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Background: In the prison environment, the nursing profession has particularly complex peculiarities and aspects, so much so that prison nurses require advanced specialist skills and specific education. Can nurses’ stereotypes and prejudices in prison settings affect nursing care? What are nurses’ perceptions of the prison environment and people in detention? This study aims, on one hand, to outline the figure of the nurse in the prison environment and current regulations and, on the other hand, to explore whether and how stereotypes and prejudices may affect the way care is provided. Methods: Starting with an analysis of the literature, the authors administered a questionnaire to a group of nurses who shared data and reflections. Results: This study sheds a new light on nursing in the prison environment, exploring how nurses’ stereotypes and prejudices may affect the care of patients. Conclusions: It would be desirable to develop research in this field to enable a more conscious approach to a world that is still considered distant and dangerous, and to overcome the misperceptions and prejudices that may negatively affect the way of caring.

The intentional homicide of female victims, which is most commonly perpetrated by intimate partners or family members, has been recognized in recent years as a matter of grave public concern that needs to be addressed from the cultural and judicial perspectives. To allow an in-depth criminological and psychopathological evaluation of female homicide in Italy in 2021 to be conducted, the authors performed a newspaper report analysis of the phenomenon. All female homicides that occurred in Italy in 2021 (n = 119) were included in the study. The analysis confirmed the low rate of female homicides in Italy when compared with other countries and also showed the phenomenon to be more complex than usually described. The highest rate of homicides was observed in elderly females when compared with other age groups, implying different criminological considerations and suggesting that gender-based violence may only explain some of the identified cases. The high incidence of suicide or attempted suicide among offenders, together with the high incidence of reported mental disorders in that population, suggests that a psychopathological perspective on the phenomenon of female homicide could help with the development and implementation of preventive strategies that focus on managing mental health at a territorial level and intervening in difficult domestic situations.

Authors acknowledge financial support from the French Agence Nationale de la Recherche (grant [ANR-18-CE11-0018-01] to B.F. and [ANR-16-CE12-0016-01] to B.C.O). This work used the platforms of the Grenoble Instruct-ERIC Centre (ISBG: UMS3518 CNRS-CEA-UGA-EMBL) with support from FRISBI (ANR-10-INBS-05-02) and GRAL, a project of the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003) within the Grenoble Partnership for Structural Biology. The IBS Electron Microscope facility is supported by the Auvergne Rhône-Alpes Region, the Fonds Feder, the Fondation pour la Recherche Médicale and GIS-IBiSA. The proteasome system allows the elimination of functional or structurally impaired proteins. This includes the degradation of nascent peptides. In Archaea, how the proteasome complex interacts with the translational machinery remains to be described. Here, we characterised a small orphan protein, Q9UZY3 (Uniprot ID) conserved in Thermococcales. The protein was identified in native pull-down experiments using the proteasome regulatory complex (PAN) as bait. X-ray crystallography and SAXS experiments revealed that the protein is monomeric and adopts a β-barrel core structure with an Oligonucleotide/oligosaccharide-Binding (OB) fold, typically found in translation elongation factors. Mobility shift experiment showed that Q9UZY3 displays tRNA binding properties. Pull-downs, co-immunoprecipitation and ITC studies revealed that Q9UZY3 interacts in vitro with PAN. Native pull-downs and proteomic analysis using different versions of Q9UZY3 showed that the protein interacts with the assembled PAN-20S proteasome machinery in Pyrococcus abyssi cellular extracts. The protein was therefore named Pbp11, for Proteasome Binding Protein of 11 kDa. Interestingly, the interaction network of Pbp11 also includes ribosomal proteins, tRNA processing enzymes and exosome subunits dependent on Pbp11's N-terminal domain that was found to be essential for tRNA binding. Together these data suggest that Pbp11 participates in an interface between the proteasome and the translational machinery. Publisher PDF

