Flutamide-induced hypospadias in rats: A critical assessment.

This paper provides the first detailed description of flutamide-induced hypospadias in the rat based upon wholemount, histologic, three-dimensional reconstruction, scanning electron microscopic, and immunocytochemical analysis. The penile malformations elicited by this potent anti-androgen include a substantial proximal shift in the urethral meatus that clearly conforms to the definition of hypospadias based upon specific morphological criteria for this malformation. Through examination of the normal penile development and flutamide-induced abnormal penile development observed in prenatally oil- and flutamide-treated rats, our analysis provides insights into the morphogenetic mechanism of development of hypospadias. In this regard, a common theme in normal penile development is midline fusion of epithelia followed by removal of the epithelial seam and establishment of midline mesenchymal confluence during development of the penile urethra and prepuce, processes which are impaired as a result of prenatal flutamide treatment. The developmental processes occurring in normal penile development, through comparison with development of female external genitalia and those impaired due to prenatal flutamide treatment, are consistent with critical role of androgen receptors in normal penile development in the rat, and the specific penile abnormalities embodied in flutamide-induced rat hypospadias

Biomarkers in chronic adult hydrocephalus

Awareness of the importance of chronic adult hydrocephalus has been raised again with the recent emergence of epidemiological studies. It is estimated that between 5 and 10% of patients suffering from dementia might, in fact, have chronic hydrocephalus. Although, surgical diversion of the cerebrospinal fluid (CSF) represents the only known procedure able to treat the symptoms of this condition, the selection of surgical patients has always been problematic. In the last 40 years, we have become wiser in using appropriate diagnostic tests for the selection of these patients; however, the area of biological markers has so far been overlooked in this condition, in contrast to that for other neurodegenerative disorders and dementias. Biomarkers are biological substances that may be used to indicate either the onset or the presence, and the progression of a clinical condition, being closely linked to its pathophysiology. In such a setting they might assist in the more appropriate selection of patients for shunt surgery. In this article, we have reviewed research carried out in the last 25 years regarding the identification of serum and CSF biomarkers for chronic hydrocephalus, discussed the potential for each one, and finally discussed the limitations for use, as well as future directions and possibilities in this field. It is concluded that tumour-necrosis factor, tau protein, lactate, sulfatide and neurofilament triple protein are the most promising CSF markers for chronic hydrocephalus. At present however, none of these meet the criteria required to justify a change clinical practice. In the future, collaborative multi-centre projects will be needed to obtain more substantial data that overcome the problems that arise from small individual and uncoordinated studies

Natural capital metrics. Phase 1 final report: central components

This is a condensed version of the Natural Capital Metrics (NCMet) project Phase 1 report. It focuses on three key components: i) the conceptual framework, ii) development of six example evidence-chains and their associated data and model inventories, and iii) early development work towards a Natural Capital Portal to provide access to relevant data, models and maps of natural capital. All outputs are preliminary and are undergoing considerable refinement in the second phase of the project. Phase 2 outputs will be available in 2018

Characterization of patients with idiopathic normal pressure hydrocephalus using natural language processing within an electronic healthcare record system

OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) is an underdiagnosed, progressive, and disabling condition. Early treatment is associated with better outcomes and improved quality of life. In this paper, the authors aimed to identify features associated with patients with iNPH using natural language processing (NLP) to characterize this cohort, with the intention to later target the development of artificial intelligence–driven tools for early detection. / METHODS: The electronic health records of patients with shunt-responsive iNPH were retrospectively reviewed using an NLP algorithm. Participants were selected from a prospectively maintained single-center database of patients undergoing CSF diversion for probable iNPH (March 2008–July 2020). Analysis was conducted on preoperative health records including clinic letters, referrals, and radiology reports accessed through CogStack. Clinical features were extracted from these records as SNOMED CT (Systematized Nomenclature of Medicine Clinical Terms) concepts using a named entity recognition machine learning model. In the first phase, a base model was generated using unsupervised training on 1 million electronic health records and supervised training with 500 double-annotated documents. The model was fine-tuned to improve accuracy using 300 records from patients with iNPH double annotated by two blinded assessors. Thematic analysis of the concepts identified by the machine learning algorithm was performed, and the frequency and timing of terms were analyzed to describe this patient group. / RESULTS: In total, 293 eligible patients responsive to CSF diversion were identified. The median age at CSF diversion was 75 years, with a male predominance (69% male). The algorithm performed with a high degree of precision and recall (F1 score 0.92). Thematic analysis revealed the most frequently documented symptoms related to mobility, cognitive impairment, and falls or balance. The most frequent comorbidities were related to cardiovascular and hematological problems. / CONCLUSIONS: This model demonstrates accurate, automated recognition of iNPH features from medical records. Opportunities for translation include detecting patients with undiagnosed iNPH from primary care records, with the aim to ultimately improve outcomes for these patients through artificial intelligence–driven early detection of iNPH and prompt treatment

