoxide reductase (hMsrA)
Authors: Kuschel Lioba , Hansel Alfred , Schönherr Roland , Weissbach Herbert , Brot Nathan , Hoshi Toshinori , Heinemann Stefan H.
Published: July 2002

Oxidation of methionine residues in proteins to methionine sulfoxide can be reversed by the enzyme peptide methionine sulfoxide reductase (MsrA, EC 1.8.4.6). We cloned the gene encoding a human homologue (hMsrA) of the enzyme, which has an 88% amino acid sequence identity to the bovine version (bMsrA). With dot blot analyses based on RNA from human tissues, expression of hMsrA was found in all tissues tested, with highest mRNA levels in adult kidney and cerebellum, followed by liver, heart ventricles, bone marrow and hippocampus. In fetal tissue, expression was highest in the liver. No expression of hmsrA was detected in leukemia and lymphoma cell lines. To test if hMsrA is functional in cells, we assayed its effect on the inactivation time course of the A‐type potassium channel ShC/B since this channel property strongly depends on the oxidative state of a methionine residue in the N‐terminal part of the polypeptide. Co‐expression of ShC/B and hMsrA in Xenopus oocytes significantly accelerated inactivation, showing that the cloned enzyme is functional in an in vivo assay system. Furthermore, the activity of a purified glutathione‐S‐transferase‐hMsrA fusion protein was demonstrated in vitro by measuring the reduction of [3H]N‐acetyl methionine sulfoxide.
Progress in gynecologic cancer detection and treatment
Authors: Benedet J.L.
Published: July 2002

Slow but steady progress has been made in the earlier diagnosis and better treatment of gynecological cancers, particularly over the last 50 years. Cervical cytology screening programs, where implemented, have led to a remarkable reduction in both the incidence and mortality from clinically invasive cervical cancer. This relatively simple technology has been truly one of the major success stories of modern medicine, but unfortunately this technique has not been uniformly applied to all women in the world, particularly to women in developing countries. New research into cervical cancer etiology, the role of HPV, and the development of vaccines against this virus offer a great hope particularly for developing countries. In addition, the combination of radiotherapy and chemotherapy has resulted in a marked improvement in outcome results for women with advanced cervical cancer. Ovarian cancer has seen the development of effective chemotherapy strategies for this disease. Currently this disease remains one of the major scourges in industrialized countries but the continued evolution of knowledge with regard to optimum sequencing of chemotherapeutic agents and surgery offers the prospect for better outcomes, less morbidity and a better quality of life. Ongoing research into the development of newer chemotherapeutic agents and a better understanding of the actual mechanisms regarding the efficacy of chemotherapy and drug resistance offers great promise for the future. Endoscopic surgery for staging and also for therapy shows promise for improved quality of life as well as outcomes for patients in the future and offers the challenge of trying to make this technology readily available to all women in the world. As we gain a better understanding of the molecular basis of disease and health we will truly be able to intervene in a preventive mode in the new millennium.
Attitudes, management and consequences of nausea and vomiting of pregnancy in the United States and Canada
Authors: Mazzotta P. , Maltepe C. , Navioz Y. , Magee L.A. , Koren G.
Published: July 2002

Background: Nausea and vomiting of pregnancy (NVP) affects a large proportion of pregnant women. In 1983, Bendectin®, the only FDA‐approved drug for NVP, was removed from the market by its manufacturer due to legal costs based on claims of teratogenicity, which were subsequently proven to be unsubstantiated. In Canada, a generic form of Bendectin® (Diclectin®; a doxylamine/pyridoxine combination) has continued to be available, with increasing use over the last few years. Objective: To characterize the attitudes, management and consequences of NVP among pregnant women in the USA, where no approved drug for NVP is available, and in Canada, where such a drug is available. Design: Prospective, observational study. Results: Women suffering from NVP (N=1444) were interviewed, of which 42% were American and 58% were Canadian. The two groups had similar maternal characteristics and a similar distribution of severity of NVP, although among Canadian women the NVP continued for slightly longer. American respondents were treated significantly more often by an obstetrician as their primary caregiver, were more commonly advised by their caregiver to change their diet and/or lifestyle and to use non‐pharmacological agents to manage their NVP, and more often perceived anti‐emetics as posing an increased risk for malformations (all P<0.001). Canadian respondents reported a family physician as their primary caregiver significantly more often, were more commonly advised to take anti‐emetic medications and perceived their NVP as causing a concern to their unborn (all P<0.001). American women experienced significantly larger weight loss, more hospitalizations and more time lost from paid work. Conclusions: Lack of an approved drug for symptoms of NVP may be associated with unwarranted and preventable adverse health effects. Because this is an observational study, these associations do not necessarily prove causation.
Molar pregnancy in a 60‐year‐old woman
Authors: Davidson S.A. , Gottesfeld J. , La Rosa F.G.
Published: July 2002