Whereas proteolytic cleavage is crucial for peptide presentation by classical major histocompatibility complex (MHC) proteins to T cells, glycolipids presented by CD1 molecules are typically presented in an unmodified form. However, the mycobacterial lipid antigen mannosyl-β1-phosphomycoketide (MPM) may be processed through hydrolysis in antigen presenting cells, forming mannose and phosphomycoketide (PM). To further test the hypothesis that some lipid antigens are processed, and to generate antigens that lead to defined epitopes for future tuberculosis vaccines or diagnostic tests, we aimed to create hydrolysis-resistant MPM variants that retain their antigenicity. Here, we designed and tested three different, versatile synthetic strategies to chemically stabilize MPM analogs. Crystallographic studies of CD1c complexes with these three new MPM analogs showed anchoring of the lipid tail and phosphate group that is highly comparable to nature-identical MPM, with considerable conformational flexibility for the mannose head group. MPM-3, a difluoromethylene-modified version of MPM that is resistant to hydrolysis showed altered recognition by cells, but not by CD1c proteins, supporting the cellular antigen processing hypothesis. Furthermore, the synthetic analogs elicited T cell responses that were cross-reactive with nature-identical MPM, fulfilling important requirements for future clinical use.

There is a vast genomic resource for enzymes active on carbohydrates. Lagging far behind, however, are functional chemical tools for the rapid characterization of carbohydrate‐active enzymes. Activity‐based probes (ABPs) offer one chemical solution to these issues with ABPs based upon cyclophellitol epoxide and aziridine covalent and irreversible inhibitors representing a potent and widespread approach. Such inhibitors for enzymes active on polysaccharides are potentially limited by the requirement for several glycosidic bonds, themselves substrates for the enzyme targets. Here, it is shown that non‐hydrolysable trisaccharide can be synthesized and applied even to enzymes with challenging subsite requirements. It was found that incorporation of carbasugar moieties, which was accomplished by cuprate‐assisted regioselective trans‐diaxial epoxide opening of carba‐mannal synthesised for this purpose, yields inactivators that act as powerful activity‐based inhibitors for α‐1,6 endo‐mannanases. 3‐D structures at 1.35–1.47 Å resolutions confirm the design rationale and binding to the enzymatic nucleophile. Carbasugar oligosaccharide cyclophellitols offer a powerful new approach for the design of robust endoglycosidase inhibitors, while the synthesis procedures presented here should allow adaptation towards activity‐based endoglycosidase probes as well as configurational isosteres targeting other endoglycosidase families., Carba‐trisaccharide cyclophellitols are potent GH76 α‐1,6 endo‐mannanase inactivators and resistant to endoglycosidic bond cleavage.

BackgroundLimited data have shown that, compared to uncomplicated twin pregnancies, pregnancies complicated by twin-twin transfusion syndrome (TTTS), a life-threatening condition, are associated with higher maternal serum levels of both human chorionic gonadotropin (hCG) and thyroid hormones. With the continuing expansion of assisted reproductive technologies, the rate of twin pregnancies, including those complicated by TTTS and associated hyperemesis gravidarum, is expected to increase further. Therefore, detailed descriptions of the maternal and fetal clinical outcomes of maternal thyrotoxicosis linked to TTTS can be useful for timely diagnosis and management. However, such descriptions are currently lacking in the literature.Case PresentationWe report the case of a 30-year-old woman carrying a monochorionic twin pregnancy complicated by TTTS that induced a relapse of severe hyperemesis gravidarum with overt non-autoimmune hyperthyroidism at 17 weeks of gestation. Following fetoscopic laser coagulation (FLC), both hyperemesis and hyperthyroidism improved within 1 week.ConclusionsThe present experience contributes to the knowledge base on maternal thyrotoxicosis linked to TTTS and can be useful in the diagnosis and treatment of future cases; it also emphasizes the need for a high degree of clinical suspicion and for close collaboration between endocrinologists and obstetricians. Another key point is that TTTS-associated hyperemesis gravidarum and maternal hyperthyroidism should be considered in the differential diagnosis of refractory or relapsing hyperemesis gravidarum in women with monochorionic twin pregnancy, because this condition may require more stringent supportive treatment before and during the FLC procedure when the mother is overtly hyperthyroid.

