Search

The epidemiological and societal burden of dementia is expected to increase in the coming decades due to the world population aging. In this context, the evaluation of the potential impact of intervention scenarios aiming at reducing the prevalence of dementia risk factors is an active area of research. However, such studies must account for the associated changes in mortality and the dependence between the risk factors. Using micro-simulations, this study aims to estimate the changes in dementia burden in France in 2040 according to intervention scenarios targeting the prevention or treatment of hypertension, diabetes and physical inactivity. Accounting for their communality and their effects on mortality, the results show that the disappearance of hypertension, diabetes and physical inactivity in France in 2020 could decrease dementia prevalence by 33% among men and 26% among women in 2040 and increase the life expectancy without dementia at age 65 by 3.4 years (men) and 2.6 years (women). Among the three factors, the prevention of hypertension would be the most efficient. These projections rely on current estimates of the risk of dementia and death associated with risk factors. Thanks to the R package developed they could be refined for different countries or different interventions and updated with new estimates., (© 2023. Springer Nature B.V.)

Introduction: Prodromal non-motor symptoms precede, often by decades, motor signs and diagnosis of Parkinson's disease. It is however still uncertain if cognitive changes belong to the spectrum of non-motor prodromal Parkinson's disease. Thanks to the very long-term follow-up of the PAQUID population-based cohort, we assessed trajectories of cognitive complaints and functioning over a 13-year period before the diagnosis of late onset Parkinson's disease., Methods: This study relies on a matched nested case-control sample selected from the cohort. Of the 3777 initial subjects of the cohort, 43 developed incident Parkinson's disease over the follow-up. The mean age at diagnosis was 78.0 (standard deviation = 5.8) years and 46.5% were men. These cases were matched to 86 elderly control subjects. Scores of different cognitive domains, daily function, and depressive symptoms were described throughout the follow-up using mixed-effects models., Results: No significant global cognitive decline preceded the diagnosis of late onset Parkinson's disease. However, psychomotor speed appeared significantly slower 2 years before the diagnosis and depressive symptoms 12 years before. Global score of instrumental activities of daily living became altered 2-3 years preceding the diagnosis of late onset Parkinson's disease, including the use of public transportation that was altered ten years before the diagnosis., Conclusion: In late onset Parkinson's disease, while global cognitive functions seem preserved, psychomotor speed starts to decline 2 years before the diagnosis and activities of daily living are also impacted. Depressive symptoms appear very early in the prediagnosic phase., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dementia is a major public health issue worldwide and chronic use of benzodiazepine, which is very frequent in northern countries, was found to be a risk factor of dementia. This work aims at evaluating the impact of a reduction in chronic use of benzodiazepine on the future burden of dementia in France. Using estimations of dementia incidence and of benzodiazepine use and nation-wide projections of mortality and population sizes, a Monte Carlo approach based on an illness-death model provided projections of several indicators of dementia burden. With no change in benzodiazepine consumption, the prevalence of dementia between age 65 and 99 in France in 2040 was estimated at 2.16 millions (95% confidence interval (CI) 1.93-2.38), with a life expectancy without dementia at 65 years equal to 25.0 years (24.7-25.3) for women and 23.8 years (23.5-24.2) for men. Assuming a disappearance of chronic use of benzodiazepine in 2020, the prevalence would be reduced by about 6.6% in 2040 and the life expectancy without dementia would increase by 0.99 (0.93-1.06) year among women and 0.56 (0.50-0.62) among men. To conclude, a modest but significant reduction in future dementia burden could be obtained by applying current recommendation for duration of benzodiazepine use.