Molar pregnancy has not been reported in women past the age of 57 in the English literature. This report reviews a 60‐year‐old woman who presented with irregular bleeding and was diagnosed as having a complete hydatidiform mole. The patient underwent hysterectomy and had spontaneous return of her human chorionic gonadotropin levels to normal. Diagnosis in this age group depends on a high level of suspicion, and hysterectomy should be considered due to the high risk of postmolar gestational trophoblastic tumor after suction uterine evacuation.
Timing of insults causing abnormal outcome in preterm infants 1989–1992
Authors: Morikawa S. , Itakura A. , Hayakawa F. , Mizutani S. , Matsuzawa K. , Kurauchi O.
Published: July 2002

Objective: The purpose of this study was to clarify the influence of timing of brain insults causing abnormal outcome in preterm infants. Methods: One hundred and thirty‐one preterm infants were examined. The timing of brain insult was estimated from EEG or clinical findings. Development was assessed until a corrected age of 48 months. Results: 39% and 4% of infants, respectively, born before and after the 28‐week time point subsequently died (P < 0.05). Abnormal development was observed in 16% of the first group and 13% of the second (N.S.). None of those born before 28 weeks showed intrauterine injuries while nine of the infants which were born after this time showed intrauterine injuries (P < 0.05). Fetal distress was noted in all infants suffering neonatal death born after 28 weeks. Conclusion: Intrauterine brain insult was concluded to be the cause of neonatal death or abnormal development in many infants born after 28 weeks.
Heterochronous maturation of regional brain astroglia: neuronal modulation of striatal glial cells differentiation ex vivo
Authors: Napp Mónica I. , Colombo Jorge A.
Published: July 2002

Subcultured astroglial cells from striatum, cerebral cortex and ventral mesencephalon obtained from primary cultures of fetal (E14, E17 and E21) or postnatal (days 5–6) rats showed different regional, age‐dependent morphological response (stellation) to cyclic AMP. While most of the cerebral cortex and ventral mesencephalic astroglial cell population was responsive at all ages tested, striatal cells at E14 and E17 were not. At age E21 striatal astroglia showed a significant shift toward a mature‐like type of response to cyclic AMP. Postnatal striatal astroglia responded to cyclic AMP as the cortical and ventral mesencephalic astroglia did, with generalized stellation. Prenatal striatal astroglia was characterized immunocytochemically as A2B5+, fibronectin+, vimentin+, S‐100+ and GFAP−. Failure of early prenatal (E14, E17) striatal astroglia to differentiate in response to cyclic AMP, was overcome by previous (5–7 days) co‐culture with primary cell dissociates from postnatal‐, but not from prenatal donors, from all brain regions tested including a non‐target region for striatal cells, such as septum. This effect was duplicated when striatal astroglia was co‐cultured with cell populations enriched in neurons through Percoll gradients. Only cell‐to‐cell contact co‐cultures were able to induce a change in the studied response. Dead neuron‐enriched populations obtained following various types of physical treatments were also able to change significantly striatal cell response toward cyclic AMP. Enriched astroglial populations from postnatal donors did not change striatal astroglial response toward cyclic AMP, except for ventral mesencephalic astroglia which induced a comparatively reduced but significant increase in striatal cell responsiveness. It is concluded that astroglial maturation and potential for phenotype expression during brain development proceeds with regional heterochrony. Also, that maturation of prenatal striatal astroglia responsiveness toward cyclic AMP is inducible by non‐diffusible factors, probably of neuronal origin, expressed in live or dead primary cultures from various, homotopic and heterotopic, postnatal brain regions. It is further suggested that striatal afferents and/or mature local striatal neurons express membrane associated molecules that regulate responsiveness for phenotype expression of striatal glial cells, thus reinforcing the concept of a highly interactive, continuous neuron‐glial developmental process that takes place during brain organization.
Dendrite development and target innervation of displaced retinal ganglion cells of the chick (Gallus gallus)
Authors: Mey Jörg , Johann Verena
Published: July 2002