Summary Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens. Learning points N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome. Surgical removal of testosterone-producing gonads can result in loss of libido. Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS. A previously unreported AR mutation – p.Glu2_Met190del (c.2T>C) – is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.

© The Author(s) 2020., Matrix metalloproteinases (MMPs) occur in 23 human paralogues with key functions in physiology, and their activity is controlled by protein inhibitors. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), which is essential for embryogenesis and tumour suppression, has been reported to inhibit MMPs. Here, we developed eukaryotic and bacterial expression systems for different RECK variants and analysed their inhibitory capacity against representative MMPs in vitro. We could not detect any significant inhibition. Instead, we found that partially purified RECK from the conditioned medium of transfected Expi293F cells but not that of ExpiCHO-S or Drosophila Schneider cells contained a contaminant with proteolytic activity. The contaminant was removed through treatment with a small-molecule serine peptidase inhibitor and additional chromatographic purification. A tantamount contaminant was further detected in an equivalent expression system of the N-terminal fragment of the proteoglycan testican 3, but not in those of two other proteins. These results indicate that previous reports of inhibitory activity of recombinant RECK on MMPs, which were performed with partially purified samples, were probably masked by a coeluting contaminant present in the supernatant of HEK293-derived cells. Thus, RECK is probably not a direct inhibitor of MMP catalytic activity but may still regulate MMPs through other mechanisms., This study was supported in part by grants from Spanish and Catalan public and private bodies (grant/ fellowship references BFU2015–64487R, MDM-2014–0435, BES-2015–074583, BES-2016–076877, 2017SGR3 and Fundació “La Marató de TV3” 201815).

In each professional practice, a greater or lesser part of the activity is devoted to teaching. Indeed, the transmission of the medical knowledge is an essential objective for the training of students and residents, but also an opportunity to adapt one's own practices to the current context, since fast changes are not necessarily easy to follow and assimilate. If the relationship with Medical school is rather straightforward in the university hospitals, it is not always the same for those who are more distant, but whose participation in teaching is desired, and clearly growing. In this way, it is therefore crucial that everyone is informed about recent changes to the undergraduated learning objectives (PROFILES) and the resulting needs for educational reforms for all Medical schools in Switzerland.Dans chaque pratique professionnelle, une part plus ou moins grande de l’activité est dévolue à l’enseignement. En effet, la transmission de l’art médical représente un objectif essentiel pour la formation des étudiant·e·s et des jeunes collègues, mais aussi une opportunité pour adapter ses pratiques au contexte actuel, car les changements, rapides, ne sont pas forcément faciles à assimiler. Si, dans les hôpitaux universitaires, le contact avec les Facultés de médecine est plutôt aisé, il n’en va pas toujours de même pour ceux qui en sont plus distants, mais dont la participation à l’enseignement est souhaitée et croissante. En ce sens, il apparaît crucial que tou·te·s soient informé·e·s sur les modifications récentes des objectifs d’apprentissage prégradué (PROFILES) et sur les réformes qui en découlent pour les Facultés de médecine en Suisse.

Purpose Visceral adipose tissue (VAT) is associated with cardiometabolic risk factors and insulin resistance. The physiological mechanisms underlying the benefits of Roux-en-Y gastric bypass surgery (RYGB) on glucose metabolism remain incompletely understood. The impact of RYGB on VAT was assessed among three groups of patients stratified by their glucose tolerance before surgery. Methods Forty-four obese women were categorized into normoglycemia (n = 21), impaired glucose tolerance (IGT, n = 18) and diabetes (n = 5) before surgery. Body composition measured by dual-energy X-ray absorptiometry (DXA) was performed before surgery, 6 months and 12 months after. Results The three groups had comparable mean age (mean 38.6 ± SD 9.9) and BMI at baseline (41.9 ± 4.3 kg/m2). After 12 months, total weight loss (mean 35.1% ± 7.5) and excess weight loss (91.1% ± 25.1) were similar between groups. Pre-surgery mean VAT was significantly higher in diabetes (mean 2495 ± 616 g) than in normoglycemia (1750 ± 617 g, p = 0.02). The percentage of VAT to total body fat was significantly higher in diabetes (mean 4.4% ± 0.9) compared to normoglycemia (2.9% ± 0.8, p = 0.003). Twelve months after surgery, VAT loss was significantly greater among patients with diabetes (mean 1927 ± 413 g) compared to normoglycemia (1202 ± 450, p = 0.009). Conclusions RYGB leads to important VAT loss, and this loss is greater in patients with diabetes prior to surgery. As VAT is associated with insulin resistance, this reduction may account for the profound impact of this surgery on glucose metabolism.