Multiple system atrophy (MSA) is a rare neurodegenerative disease, with limited understanding of disease progression and prognostic factors. We leveraged the data of a large prospective cohort of MSA to study both clinical progression and survival and assess their determinants. All consecutive patients seen at the French Reference Centre for MSA since 2007 were included in a prospective cohort with an annual follow-up including the Unified MSA Rating Scale (UMSARS). We used joint models to evaluate the risk of death, the mean trajectory of each UMSARS subscale and to determine the potential factors. Investigated factors included gender, age at baseline, MSA subtype, diagnosis certainty, type of first symptoms and the duration between symptom onset and the first visit. Among the 261 MSA patients included in our cohort, the median duration of clinical follow-up was 2.1 years (up to 10.3 years) and the median survival was 4.0 years since the first visit. Main factors for poor survival were the progression over time of UMSARS score (I + II and IV) and the severity of orthostatic hypotension. MSA subtype had no effect on progression or survival. The UMSARS I + II score progressed faster over time in subjects with autonomic dysfunction as the initial feature and in women. Despite a faster progression, women and men had similar survival. From this large MSA cohort, we confirm the rapid progression and poor prognosis of MSA. We provide additional evidence for a negative impact of early autonomic dysfunction and the severity of orthostatic hypotension on both disease progression and survival., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

1. We have applied the concept of using MBIs to produce CYP-Silensomes to quantify the contribution of the major CYPs to drug metabolism (fmCYP). 2. The target CYPs were extensively and selectivity inhibited by the selected MBIs, while non-target CYPs were inhibited by less than 20% of the homologous control activities. Only CYP2D6-Silensomes exhibited a CYP2B6 inhibition that could be easily and efficiently encountered by subtracting the fm CYP2B6 measured using CYP2B6-Silensomes to adjust the fm CYP2D6 . 3. To validate the use of a panel of 6 CYP-Silensomes, we showed that the fmCYP values of mono- and multi-CYP metabolised drugs were well predicted, with 70% within ± 15% accuracy. Moreover, the correlation with observed fmCYP values was higher than that for rhCYPs, which were run in parallel using the same drugs (<45% within ±15% accuracy). Moreover, the choice of the RAF substrate in rhCYP predictions was shown to affect the accuracy of the fmCYP measurement. 4. These results support the use of CYP1A2-, CYP2B6-, CYP2C8-, CYP2C9-, CYP2D6 and CYP3A4-Silensomes to accurately predict fmCYP values during the in vitro enzyme phenotyping assays in early, as well as in development, phases of drug development.

In a screening of natural products for allosteric modulators of GABA A receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABA A and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds., (Copyright © 2017 Elsevier B.V. All rights reserved.)

1. Among the different in vitro studies recommended by the regulatory agencies, no gold-standard model can easily and directly measure the quantitative CYP450 contributions to drug biotransformation. In this article, we propose an original strategy, called Silensomes TM , to produce human liver microsomes silenced for one specific CYP450, thanks to specific mechanism-based inhibitors (MBI). 2. Using azamulin as a specific CYP3A4 MBI, we demonstrated the proof of concept that CYP3A4 can be totally, specifically (even against 3A5) and permanently (at least for six years) inhibited by our process. Thus, comparing clearance in control and CYP3A4-Silensomes TM , CYP3A4 contributions were determined for 11 CYP3A4 substrates which correlated with known in vivo contributions and revealed accuracy with less than 10% error. In comparison, contributions determined using recombinant human CYP450 (rhCYP450s) were less accurate (more than 10% error for 30% of the tested CYP3A4 substrates). 3. This easy and ready-to-use in vitro method combines the advantages of existing models (specificity of rhCYP450s and representativeness of HLM) without their drawbacks. The same strategy could be used to silence other major CYP450s one-by-one to provide a complete direct CYP450 quantitative phenotyping kit.

We present experiments and numerical simulations of hypervelocity impacts of 0.5 mm steel spheres into graphite, for velocities ranging between 1100 and 4500 m s -1 Experiments have evidenced that, after a particular striking velocity, depth of penetration no longer increases but decreases. Moreover, the projectile is observed to be trapped below the crater surface. Using numerical simulations, we show how this experimental result can be related to both materials, yield strength. A Johnson-Cook model is developed for the steel projectile, based on the literature data. A simple model is proposed for the graphite yield strength, including a piecewise pressure dependence of the Drucker-Prager form, which coefficients have been chosen to reproduce the projectile penetration depth. Comparisons between experiments and simulations are presented and discussed. The damage properties of both materials are also considered, by using a threshold on the first principal stress as a tensile failure criterion. An additional compressive failure model is also used for graphite when the equivalent strain reaches a maximum value. We show that the experimental crater diameter is directly related to the graphite spall strength. Uncertainties on the target yield stress and failure strength are estimated.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'., (© 2016 The Author(s).)