The avian accessory optic system (AOS) processes visual signals of translational and rotational flowfields resulting from self‐motion. It has been investigated extensively with physiological methods and, because of its anatomical distinction from other retinofugal projections, is well suited for the investigation of dendritic differentiation and axonal pathfinding. Displaced retinal ganglion cells (dRGC) constitute the retinal origin of the AOS. Since little is known about the time course of the development of this projection, we studied the dendritic differentiation of dRGC, their innervation of the nucleus of the basal optic root (nBOR) and the histological development of this target area. dRGC, visualized by retrograde 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethyl‐indocarbocyanine perchlorate labeling, migrated into the inner nuclear layer of the retina and subsequently developed their characteristic dendritic morphology between E9 and E14. At this stage, dendrites were unistratified in the inner plexiform layer and displayed characteristic branches with 45–90° angles. The frequency of dendritic branches increased from an average of 44 branches per cell at E9 to an average of 155 at E15. This phase was followed by a period of dendritic pruning, E15–E17, where a large number of small branches were eliminated. At the time of hatching, dRGC were morphologically mature with mean dendritic field sizes of 0.28 mm2 and an average of 108 dendritic branches per cell. Retinal innervation of the nBOR occurred between E8 and E11, and tracer injections at later stages revealed no further changes. In addition to the predominant contralateral projection, we have also described a connection to the ipsilateral nBOR. This ipsilateral pathway persisted at least to juvenile stages (P14). The histological development of the nBOR proceeded such that calretinin‐immunoreactive neurons were observed from E10 onwards and morphologically described cell types evolved after E12.
Do early‐life events permanently alter behavioral and hormonal responses to stressors?
Authors: Anisman Hymie , Zaharia Marilee D. , Meaney Michael J. , Merali Zul
Published: July 2002

Early‐life stimulation (e.g. brief handling) attenuates the behavioral and neuroendocrine responses to stressors encountered in adulthood, particularly with respect to activation of hypothalamic‐pituitary‐adrenal (HPA) activity. In contrast, if neonates were subjected to a more severe stressor, such as protracted separation from the dam or exposure to an endotoxin, then the adult response to a stressor was exaggerated. These early‐life experiences program HPA functioning, including negative feedback derived from stimulation of hippocampal glucocorticoid receptors, and corticotropin‐releasing hormone (CRH) and arginine vasopressin (AVP) coexpression in PVN neurons, to modify the response to subsequent stressor experiences. The persistent variations of HPA activity observed in handled/stimulated animals may stem from alterations in dam–pup interactions (e.g. increased arched‐back feeding, licking, grooming). In addition genetic makeup is critical in determining stress reactivity. For instance, BALB/cByJ mice are more reactive to stressors than C57BL/6ByJ mice, exhibiting greater HPA hormonal alterations and behavioral disturbances. BALB/cByJ also fail to acquire a spatial learning response in a Morris water‐maze paradigm, which has been shown to be correlated with hippocampal cell loss associated with aging. Early‐life handling of BALB/cByJ mice prevented these performance deficits and attenuated the hypersecretion of ACTH and corticosterone elicited by stressors. The stressor reactivity may have been related to maternal and genetic factors. When BALB/cByJ mice were raised by a C57BL/6ByJ dam, the excessive stress‐elicited HPA activity was reduced, as were the behavioral impairments. However, cross‐fostering the more resilient C57BL/6ByJ mice to a BALB/cByJ dam failed to elicit the behavioral disturbances. It is suggested that genetic factors may influence dam–pup interactive styles and may thus proactively influence the response to subsequent stressors among vulnerable animals. In contrast, in relatively hardy animals the early‐life manipulations may have less obvious effects.
Affective symptomatology in schizophrenia: a risk factor for tardive dyskinesia?
Authors: Schulze T.G. , Müller D.J. , Krauss H. , Marwinski K. , Maroldt A.-O. , Novo y Fernández A. , Fimmers R. , Held T. , Maier W. , Nöthen M.M. , Rietschel M.
Published: July 2002