The recent update of The Bethesda System for Reporting Thyroid Cytology (TBSRTC) is a very important development in the evaluation of thyroid nodules. Clinical experience and scientific literature both show that practitioners performing thyroid fine-needle aspiration are accustomed to basing the clinical management of patients on reports using TBSRTC. Specifically, clinicians are familiar with the percent risk of malignancy corresponding to each TBSRTC diagnostic category (DC), as well as with the respective recommendation for clinical management. However, most clinicians are much less familiar with the specific considerations that lie between a given DC, on the one end, and the respective risk of malignancy and associated management recommendation, on the other end.A deeper understanding of the system can enlighten the clinician's thinking about the specific nodule under examination and can guide the decision-making process in a more meaningful way. Such an understanding can only be developed via close two-way communication between cytopathologists and clinicians. Through this type of interaction in the authors' tertiary medical center, recurring issues of particular importance for clinical practice were identified, which are reported here in the form of 16 frequently asked questions posed by the clinician to the cytopathologist.For each frequently asked question, an answer is provided based on the literature, the authors' experience, the new version of TBSRTC, and the new World Health Organization classification of tumors of endocrine organs.

Peptidases must be exquisitely regulated to prevent erroneous cleavage and one control is provided by protein inhibitors. These are usually specific for particular peptidases or families and sterically block the active-site cleft of target enzymes using lock-and-key mechanisms. In contrast, members of the +1400-residue multi-domain α2-macroglobulin inhibitor family (α2Ms) are directed against a broad spectrum of endopeptidases of disparate specificities and catalytic types, and they inhibit their targets without disturbing their active sites. This is achieved by irreversible trap mechanisms resulting from large conformational rearrangement upon cleavage in a promiscuous bait region through the prey endopeptidase. After decades of research, high-resolution structural details of these mechanisms have begun to emerge for tetrameric and monomeric α2Ms, which use ‘Venus-flytrap’ and ‘snap-trap’ mechanisms, respectively. In the former, represented by archetypal human α2M, inhibition is exerted through physical entrapment in a large cage, in which preys are still active against small substrates and inhibitors that can enter the cage through several apertures. In the latter, represented by a bacterial α2M from Escherichia coli, covalent linkage and steric hindrance of the prey inhibit activity, but only against very large substrates., This study was supported in part by grants from European, Spanish, and Catalan agencies (grant references FP7-HEALTH-2012-306029-2 ‘TRIGGER’, BFU2015-64487R, MDM-2014-0435, BIO2013-49320-EXP, and 2014SGR9). The Structural Biology Unit (www.sbu.csic.es) of IBMB has been named a ‘María de Maeztu’ Unit of Excellence by the Spanish Ministry of Economy and Competitiveness. T.G. and I.G.-F. acknowledge a ‘Juan-dela-Cierva’ contract from the Spanish Ministry of Economy and Competitiveness (JCI-2012-13573) and an FPU fellowship from the Spanish Ministry of Education and Culture (AP-2010-03799), respectively