Purpose: If several studies analyse the working abilities of cancer survivors two years after the diagnosis, few of them analyse the long term becoming at work of these patients. Here we study a cohort of 153 workers, 6 years after they returned to work after experiencing a cancer in 2005 or 2006. All these workers participated in a previous study realised in 2008, two years after the diagnosis., Material and Methods: Fourty occupational physicians included 153 workers out of the 319 particpating in a first study conducted in 2008. Two questionnaires were completed by both the worker and the occupationnal physician. Twenty four patients' interviews and nine physician's interviews were also realized for qualitative analysis., Results: Six years after they returned to work, 46% were still working in the same company. Among patients aged less than 55 years (113 out of 153), they were 20% to leave the company (a 4% annual rate). Concerning the 83 salaries still at work, sequelaes of the disease are often still present: fatigue (57%), sleep disorders (56% vs 34% at 2 years), memory and concentration disorders (34%) and chronic pain (16%). Thirty one percent reported serious anxious disorders vs 29% in 2008. Difficulties are still present in 71% of the responders. Fourty percent of the nonexecutive workers feeled penalized. Qualitative study shows that a successfull return to work is associated with a friendly environement, the support of the company, and a long term accompagnying policy., Conclusions: Six years after returning to work, one employee out of two is still working in the same company. Far to disappear, the identified difficulties two years after the diagnosis are still present, long time after stopping the treatments. A successfull return to work needs an important support from both the company and the co-workers., (Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Humans are usually exposed to several pesticides simultaneously; consequently, combined actions between pesticides themselves or between pesticides and other chemicals need to be addressed in the risk assessment. Many pesticides are efficient activators of pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR), two major nuclear receptors that are also activated by other substrates. In the present work, we searched for interactions between endosulfan and methoxychlor, two organochlorine pesticides whose major routes of metabolism involve CAR- and PXR-regulated CYP3A4 and CYP2B6, and whose mechanisms of action in humans remain poorly understood. For this purpose, HepaRG cells were treated with both pesticides separately or in mixture for 24 hours or 2 weeks at concentrations relevant to human exposure levels. In combination they exerted synergistic cytotoxic effects. Whatever the duration of treatment, both compounds increased CYP3A4 and CYP2B6 mRNA levels while differently affecting their corresponding activities. Endosulfan exerted a direct reversible inhibition of CYP3A4 activity that was confirmed in human liver microsomes. By contrast, methoxychlor induced this activity. The effects of the mixture on CYP3A4 activity were equal to the sum of those of each individual compound, suggesting an additive effect of each pesticide. Despite CYP2B6 activity being unchanged and increased with endosulfan and methoxychlor, respectively, no change was observed with their mixture, supporting an antagonistic effect. Altogether, our data suggest that CAR and PXR activators endosulfan and methoxychlor can interact together and with other exogenous substrates in human hepatocytes. Their effects on CYP3A4 and CYP2B6 activities could have important consequences if extrapolated to the in vivo situation., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

In this work, rapidly grown KH2PO4 (KDP) crystals extracted from the prismatic and the pyramidal growth sectors of crystal boules were analyzed using photoluminescence measurements. From the spectra, we deduced a robust criterion to discriminate between both growth sectors in an unknown KDP plate. Moreover, spatially resolved photoluminescence was shown to enable a local probing of different planes in the bulk of the material leading to accurate and nondestructive three-dimensional mapping of the sector boundary, which is often the weakest point in terms of laser-damage resistance in rapidly grown KDP crystals.

In this work are described the syntheses of p-sexiphenyl and p-octiphenyl starting from 4-bromo-p-terphenyl and 4-bromo-p-quaterphenyl, respectively, by using a nickel complex in the presence of bipyridine with DMF as solvent. This type of synthesis was shown to give an improved yield as well as easy preparation and purification of these phenylene oligomers.