Affective symptomatology has repeatedly been suggested to confer susceptibility to tardive dyskinesia (TD). In our sample of 174 schizophrenic patients a history of depressive symptoms was not associated with the occurrence of TD, whereas manic symptomatology was significantly associated with the absence of TD. Thus, our data suggest that affective symptomatology cannot unambiguously be considered to predispose to TD.
Postoperative psychosis in homocystinuria
Authors: Eschweiler GW , Rosin R , Thier P , Giedke H
Published: July 2002

Young homocystinuria patients suffering from lens dislocation frequently have to undergo eye surgery. We describe a 16-year-old girl with mild mental retardation who became psychotic-delirant immediately after the last of three lentectomia operations performed under general thiopental anaesthesia. Because methionine, homocysteine, its oxidation product homocysteate and cysteine are potent glutamate agonists, the disturbance of the sulphur containing amino acid (SCAA) metabolism in homocystinuria patients may alter the function of cerebral glutamatergic transmission. The chronic and acute neurological and psychiatric symptoms of homocystinuria patients offer a clue to studies of the neurotoxic but also antipsychotic potency of glutamate agonists like the SCAAs in humans.
Who needs needs?
Authors: Priebe S. , Huxley P. , Burns T.
Published: July 2002

The idea of assessing needs both in individuals and in populations is popular in health and social care, but has serious conceptual shortcomings. The concept of needs does not distinguish between the identification of a problem and its solution. It inhibits a consideration of the probabilities as to how effective various interventions may be in any given case — nor does it reflect the iterative process that is the reality of most health and social care. It does not specify goals and oversimplifies evaluation of outcome because it does not take into account different degrees of
change. In assessing population needs, there is the special risk of equating service use with service need, thereby entrenching the status quo. Instead of assessing needs, it is proposed that we identify problems, specify goals and choose interventions on the basis of probabilities of effectiveness. The outcome of any given intervention can be repeatedly reviewed with respect to its goals, and priorities may be reset accordingly.
Family friendly firms
Authors: Preece Dianna C. , Filbeck Greg
Published: July 2002

In this paper we examine the returns to a portfolio of 29 firms that are perceived as family-oriented. The sample is based on firms awarded the best 100 companies for working mothers in Working Mother Magazine’s annual survey. There is much anecdotal evidence supporting the benefits of these programs, but little evidence relating family-oriented policies to shareholder wealth. We find, based on raw returns, that family-friendly firms do not earn statistically significant excess returns relative to a matched sample or to the S & P 500. Based on risk-adjusted returns, the family-friendly portfolio outperforms the market, but underperforms a matched sample portfolio. © 1999 Elsevier Science Inc. All rights reserved.
Mitral valve repair in heart failure
Authors: Smolens Iva A. , Pagani Francis D. , Bolling Steven F.
Published: July 2002

Mitral regurgitation (MR) is a frequent complication of end‐stage heart failure. Historically, these patients were either managed medically or with mitral valve replacement, both associated with poor outcomes. Mitral valve repair via an ‘undersized’ annuloplasty repair is safe and effectively corrects MR in heart‐failure patients. All of the observed changes contribute to reverse remodeling and restoration of the normal left‐ventricular geometric relationship. Mitral valve repair offers a new strategy for patients with MR and end‐stage heart failure.
An evaluation of symptom classification systems used for the assessment of patients with heart failure in France
Authors: Gibelin P.
Published: July 2002

Many systems have been proposed to assess the degree of functional impairment in patients with chronic heart failure in order to be able to draw comparisons between patients and assess the development of the disease in the same patient. The NYHA classification is subjective and insufficiently reproducible and has no real predictive value with respect to the exertion test. The Canadian classification does not contribute much in terms of validation. The Feinstein and Duke University classifications are too complex, not very easy to use and have never been validated. The scale of activity proposed by Goldman gives details on functional impairment by using examples from daily activities, selected for their variety and grouped according to the energy that they require. This classification is highly reproducible and is concordant with the exertion test (duration of the exertion test, VO2 max). However, it is not suitable for France. The examples are not precise enough: in addition, they do not eliminate contradictions that can make the patient impossible to classify. We propose a scale of activity specifically designed for use in France. It is reproducible and the VO2 peaks are highly concordant. Lastly, the questions the patient is asked are progressive, thus avoiding contradictory answers. This classification could prove to be useful in everyday life and also for multi‐center studies in French‐speaking countries.
Evaluation of Fall and Fracture Risk Among Men With Prostate Cancer Treated With Androgen Receptor Inhibitors
Authors: Myint Zin W. , Momo Harry D. , Otto Danielle E. , Yan Donglin , Wang Peng , Kolesar Jill M.
Published: November 2020