Monoclonal antibodies that inhibit the interaction between PD1 and PD-L1 are approved for clinical use in several cancer types, and they are also in clinical trials for additional indications, including thyroid carcinomas. A few papers have reported on PD-L1 expression in thyroid carcinomas, including a recent large study by Ahn et al. in Endocrine-Related Cancer using tissue microarrays on differentiated and anaplastic thyroid carcinoma. However, the expression of PD-L1 in medullary thyroid carcinoma (MTC) has not been reported so far, even though ongoing clinical studies aim to test the effectiveness of checkpoint inhibitors in this rare histotype as well. We thus assessed PD-L1 expression in both tumor cells and tumor-infiltrating immune cells in a series of 16 MTC cases at a tertiary center. Tumor cells were positive in only one case, which had 5% positive cells. 1% and 2% of the inflammatory cells were stained in two cases. No correlation was evident between PD-L1 expression and survival in our series. Our results are indicative of near uniform absence of PD-L1 expression in MTC and its accompanying inflammatory cells; these results should be replicated on a larger scale in other centers. Definitive answers regarding the utility of PD1/PD-L1 immunophenotyping in MTC and of the use of checkpoint inhibitors in the treatment of this aggressive and rare thyroid cancer are expected from ongoing clinical trials, which should perform correlations with PD1/PD-L1 expression.

Apres une operation, une fibrillation auriculaire rapide survient. L´examen montre, entre autres, une baisse de la valeur du TSH, mais un dosage anterieur etait dans la norme. Y a-t-il une pathologie thyroidienne?

Nach einer Operation tritt schnelles Vorhofflimmern auf. Die Untersuchung zeigt u.a. einen erniedrigten TSH-Wert, eine fruhere TSH-Bestimmung lag aber im Normbereich. Liegt eine Schilddrusenerkrankung vor?

Un patient de 53 ans, connu pour une cardiopathie ischemique se presente aux urgences en raison d’une asthenie evoluant depuis plusieurs semaines. Il decrit des douleurs abdominales crampiformes associees a des nausees.

Ein 53-jahriger Patient mit vorbekannter ischamischer Herzkrankheit stellt sich wegen einer seit mehreren Wochen fortschreitenden Asthenie in der Notaufnahme vor. Er klagt uber krampfartige Bauchschmerzen mit Ubelkeit.

© The Author(s) 2019., α2-Macroglobulins (α2Ms) regulate peptidases, hormones and cytokines. Mediated by peptidase cleavage, they transit between native, intact forms and activated, induced forms. α2Ms have been studied over decades using authentic material from primary sources, which was limited by sample heterogeneity and contaminants. Here, we developed high-yield expression systems based on transient transfection in Drosophila Schneider 2 and human Expi293F cells, which produced pure human α2M (hα2M) at ~1.0 and ~0.4 mg per liter of cell culture, respectively. In both cases, hα2M was mainly found in the induced form. Shorter hα2M variants encompassing N-/C-terminal parts were also expressed and yielded pure material at ~1.6/~1.3 and ~3.2/~4.6 mg per liter of insect or mammalian cell culture, respectively. We then analyzed the binding of recombinant and authentic hα2M to recombinant latent human transforming growth factor-β2 (pro-TGF-β2) and bacterial G-related α2M binding protein (GRAB) by surface plasmon resonance, multiple-angle laser light scattering, size-exclusion chromatography, fluorogenic labelling, gel electrophoresis and Western-blot analysis. Two GRAB molecules formed stable complexes of high affinity with native and induced authentic hα2M tetramers. The shorter recombinant hα2M variants interacted after preincubation only. In contrast, pro-TGF-β2 did not interact, probably owing to hindrance by the N-terminal latency-associated protein of the cytokine., This study was supported in part by grants from Spanish and Catalan public and private bodies (grant/fellowship references BFU2015-64487R; MDM-2014-0435; JCI-2012-13573; BES-2015-074583; BES2013-064651; 2017SGR3; and Fundació “La Marató de TV3” 201815). Te Structural Biology Unit of IBMB is a “María de Maeztu” Unit of Excellence from the Spanish Ministry of Science, Innovation and Universities.