A Randomized Controlled Trial of Folate Supplementation When Treating Malaria in Pregnancy with Sulfadoxine-Pyrimethamine

OBJECTIVES: Sulfadoxine-pyrimethamine (SP) is an antimalarial drug that acts on the folate metabolism of the malaria parasite. We investigated whether folate (FA) supplementation in a high or a low dose affects the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. DESIGN: This was a randomized, placebo-controlled, double-blind trial. SETTING: The trial was carried out at three hospitals in western Kenya. PARTICIPANTS: The participants were 488 pregnant women presenting at their first antenatal visit with uncomplicated malaria parasitaemia (density of ≥ 500 parasites/μl), a haemoglobin level higher than 7 g/dl, a gestational age between 17 and 34 weeks, and no history of antimalarial or FA use, or sulfa allergy. A total of 415 women completed the study. INTERVENTIONS: All participants received SP and iron supplementation. They were randomized to the following arms: FA 5 mg, FA 0.4 mg, or FA placebo. After 14 days, all participants continued with FA 5 mg daily as per national guidelines. Participants were followed at days 2, 3, 7, 14, 21, and 28 or until treatment failure. OUTCOME MEASURES: The outcomes were SP failure rate and change in haemoglobin at day 14. RESULTS: The proportion of treatment failure at day 14 was 13.9% (19/137) in the placebo group, 14.5% (20/138) in the FA 0.4 mg arm (adjusted hazard ratio [AHR], 1.07; 98.7% confidence interval [CI], 0.48 to 2.37; p = 0.8), and 27.1% (38/140) in the FA 5 mg arm (AHR, 2.19; 98.7% CI, 1.09 to 4.40; p = 0.005). The haemoglobin levels at day 14 were not different relative to placebo (mean difference for FA 5 mg, 0.17 g/dl; 98.7% CI, −0.19 to 0.52; and for FA 0.4 mg, 0.14 g/dl; 98.7% CI, −0.21 to 0.49). CONCLUSIONS: Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. Countries that use SP for treatment or prevention of malaria in pregnancy need to evaluate their antenatal policy on timing or dose of FA supplementation

RNA and DNA Bacteriophages as Molecular Diagnosis Controls in Clinical Virology: A Comprehensive Study of More than 45,000 Routine PCR Tests

Real-time PCR techniques are now commonly used for the detection of viral genomes in various human specimens and require for validation both external and internal controls (ECs and ICs). In particular, ICs added to clinical samples are necessary to monitor the extraction, reverse transcription, and amplification steps in order to detect false-negative results resulting from PCR-inhibition or errors in the technical procedure. Here, we performed a large scale evaluation of the use of bacteriophages as ICs in routine molecular diagnosis. This allowed to propose simple standardized procedures (i) to design specific ECs for both DNA and RNA viruses and (ii) to use T4 (DNA) or MS2 (RNA) phages as ICs in routine diagnosis. Various technical formats for using phages as ICs were optimised and validated. Subsequently, T4 and MS2 ICs were evaluated in routine real-time PCR or RT-PCR virological diagnostic tests, using a series of 8,950 clinical samples (representing 36 distinct specimen types) sent to our laboratory for the detection of a variety of DNA and RNA viruses. The frequency of inefficient detection of ICs was analyzed according to the nature of the sample. Inhibitors of enzymatic reactions were detected at high frequency in specific sample types such as heparinized blood and bone marrow (>70%), broncho-alveolar liquid (41%) and stools (36%). The use of T4 and MS2 phages as ICs proved to be cost-effective, flexible and adaptable to various technical procedures of real-time PCR detection in virology. It represents a valuable strategy for enhancing the quality of routine molecular diagnosis in laboratories that use in-house designed diagnostic systems, which can conveniently be associated to the use of specific synthetic ECs. The high rate of inhibitors observed in a variety of specimen types should stimulate the elaboration of improved technical protocols for the extraction and amplification of nucleic acids