Importance

A high incidence of fall and fracture in a subset of patients treated with androgen receptor inhibitors (ARIs) has been reported, although the relative risk (RR) of fall and fracture for patients who receive ARI treatment is unknown.

Objective

To evaluate whether treatment with ARIs is associated with an elevated relative risk for fall and fracture in patients with prostate cancer.

Data Sources

Cochrane, Scopus, and MedlinePlus databases were searched from inception through August 2019.

Study Selection

Randomized clinical trials comparing patients with prostate cancer treated with any ARI or placebo were included.

Data Extraction and Synthesis

Two independent reviewers used a standardized data extraction and quality assessment form. A mixed effects model was used to estimate the effects of ARI on relative risk, with included studies treated as random effects and study groups treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Statistical analysis was performed from August to October 2019.

Main Outcomes and Measures

The primary outcome was RR of fall and fractures for patients receiving ARI treatment.

Results

Eleven studies met this study’s inclusion criteria. The total population was 11 382 men (median [range] age: 72 [43-97] years), with 6536 in the ARI group and 4846 in the control group. Participants in the ARI group could have received enzalutamide, apalutamide, or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations; patients in the control group could have received placebo, bicalutamide, or abiraterone. The reported incidence of fall was 525 falls (8%) in the ARI group and 221 falls (5%) in the control group. The incidence of fracture was 242 fractures (4%) in the ARI group and 107 fractures (2%) in the control group. Use of an ARI was associated with an increased risk of falls and fractures: all-grade falls (RR, 1.8; 95% CI, 1.42-2.24; P < .001); grade 3 or greater fall (RR, 1.6; 95% CI, 1.27-2.08; P < .001); all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; P < .001), and likely grade 3 or greater fracture (RR, 1.71; 95% CI, 1.12-2.63; P = .01).

Conclusions and Relevance

Use of ARI was associated with an increase in falls and fractures in patients with prostate cancer as assessed by a retrospective systematic review and meta-analysis. Further studies are warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.
Adverse Effects of Low‐Dose Methotrexate in a Randomized Double‐Blind Placebo‐Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial
Authors: Vanni Kathleen M.M. , Berliner Nancy , Paynter Nina P. , Glynn Robert J. , MacFadyen Jean , Colls Joshua , Lu Fengxin , Xu Chang , Ridker Paul M. , Solomon Daniel H.
Published: November 2020

Objective

Low‐dose methotrexate (LD‐MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD‐MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD‐MTX versus placebo in a large randomized controlled trial (RCT).

Methods

We prespecified secondary analyses of a double‐blind, placebo‐controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada. Subjects were randomly allocated to LD‐MTX (20 mg/week maximum) or placebo. All subjects received folic acid (1 mg daily for 6days/week). We assessed the frequency of blindly adjudicated hematologic and malignant adverse events (AEs).

Results

A total of 2391 subjects were randomized to LD‐MTX (mean dosage 14.9 mg/week), and 2395 were randomized to placebo. During follow‐up, in the LD‐MTX arm, simultaneous two‐line cytopenias (n = 92 [3.9%]) or pancytopenia (n = 13 [0.54%]) were infrequent. Pancytopenia developed as soon as 4 months and as late as 3.5 years after beginning LD‐MTX, though the latter subject had been recently diagnosed with multiple myeloma. Overall skin cancer risk was increased in users of LD‐MTX compared with users of placebo, which driven largely by a statistically significant increased risk of squamous cell skin cancer (hazard ratio [HR] 3.31; 95% confidence interval [CI] 1.63‐6.71). Melanoma was increased in LD‐MTX, but this was not statistically significant (HR 2.33; 95% CI 0.60‐9.01).