© The Author(s) 2019., Transforming growth factor β is a disulfide-linked dimeric cytokine that occurs in three highly related isoforms (TGFβ1–TGFβ3) engaged in signaling functions through binding of cognate TGFβ receptors. To regulate this pathway, the cytokines are biosynthesized as inactive pro-TGFβs with an N-terminal latency-associated protein preceding the mature moieties. Due to their pleiotropic implications in physiology and pathology, TGFβs are privileged objects of in vitro studies. However, such studies have long been limited by the lack of efficient human recombinant expression systems of native, glycosylated, and homogenous proteins. Here, we developed pro-TGFβ2 production systems based on human Expi293F cells, which yielded >2 mg of pure histidine- or Strep-tagged protein per liter of cell culture. We assayed this material biophysically and in crystallization assays and obtained a different crystal form of mature TGFβ2, which adopted a conformation deviating from previous structures, with a distinct dimeric conformation that would require significant rearrangement for binding of TGFβ receptors. This new conformation may be reversibly adopted by a certain fraction of the mature TGβ2 population and represent a hitherto undescribed additional level of activity regulation of the mature growth factor once the latency-associated protein has been separated., This study was supported in part by grants from Spanish and Catalan public and private bodies (grant/fellowship references BFU2015-64487R; MDM-2014-0435; JCI-2012-13573; BES-2015-074583; BES-2013-064651; 2017SGR3; and Fundació “La Marató de TV3” 201815). Te Structural Biology Unit of IBMB is a “María de Maeztu” Unit of Excellence from the Spanish Ministry of Science, Innovation and Universities.

In 2010, the Acromegaly Consensus Group revised the criteria for cure of acromegaly and thus rates of surgical remission need to be revised in light of these new thresholds. Two subgroups consisted of patients with discordant GH and IGF-1 levels and patients in remission according to the 2000 criteria, but not to the 2010 criteria, have been reported after adenomectomy and for these subgroups the precise incidence and management has not been established. The objective of the study was to update rates of surgical remission and complications and to evaluate the incidence, management, and long-term outcome of the two previously described subgroups of patients. Systematic review and meta-analysis of surgical series that defined remission according to the 2010 biochemical criteria. We included 13 studies (1105 patients). The pooled rate of overall surgical remission was 54.8 % (95 % CI 44.4–65.2 %), and 72.2 % with previous criteria. Remission was achieved in 77.9 % (95 % CI 68.1–87.6 %) of microadenomas; 52.7 % (95 % CI 41–64.4 %) of macroadenomas; 29 % (95 % CI 20.1–37.8 %) of invasive and 68.8 % (95 % CI 60–77.6 %) of non-invasive adenomas. Complication rates were 1.2 % (95 % CI 0.6–1.9 %) for CSF leak, 1.3 % (95 % CI 0.6–2.1 %) for permanent diabetes insipidus, 8.7 % (95 % CI 4.8–12.5 %) for new anterior pituitary dysfunction and 0.6 % (95 % CI 0.1–1.1 %) for severe intraoperative hemorrhage. We identified an intermediate group of patients, defined as: (1) Remission according to one, but not the other biochemical criteria (GH or IGF-1) or 2010 criteria (14.3 % and 47.1 % cases), (2) Remission according to 2000, but not 2010 criteria (13.2–58.8 % cases). Two studies reported a remission rate of 56.5 % and 100 %, in the two subgroups respectively, in a long-term outcome without adjuvant therapy. Overall remission with transsphenoidal surgery is achieved in ∼55 % of patients. For the intermediate group of patients, future prospective studies with long-term follow-up are required to determine the long-term biochemical remission rates and clinical implications.

Objective Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. Design We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Methods Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Results Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7). Conclusions Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

No abstract needed for a Letter to the Editor according to the journal's guidelines for Authors.

PurposeCongenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined.MethodsRare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated.ResultsOf the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01).ConclusionPathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.Genetics in Medicine advance online publication, 16 November 2017; doi:10.1038/gim.2017.197.