Mammalian and avian T-cells exhibit a large number of well characterized surface molecules associated with their maturation degree. Very little is known in comparison with T-cell differentiation in ectothermic vertebrates. This is mainly due to the lack of probes to identify T-cell subsets. We cloned and sequenced the first ectothermic CD8 beta DNA complementary to RNA from an amphibian species, the Mexican axolotl. The CD8 beta chain was 30-36% identical with its avian and mammalian homologues. The extracellular V-like domain contained the two typically conserved cysteines and was followed by a J-like sequence containing the canonical Phe-Gly-X-Gly stretch. The connecting peptide was much longer than in other species and contained potential O-glycosylation sites. The axolotl CD8 beta and major histocompatibility complex class I molecules were modeled using human HLA-A2/CD8 alphaalpha complex as template. The backbone conformation of axolotl CD8 beta matched well with the CD8 alpha-2 subunit of the human complex but significant structural differences were located in the CDR1, CDR2 and DE loops. Both axolotl and human class I showed large negative surface potential. The interacting area of the human CD8 alpha chain and of the corresponding region of axolotl CD8 beta had positive electrostatic potential compatible with complexation with the corresponding class I molecules. The presence of a CD8 beta homologue in an amphibian species implies that it was already present in the Devonian ancestor of amphibians and mammals, i.e. more than 400 million years ago.

We report here the structure of cDNA clones encoding axolotl light chains of the lambda type. A single IGLC gene and eight different potential IGLV genes belonging to four different families were detected. The axolotl Cgamma domain has several residues or stretches of residues that are typically conserved in mammalian, avian, and Xenopus Cgamma, but the KATLVCL stretch, which is well conserved in the Cgamma and T-cell receptor Cbeta domains of many vertebrate species, is not well conserved. All axolotl Vgamma sequences closely match several human and Xenopus Vgamma-like sequences and, although the axolotl Cgamma and Vgamma sequences are very like their tetrapod homologues, they are not closely related to nontetrapod L chains. Southern blot experiments suggested the presence of a single IGLC gene and of a limited number of IGLV genes, and analysis of IGLV-J junctions clearly indicated that at least three of the IGLJ segments can associate with IGLV1, IGLV2, or IGLV3 subgroup genes. The overall diversity of the axolotl Vgamma CDR3 junctions seems to be of the same order as that of mammalian Vgamma chains. However, a single IGLV4 segment was found among the 45 cDNAs analyzed. This suggests that the axolotl IGL locus may have a canonical tandem structure, like the mammalian IGK or IGH loci. Immunofluorescence, immunoblotting, and microsequencing experiments strongly suggested that most, if not all L chains are of the gamma type. This may explain in part the poor humoral response of the axolotl.

We have identified and analyzed cDNA clones encoding a major 26 kDa protein of the HMG1-2 family which is abundant in the cytoplasm and nucleus of axolotl hydrocortisone-sensitive thymocytes. The axolotl HMG2 protein is very similar to proteins belonging to the HMG1-2 family, from teleost fish to mammals. All the molecular features of the HMG1-2 proteins are conserved, including the high proportion of basic and aromatic residues, and the characteristic acidic C-terminus tail. The 3'-untranslated region of the HMG2 axolotl cDNA is also similar to the avian and mammalian HMG2 3'-UT sequences, suggesting that some selective events have acted at the DNA level to conserve this region, which could be important in the differential expression of the HMG1 and HMG2 genes. The axolotl HMG2 protein contains the two well conserved HMG boxes which are thought to be the DNA-binding domains of the molecule. Axolotl thymocytes and spleen cells contain almost identical amounts of HMG2 mRNAs but HMG2 polypeptide is undetectable in spleen cells using anti-26 kDa antibodies. The reason for the accumulation of HMG1-2 molecules in vertebrate hydrocortisone-sensitive thymocytes is discussed, as well as their possible role in apoptosis.