Conclusions

Among subjects using LD‐MTX, simultaneous two‐line cytopenias and pancytopenia were uncommon. We found more cases of skin cancer, particularly squamous cell carcinomas, in the LD‐MTX arm than the placebo arm.
3D Bioprinting of Neural Tissues
Authors: Cadena Melissa , Ning Liqun , King Alexia , Hwang Boeun , Jin Linqi , Serpooshan Vahid , Sloan Steven A.
Published: November 2020

The human nervous system is a remarkably complex physiological network that is inherently challenging to study because of obstacles to acquiring primary samples. Animal models offer powerful alternatives to study nervous system development, diseases, and regenerative processes, however, they are unable to address some species‐specific features of the human nervous system. In vitro models of the human nervous system have expanded in prevalence and sophistication, but still require further advances to better recapitulate microenvironmental and cellular features. The field of neural tissue engineering (TE) is rapidly adopting new technologies that enable scientists to precisely control in vitro culture conditions and to better model nervous system formation, function, and repair. 3D bioprinting is one of the major TE technologies that utilizes biocompatible hydrogels to create precisely patterned scaffolds, designed to enhance cellular responses. This review focuses on the applications of 3D bioprinting in the field of neural TE. Important design parameters are considered when bioprinting neural stem cells are discussed. The emergence of various bioprinted in vitro platforms are also reviewed for developmental and disease modeling and drug screening applications within the central and peripheral nervous systems, as well as their use as implants for in vivo regenerative therapies.
Aluminum Plasmonics Enriched Ultraviolet GaN Photodetector with Ultrahigh Responsivity, Detectivity, and Broad Bandwidth
Authors: Dubey Abhishek , Mishra Ragini , Hsieh Yu‐Hung , Cheng Chang‐Wei , Wu Bao‐Hsien , Chen Lih‐Juann , Gwo Shangjr , Yen Ta‐Jen
Published: November 2020

Plasmonics have been well investigated on photodetectors, particularly in IR and visible regimes. However, for a wide range of ultraviolet (UV) applications, plasmonics remain unavailable mainly because of the constrained optical properties of applicable plasmonic materials in the UV regime. Therefore, an epitaxial single‐crystalline aluminum (Al) film, an abundant metal with high plasma frequency and low intrinsic loss is fabricated, on a wide bandgap semiconductive gallium nitride (GaN) to form a UV photodetector. By deliberately designing a periodic nanohole array in this Al film, localized surface plasmon resonance and extraordinary transmission are enabled; hence, the maximum responsivity (670 A W−1) and highest detectivity (1.48 × 1015 cm Hz1/2 W−1) is obtained at the resonance wavelength of 355 nm. In addition, owing to coupling among nanoholes, the bandwidth expands substantially, encompassing the entire UV range. Finally, a Schottky contact is formed between the single‐crystalline Al nanohole array and the GaN substrate, resulting in a fast temporal response with a rise time of 51 ms and a fall time of 197 ms. To the best knowledge, the presented detectivity is the highest compared with those of other reported GaN photodetectors.
Agrivoltaics—The Perfect Fit for the Future of Organic Photovoltaics
Authors: Meitzner Rico , Schubert Ulrich S. , Hoppe Harald
Published: November 2020

This Essay presents a possible pathway for the advancement of organic photovoltaics toward broader commercial success and enlarged market size. This vision aims at broad scale applications in photovoltaic greenhouses and polytunnels, which harvest those portions of the solar spectrum that are not used or required by plants. Based on the assumptions of the Shockley–Queisser–Limit, respectively detailed balance, and the additional postulation of using no absorption in the visible part of the AM 1.5G solar spectrum a power conversion efficiency of ≈17% is theoretically predicted. The suggestion is supported by the existence of a number of organic compounds, which already exhibit a good spectral compatibility with the typical photosynthetic action spectrum of chloroplasts. It is hoped that more suitable materials development shall be triggered and fertilized as a result of this Essay.
Robust Three‐Component Elastomer–Particle–Fiber Composites with Tunable Properties for Soft Robotics
Authors: Mohammadi Nasab Amir , Sharifi Siavash , Chen Shuai , Jiao Yang , Shan Wanliang
Published: November 2020

Materials with tunable properties, especially dynamically tunable stiffness, have been of great interest for the field of soft robotics. Herein, a novel design concept of robust three‐component elastomer–particle–fiber composite system with tunable mechanical stiffness and electrical conductivity is introduced. These smart materials are capable of changing their mechanical stiffness rapidly and reversibly when powered with electrical current. One implementation of the composite system demonstrated here is composed of a polydimethylsiloxane (PDMS) matrix, Field's metal (FM) particles, and nickel‐coated carbon fibers (NCCF). It is demonstrated that the mechanical stiffness and the electrical conductivity of the composite are highly tunable and dependent on the volume fraction of the three components and the temperature, and can be reasonably estimated using effective medium theory. Due to its superior electrical conductivity, Joule heating can be used as the activation mechanism to realize ≈20× mechanical stiffness changes in seconds. The performance of the composites is thermally and mechanically robust. The shape memory effect of these composites is also demonstrated. The combination of tunable mechanical and electrical properties makes these composites promising candidates for sensing and actuation applications for soft robotics.
Rapid Fabrication Method for Soft Devices Using Off‐the‐Shelf Conductive and Dielectric Acrylic Elastomers
Authors: Kanno Ryo , Nagai Toshiaki , Shintake Jun
Published: November 2020

Herein, a method to fabricate soft and stretchable devices rapidly by using only commercially available conductive and dielectric elastomer materials with the aid of laser cutting and a layer‐by‐layer process is presented. The conductive acrylic elastomer is first characterized in terms of its mechanical and electrical characteristics and then applied to various devices, such as soft electrostatic actuators, strain sensors, and stretchable pumps. These devices, which can be fabricated within 15–30 min, exhibit areal actuated strains of up to 163.0 ± 1.0% at 4 kV in the actuators, a highly linear response (R2 = 0.995) for strains of up to 100% with a gauge factor of 0.98 in the sensors, and an output pressure of 0.11 ± 0.08 kPa and flow rate of 20 ± 4 μL s−1 at 7 kV in the pumps. These performance characteristics are comparable to those reported in the literature. To demonstrate the potential for soft robotic applications, a wearable device is developed (fabrication time of ≈15 min), which exhibits multiple functionalities, such as detection of deformations of a human finger, haptic presentation through vibration, and electroadhesion. The results illustrate the high applicability of the presented strategy in soft intelligent systems.
Autonomous Directional Motion of Actin‐Containing Cell‐Sized Droplets
Authors: Haller Barbara , Jahnke Kevin , Weiss Marian , Göpfrich Kerstin , Platzman Ilia , Spatz Joachim Pius
Published: November 2020

Cell motility is potentially the most apparent distinction of living matter, serving an essential purpose in single cells and multicellular organisms alike. Thus, the bottom‐up reconstitution of autonomous motion of cell‐sized compartments remains an exciting but challenging goal. Herein, actin‐driven Marangoni flows are engineered to generate rotational and translational motility of surfactant‐stabilized emulsion droplets. The interaction between actin filaments and the negatively charged block‐copolymer Krytox is identified as the driving force for Marangoni flows at the droplet interface. Tuning the actin–Krytox interplay, sustained autonomous unidirectional droplet rotation with 1.7 rot h−1 is achieved. Ultimately, this rotational motion is transformed into a translational rolling motion by introducing interactions between the droplets and the surface of the observation chamber. Accordingly, translational motility of actin‐containing droplets at velocities of 0.061 ± 0.014 μm s−1 is reported herein and an overall displacement of several hundreds of micrometers within 30 min is observed. These self‐propelled systems with biologically active molecules demonstrate how motility could be implemented for synthetic cells.
Neuromorphic Motion Detection and Orientation Selectivity by Volatile Resistive Switching Memories
Authors: Wang Wei , Covi Erika , Milozzi Alessandro , Farronato Matteo , Ricci Saverio , Sbandati Caterina , Pedretti Giacomo , Ielmini Daniele
Published: November 2020

Motion detection is a primary visual function, crucial for the survival of animals in nature. Direction‐selective (DS) neurons can be found in multiple locations in the visual neural system, both in the retina and in the visual cortex. For instance, the DS ganglion cell in the retina provides a real‐time response to moving objects, which is much faster than the image recognition executed in the visual cortex. Such in‐retina biological signal processing capability is enabled by the spatiotemporal correlation within different receptive fields of the DS ganglion cells. Taking inspiration from the biological DS ganglion cells in the retina, the motion detection is demonstrated in an artificial neural network made of volatile resistive switching devices with short‐term memory effects. The motion detection arises from the spatiotemporal correlation between the adjacent excitatory and inhibitory receptive fields with short‐term memory synapses, closely resembling the physiological response of DS ganglion cells in the retina. The work supports real‐time neuromorphic processing of sensor data by exploiting the unique physics of innovative memory devices.
A Pilot Randomized, Controlled, Double‐Blind Trial of Bumetanide to Treat Neonatal Seizures
Authors: Soul Janet S. , Bergin Ann M. , Stopp Christian , Hayes Breda , Singh Avantika , Fortuno Carmen R. , O'Reilly Deirdre , Krishnamoorthy Kalpathy , Jensen Frances E. , Rofeberg Valerie , Dong Min , Vinks Alexander A. , Wypij David , Staley Kevin J. ,   for the Boston Bumetanide Trial Group
Published: November 2020

Objective

In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard‐therapy control group.

Methods

A randomized, double‐blind, dose‐escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)‐confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures.

Results

Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post‐SDA (both p < 0.01) compared with 2‐hour baseline in treatment versus control groups with adjustment for seizure burden.

Interpretation

Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327–340
Synthesis of Nitride Zeolites in a Hot Isostatic Press
Authors: Wendl Sebastian , Zipkat Mirjam , Strobel Philipp , Schmidt Peter J. , Schnick Wolfgang
Published: November 2020

The recently introduced nitridophosphate synthesis in a hot isostatic press (HIP) enabled simple access to large‐scale product quantities starting from exclusively commercially available starting materials. Herein, we show that this method is suitable for the synthesis of highly condensed functional nitridophosphates, as well. Hence, the syntheses of the nitridophosphate zeolites Ba3P5N10X (X=Cl, Br) are presented as proof of concept for this innovative access. Furthermore, samples of unprecedented Sr3P5N10X (X=Cl, Br) were prepared and characterized to demonstrate the advantages of this synthetic approach over commonly used methods. Luminescence investigations on Eu2+‐doped samples of AE3P5N10X (AE=Sr, Ba; X=Cl, Br) were carried out and characteristics of observed emission bands are discussed.
Design, Synthesis, and Biological Evaluation of Chemically and Biologically Diverse Pyrroquinoline Pseudo Natural Products
Authors: Liu Jie , Cremosnik Gregor S. , Otte Felix , Pahl Axel , Sievers Sonja , Strohmann Carsten , Waldmann Herbert
Published: November 2020

Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo‐NPs, NP‐derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155‐member pyrroquinoline pseudo‐NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological “cell painting” assay followed by principal component analysis revealed that the pseudo‐NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.
Label‐Free Colorimetric Biosensors Based on Aptamers and Gold Nanoparticles: A Critical Review
Authors: Zhang Fang , Liu Juewen
Published: November 2020

Taking advantage of the adsorption of single‐stranded DNA oligonucleotides by gold nanoparticles (AuNPs) and the protection effect of the adsorbed DNA against salt‐induced aggregation of AuNPs, a label‐free colorimetric sensor for the detection of DNA was reported in 2004. Since then, the range of target molecules has extended from complementary nucleic acids to metal ions and small molecules by using aptamers. In the presence of target molecules, a blue color arising from aggregated AuNPs is expected. However, these sensors only considered aptamer binding to its target, and the adsorption of aptamers by AuNPs, while the target/AuNP interactions were ignored. We recently found that target adsorption can often dominate the system. In this Review, we list literature examples of using this label‐free strategy for sensing aptamer targets. Seven target analytes are discussed in detail. For As(III), dopamine, melamine, kanamycin, adenosine, and ATP, target adsorption dominated, and the same color change was observed even with non‐aptamer sequences. Only in the case of K+ detection, did the effect of specific aptamer binding dominate, attributable to weak K+/AuNP interactions. These examples call for a careful evaluation of target adsorption and the use of non‐aptamer control sequences in validating these sensors.