What does crown mean for philosophers? This short contribution aims at offering a narrative of the word ‘crown’ in a few accounts of political philosophy, in order to sketch a way of construing the idea of crown through exploring its relationship to the notion of power. In particular, I shall suggest that different relationships between crown and power can fit with specific kinds of account of individual sovereignty and freedom. Suggestions shall be drawn from Thomas Hobbes, John Locke and Max Weber.

The indications for levothyroxine replacement therapy for subclinical hypothyroidism (SH) remain a subject of debate, especially when prescribed for older adults. The results of the recent TRUST trial indicate that levothyroxine does not improve clinical symptom scores among elderly patients with SH. While there is much concern regarding the dilemma of introducing or withholding levothyroxine, less attention may be paid to the differential diagnosis of an elevated TSH level, which is the prerequisite for diagnosing SH. Herein, we review these issues facing endocrinologists and internists/generalists either in practice or in training. When a patient presents abnormal thyroid test results compatible with SH, a series of issues need to be addressed before the implementation of replacement therapy is considered: first, an isolated TSH elevation not linked to a primary thyroid pathology should be excluded; second, the persistent nature of the patient’s TSH elevation and SH profile should be verified; third, SH symptoms and potential complications relevant for the specific patient should be documented; fourth, expectations from levothyroxine substitution therapy for SH in the specific patient should be clarified. Only then can the decision be made whether levothyroxine substitution should be introduced or not.

The matrix metalloproteinase (MMP) family belongs to the metzincin clan of zinc-dependent metallopeptidases. Due to their enormous implications in physiology and disease, MMPs have mainly been studied in vertebrates. They are engaged in extracellular protein processing and degradation, and present extensive paralogy, with 23 forms in humans. One characteristic of MMPs is a ~ 165-residue catalytic domain (CD), which has been structurally studied for 14 MMPs from human, mouse, rat, pig and the oral-microbiome bacterium Tannerella forsythia. These studies revealed close overall coincidence and characteristic structural features, which distinguish MMPs from other metzincins and give rise to a sequence pattern for their identification. Here, we reviewed the literature available on MMPs outside vertebrates and performed database searches for potential MMP CDs in invertebrates, plants, fungi, viruses, protists, archaea and bacteria. These and previous results revealed that MMPs are widely present in several copies in Eumetazoa and higher plants (Tracheophyta), but have just token presence in eukaryotic algae. A few dozen sequences were found in Ascomycota (within fungi) and in double-stranded DNA viruses infecting invertebrates (within viruses). In contrast, a few hundred sequences were found in archaea and > 1000 in bacteria, with several copies for some species. Most of the archaeal and bacterial phyla containing potential MMPs are present in human oral and gut microbiomes. Overall, MMP-like sequences are present across all kingdoms of life, but their asymmetric distribution contradicts the vertical descent model from a eubacterial or archaeal ancestor. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman, This study was supported in part by grants from European, Spanish, and Catalan Agencies (grant references FP7-HEALTH-2012-306029-2 “TRIGGER”; BFU2015-64487R, MDM-2014-0435; BIO2013-49320- EXP; BIO2015-64216-P; BIO2013-49604-EXP; and 2014SGR9). The Structural Biology Unit (www.sbu.csic.es) of IBMB is a “María de Maeztu” Unit of Excellence from the Spanish Ministry of Economy, Industry and Competitiveness