Kant, race, and natural history

This article presents a new argument concerning the relation between Kant’s theory of race and aspects of the critical philosophy. It argues that Kant’s treatment of the problem of the systematic unity of nature and knowledge in the Critique of Pure Reason and the Critique of the Power of Judgment can be traced back a methodological problem in the natural history of the period – that of the possibility of a natural system of nature. Kant’s transformation of the methodological problem from natural history into a set of philosophical (and specifically epistemological) problems proceeds by way of the working out of his own problem in natural history – the problem of the natural history of the human races – and specifically the problem of the unity in diversity of the human species, in response to which he develops a theory of race. This theory of race is, further, the first developed model of the use of teleological judgment in Kant’s work. The article thus argues that Kant’s philosophical position on the systematic unity of nature and of knowledge in the first and third Critiques, and his account and defense of teleological judgment, are developed out of problems first articulated in his solution to the problem of the unity in diversity of the human species – that is, in his theory of race. The article does not seek to establish that these aspects of the critical philosophy are therefore racialised. But it does demonstrate, against those who deny its salience to his philosophy, how the problem of the unity in diversity of the human species and Kant’s theory of race is significant for the development of aspects of the critical philosophy and thus contributes to their philosophical problematics

Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor

Class B GPCRs can activate multiple signalling effectors with the potential to exhibit biased agonism in response to ligand stimulation. Previously, we highlighted key TM domain polar amino acids that were crucial for the function of the GLP-1 receptor, a key therapeutic target for diabetes and obesity. Using a combination of mutagenesis, pharmacological characterisation, mathematical and computational molecular modelling, this study identifies additional highly conserved polar residues located towards the TM helical boundaries of Class B GPCRs that are important for GLP-1 receptor stability and/or controlling signalling specificity and biased agonism. This includes (i) three positively charged residues (R3.30227, K4.64288, R5.40310) located at the extracellular boundaries of TMs 3, 4 and 5 that are predicted in molecular models to stabilise extracellular loop 2, a crucial domain for ligand affinity and receptor activation; (ii) a predicted hydrogen bond network between residues located in TMs 2 (R2.46176), 6 (R6.37348) and 7 (N7.61406 and E7.63408) at the cytoplasmic face of the receptor that is important for stabilising the inactive receptor and directing signalling specificity, (iii) residues at the bottom of TM 5 (R5.56326) and TM6 (K6.35346 and K6.40351) that are crucial for receptor activation and downstream signalling; (iv) residues predicted to be involved in stabilisation of TM4 (N2.52182 and Y3.52250) that also influence cell signalling. Collectively, this work expands our understanding of peptide-mediated signalling by the GLP-1 receptor

An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8 Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrated transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P<0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL. These observations provide valuable guidance for further characterisation of 7q deletion

A Retrospective Overview of Enterovirus Infection Diagnosis and Molecular Epidemiology in the Public Hospitals of Marseille, France (1985–2005)

Human enteroviruses (HEV) are frequent human pathogens and, associated in particular with large outbreaks of aseptic meningitis. Here, we have compiled a database of clinical HEV isolates from the Public Hospitals of Marseille, from 1985 to 2005. Amongst 654 isolates that could be characterized by complete sequencing of the VP1 gene, 98% belonged to species HEV-B; the most frequently isolated serotypes were Echovirus E30, E11, E7, E6 and E4. The high incidence of E30 and the recent emergence of E13 are consistent with reports worldwide and peak HEV isolation occurred mostly in the late spring and summer months. The proportion of echoviruses has decreased across the years, while that of coxsackieviruses has increased. Stool (the most frequent sample type) allowed detection of all identified serotypes. MRC5 (Human lung fibroblasts) cell line was the most conducive cell line for HEV isolation (84.9% of 10 most common serotype isolates, 96.3% in association with BGM (Buffalo green monkey kidney cells)). Previous seroneutralization-based serotype identification demonstrated 55.4% accuracy when compared with molecular VP1 analysis. Our analysis of a large number of clinical strains over 20 years reinforced the validity of VP1 serotyping and showed that comparative p-distance scores can be coupled with phylogenetic analysis to provide non-ambiguous serotype identification. Phylogenetic analysis in the VP1, 2C and 3D regions also provided evidence for recombination events amongst clinical isolates. In particular, it identified isolates with dissimilar VP1 but almost identical nonstructural regions