We previously raised a rabbit antiserum (L12) against a 38 kD polypeptide which is expressed on the surface of thymocytes and peripheral T cells of an Urodele Amphibian, the Mexican axolotl (Ambystoma mexicanum). Here we show that L12 antibodies immunoprecipitate several labelled molecules from surface iodinated axolotl spleen cells, including the 38 kD molecule, but also two polypeptides of 43 and 22 kD which are covalently linked to other elements. Another rabbit antiserum (L10) was raised against detergent-solubilized axolotl thymocyte membranes and shown to recognize the majority of thymocytes and about half of the splenocytes in immunofluorescence. In Western blotting, L10 antibodies recognized a limited number of surface polypeptides in thymocyte and splenocyte lysates, including 43, 38, and 22 kD elements. Immune complexes formed between L10 antibodies and solubilized splenocyte membranes were used to immunize BALB/c mice intrasplenically in the aim of raising MoAbs specific for axolotl T cells. Monoclonal antibody 87.16 was shown to stain in immunofluorescence 26.7% of thymocytes and 26.8% of spleen cells. This MoAb recognized a 43 kD polypeptide that can covalently associate on the T-cell surface with several other molecules to form a multimeric complex.

All jawed vertebrates possess well-differentiated thymuses and elicit T-cell-like cell-mediated responses; however, no surface T-cell receptor (TCR) molecules or TCR genes have been identified in ectothermic vertebrate species. Here we describe cDNA clones from an amphibian species, Ambystoma mexicanum (the Mexican axolotl), that have sequences highly homologous to the avian and mammalian TCR beta chains. The cloned amphibian beta chain variable region (V beta) shares most of the structural characteristics with the more evolved vertebrate V beta and presents approximately 56% amino acid identities with the murine V beta 14 and human V beta 18 families. The two different cloned axolotl beta chain joining regions (J beta) were found to have conserved all the invariant mammalian J beta residues, and in addition, the presence of a conserved glycine at the V beta-J beta junction suggests the existence of diversity elements. The extracellular domains of the two axolotl beta chain constant region isotypes C beta 1 and C beta 2 show an impressively high degree of identity, thus suggesting that a very efficient mechanism of gene correction has been in operation to preserve this structure at least from the early tetrapod evolution. The transmembrane axolotl C beta domains have been less well conserved when compared to the mammalian C beta but they do maintain the lysine residue that is thought to be involved in the charged interaction between the TCR alpha beta heterodimer and the CD3 complex.

Comparative analysis of SDS-PAGE patterns of axolotl spleen cells membrane detergent lysates showed important discrepancies between control and thymectomized animals. Among these, a 38-kD protein band, which appeared as a major protein in controls, was not or poorly expressed after thymectomy. A rabbit antiserum (L12) raised against the 38-kD eluted band labeled in indirect immunofluorescence 80-86% of thymocytes and 40-46% of mIg- lymphoid cells in the spleen. The anti-38-kD antibodies stained in Western blotting two antigenically related polypeptides of 38- and 36-kD on splenocyte membrane lysates. Two-dimensional NEPHGE-PAGE analysis indicated that the anti-38-kD antibodies reacted in the spleen with several gathered spots in the 7.8-8.2 pI range, corresponding to 38-36-kD microheterogeneous polypeptides. Most of these spots are not further expressed in thymectomized animals. These results support evidence that the 38-kD surface antigens can be considered as specific surface markers of the axolotl thymus-derived lymphocytes.

A major 26 kDa protein was identified in the cytoplasmic and nuclear compartments of axolotl thymocytes. A polyclonal antiserum was produced against the denatured form of this protein. High levels of 26 kDa were expressed by hydrocortisone-sensitive lymphocytes which represent a major thymocyte subpopulation in young animals. However, no further expression of the 26 kDa protein was observed in involuted thymus of adult animals nor in thymus of young artificially metamorphosed axolotls. The 26 kDa was never expressed by splenic and blood peripheral lymphocytes at any stage of development. Partial N-terminal amino acid sequence and amino acid composition demonstrate that the 26 kDa polypeptide is strongly homologous to HMG1-2 proteins, the most abundant members of the high mobility group (HMG) non-histone chromosomal proteins. HMG1-2 are thought to be involved in the organization of chromatin structure, as well as in the stability, replication and transcription of DNA. It was confirmed that the 26 kDa axolotl polypeptide is recognized by a well characterized rabbit antiserum to rat HMG1-2 proteins.

A comparative study of proteinograms and zymograms (LDH, MDH) has been carried out at different ontogenic stages, in Ambystoma mexicanum (A.m.), Ambystoma dumerilii (A.d.) and nucleocytoplasmic hybrids 2 n A.d/cytoplasm Am. It appears that 2 n A.d. nucleus, grafted in A.m. cytoplasm expresses only a part of its potentialities, which could account for lethality of the nucleocytoplasmic hybrids.

By means of many electrophoresis techniques, the serum of Ambystoma dumerilii was studied. The pattern in cellulose acetate is different from A. mexicanum proteinogram. Direct two-dimensional analysis in acetate/polyacrylamid gel with progressively increasing concentration from 4-30%, gives us the opportunity to observe 41 proteic components. By immunological results, the fastest proteic fraction is equivalent to a globuline with alpha-mobility more than an albumin. A nomenclature for this blood serum is proposed.

In an attempt to identify urodele amphibian lymphocyte subpopulations by their surface markers, we prepared hybridomas from BALB/c mice spleen immunized with axolotl (Ambystoma mexicanum) blood and splenic leucocytes and purified immunoglobulins. Sixty-five hybridomas were selected and subsequently subcloned. Among numerous monoclonal antibodies (mAbs) thus obtained, four mAbs were extensively characterized by immunoblotting, single and double fluorescence and immunohistology. MAb 34.38.6 recognizes polypeptides between 65,000 and 72,000 MW and labels in immunofluorescence nearly all thymocytes, 60-63% splenic lymphocytes of normal animals but only 9% splenic lymphocytes in thymectomized animals. MAb 19.14.2 reacts with a 98,000 MW protein and labels a restricted lymphocyte population in thymus (52-77%) and spleen (20-25%). The immunohistological study demonstrates that 34.38.6 and 19.14.2 label most thymocytes and a large proportion of spleen leucocytes including lymphocytes, granulocytes and macrophages. In addition, 19.14.2 labels some large interdigitating cells in thymic epithelial areas and splenic cords. MAbs 33.45.1 and 33.101.2, respectively, recognize heavy (72,000-88,000 MW) and light (20,000-27,000 MW) axolotl immunoglobulin chains. They do not react with thymocytes but label a splenic lymphocyte population not labelled by mAb 34.38.6. The proportion of surface immunoglobulin-positive (sIg+) lymphocytes in spleen is not altered by thymectomy. MAb 33.101.2 labels 40-48% of splenic lymphocytes, 33.45.1 stains only 14% of these same cells. This suggests some interesting heavy-chain isotypic differences in axolotl. For the first time in urodele amphibians, mAbs differentiate T-like and B-like lymphocyte populations by their membrane markers. This will allow further analysis of the axolotl immune system.

Ten midly hirsute women with normal serum levels of testosterone were treated with spironolactone (100 mg die), and the effectiveness of this dose-schedule regimen was evaluated after six months of therapy. Hirsutism subsided partly in all women. We estimated however, that in 6 of the 10 women, the clinical benefit was out weighed by the side effects and other drawbacks of a long term therapy and their medication was then stopped 6 months after its initiation. The changes induced on the pituitary function were evaluated by measuring basal serum T3 T4 and basal and stimulated (TRH-LHRH) TSH, PRL, FSH and LH, prior to and after one month of therapy. Spironolactone induced a greater response of TSH to TRH (p less than .025) but no change in T3 T4, PRL, FSH and LH. These data suggest that changes in TSH response are not explained by the speculated intrinsic oestrogenic activity of spironolactone but rather by a selective interaction with TSH secreting cells. We conclude that spironolactone therapy should not be recommended for the large category of normal women complaining of slight increase of facial hair.

Sixty-three consecutive unselected patients with a solitary cold nodule of the thyroid were submitted to surgery. Prior to surgery they all had clinical evaluation and a fine-needle aspiration (FNA) biopsy of the nodule. Results of this study show that the FNA biopsy was correct in predicting cancer in 12 of 13 cancers for a sensitivity of 92%. When the nodule was benign, the FNA biopsy was right in 42 of the 50 benign nodules for a specificity of 84%. In comparison the clinical criteria alone were correct in suspecting only eight of the 13 cancers for a sensitivity of 62%, while correctly identifying 39 of the 50 benign nodules for a specificity of 72%. An association of the clinical criteria with the results of the FNA biopsy would have identified all the cancers in our group.