Various histological variants of papillary thyroid carcinoma have been reported, some with clinical implications, some with peculiar, sometimes misleading morphologies. One of these rare and poorly characterized variants is papillary thyroid carcinoma with nodular fasciitis-like stroma, of which fewer than 30 cases have been documented, mostly as isolated reports. It is a dual tumor comprising a malignant epithelial proliferation that harbors typical features of conventional papillary thyroid carcinoma, admixed with a prominent mesenchymal proliferation resembling nodular fasciitis or fibromatosis. Thus, the terms papillary thyroid carcinoma with nodular fasciitis-like stroma and papillary thyroid carcinoma with fibromatosis-like stroma are used interchangeably; however, the former term suggests a self-limited and regressing disease, whereas the latter one suggests a recurrent and potentially aggressive one. Better genetic and ultrastructural characterization could lead to more appropriate terminology and management. We performed detailed clinicopathological and molecular analyses of two cases of PTC with prominent mesenchymal proliferation that developed in the thyroid gland of two male patients aged 34 and 48. In both cases, the epithelial component harbored a heterozygous somatic activating BRAF mutation (p.V600E). Also, in both cases, the mesenchymal component showed typical aberrant nuclear and cytoplasmic immunoreactivity for β-catenin and harbored a heterozygous somatic activating mutation in the corresponding CTNNB1 gene (p.S45P). This mutation has never been reported in thyroid stroma; in other tissues, it is typical of desmoid-type fibromatosis rather than nodular fasciitis-like stroma. We therefore propose that in cases of papillary thyroid carcinoma with a prominent mesenchymal component, mutations in CTNNB1 should be sought; when they are present, the term 'papillary thyroid carcinoma with desmoid-type fibromatosis' should be used. As the mesenchymal component of these tumors is not expected to concentrate radioactive iodine, special considerations apply to clinical evaluation and follow-up, which should be brought to the attention of the treating specialist.

L’hypogonadisme chez l’homme est un syndrome clinique qui resulte du defaut de production testiculaire de testosterone et/ou de sperme. Les manifestations cliniques peuvent inclure une baisse de la libido, des troubles erectiles, une osteopenie/osteoporose, et/ou une infertilite.

Der Hypogonadismus beim Mann ist ein klinisches Syndrom, das auf einer Storung der Testosteron- und/oder Spermaproduktion in den Hoden beruht. Mogliche klinische Anzeichen sind eine verringerte Libido, Erektionsstorungen, Osteopenie/Osteoporose und/oder Unfruchtbarkeit.

Most patients with hypertrophic cardiomyopathy (HCM) usually complain of a reduced exercise capacity, and several factors have been advocated as possible causes of this clinical feature. The present single-center study was designed to investigate exercise capacity and its main clinical determinants in HCM patients. One hundred ninety seven patients of 223 evaluated underwent a complete clinical assessment, including Doppler echocardiography, cardiopulmonary exercise test (CPET) and, in most cases, cardiac magnetic resonance. The HCM population (male 75 %; age 47 ± 16 years; NYHA class I or II 95 %; left ventricular ejection fraction 61 ± 3 %; resting left ventricular outflow tract gradient ≥30 mmHg 22 %; late gadolinium enhancement presence 58 %) showed slightly reduced mean peak oxygen uptake values (pVO2 75 ± 15 %, 23.2 ± 6.7 ml/kg/min) with a significant reduction of the achieved percentage of peak heart rate reserve (%pHRR 65 ± 20 %). Adopting a pVO2

Background: Growing evidence suggests that late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) is an additive marker of disease severity, and possibly of arrhythmic risk, in hypertrophic cardiomyopathy (HCM). We investigated the possible relationship between LGE and markers of myocardial repolarization dispersion in HCM. Methods and Results: Eighty-five HCM outpatients underwent CMR and short-period electrocardiogram analysis to calculate the temporal myocardial repolarization dispersion through the QT variance normalized for QT mean (QTVN) and the QT variability index (QTVI). The QT dispersion in the spatial domain was also obtained. Patients with LGE (62%) had higher left atrial volume, maximum wall thickness, and left ventricular mass (P

Applying knowledge acquired from recent medical studies to patient care poses a daily challenge to physicians. Chief residents from the Department of Internal Medicine at the University Hospital of Lausanne carried out a review of some of the issues they considered important. The conclusions of these various publications may have a significant impact on the daily practice of hospital-based internal medicine. Modern medicine based on scientific studies is a reminder that in spite of the essential importance of clinical experience, it is crucial to confront it with the results of relevant publications from the medical literature.

Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21 Cip1 and p16 INK4a expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy.