305,352 research outputs found
Ruolo dell'11β-idrossisteroidodeidrogenasi tipo 1 nella sindrome dell'ovaio policistico
No full textIl gene HSD11B1 codifica per l’enzima 11b-idrossisteroido deidrogenasi tipo 1 (11b-HSD1) che
catalizza la conversione del metabolita inattivo cortisone in cortisolo, amplificando l’attivazione dei
recettori dei glucocorticoidi, particolarmente a livello del fegato e del tessuto adiposo. Molte
malattie sono state associate sia ad una aumentata che ad una ridotta attività dell’ 11b-HSD1. Un
esempio di aumentata attività dell’ 11b-HSD1 e quindi da eccesso di glucocorticoidi è la sindrome
di Cushing, che è associata ad obesità centrale, ipertensione arteriosa e intolleranza glucidica, che
nel loro insieme costituiscono la sindrome metabolica. Il ruolo centrale dell’ 11b-HSD1 nella
sindrome metabolica è enfatizzato dagli studi sui topi transgenici, dove, una iper-espressione dell’
11b-HSD1 nel fegato o nel tessuto adiposo determina la comparsa della sindrome metabolica,
mentre, al contrario, l’inibizione o la distruzione dell’ 11b-HSD1 ne migliora tutte le caratteristiche.
In studi sull’uomo l’obesità è stata associata ad una aumentata espressione dell’ 11b-HSD1 nel
tessuto adiposo. Al contrario, alcuni dei pochi studi eseguiti nelle donne con sindrome dell’ ovaio
policistico (PCOS) hanno messo in evidenza una ridotta attività dell’11b-HSD1 che è stata
associata, attraverso la aumentata clearance metabolica del cortisolo, ad una iperattivazione
compensatoria dell’ asse ipotalamo-ipofisi-surrene, e quindi ad un iperandrogenismo surrenalico.
Questi studi hanno però come limite il fatto di aver valutato l’ attività dell’ 11b-HSD1 attraverso il
dosaggio dei metaboliti urinari del cortisolo e del cortisone. I limiti di questa analisi, che rendono
conto della inconsistenza dei risultati di questi studi, sono legati al fatto che il dosaggio dei
metaboliti urinari del cortisolo e del cortisone riflettono, più che l’ attività dell’ 11b-HSD1, il
bilancio delle attività opposte dell’ 11b-HSD1 e dell’ 11b-HSD tipo 2, e delle attività delle
reduttasi. Inoltre, questa tecnica non è in grado di discriminare tra le attività tessuto-specifiche dell’
11b-HSD1, recentemente osservate nell’obesità. Diversi fattori ormonali e nutrizionali sembrano
regolare l’ espressione dell’ 11b-HSD1. Inoltre, esistono comuni polimorfismi di singolo nucleotide
(SNP) del gene HSD11B1 che potrebbero contribuire geneticamente alle variazioni inter-individuali
nella generazione di cortisolo. In particolare, due SNPs, uno localizzato nella regione del promotore
(rs846910, A ® G, ‘SNP 1’) and l’altro nel terzo introne (rs12086634, G ® T, ‘SNP5’), sono stati
associati indipendentemente con l’insulino-resistenza, il diabete tipo 2, e l’ipertensione arteriosa,
ma non con l’obesità nella maggior parte delle popolazioni studiate. Viceversa, l’allele G dello
SNP5, cha causa una ridotta espressione di 11b-HSD1 in vitro, è stato associato
all’iperandrogenismo surrenalico nelle donne magre con PCOS. La PCOS è caratterizzata da una
elevata prevalenza della sindrome metabolica, ma il ruolo giocato dall’ HSD11B1 è al momento
sconosciuto. In aggiunta, sono al momento sconosciuti anche le conseguenze degli SNPs sulla
espressione e l’attività dell’ 11b-HSD1 in vitro (con l’eccezione dello SNP5) ed in vivo. In un
campione di tessuto adiposo sottocutaneo l’ allele A dello SNP5 è stato recentemente associato a
bassi livelli di mRNA di 11b-HSD1. Tuttavia, questo dato non è stato confermato in un altro studio
nel quale sono stati analizzati 61 Indiani Pima. Non è stata inoltre rilevata alcuna associazione tra il
genotipo dello SNP5 e il rapporto urinario dei metaboliti del cortisolo e del cortisone. L’obiettivo
del presente studio è stato pertanto quello di stabilire le conseguenze dei polimorfismi SNP1 e
SNP5 sulle caratteristiche della sindrome metabolica e della PCOS, e di definire la loro influenza
sulla attività totale corporea e tessuto-specifica (adipose ed epatica) dell’ 11b-HSD1. Abbiamo
pertanto genotipizzato una coorte di 600 donne di cui 300 con PCOS e 300 controlli, nelle quali è
stata eseguita una attenta valutazione delle variabili metaboliche ed endocrine. Successivamente,
sono state richiamate 40 donne, 20 PCOS e 20 controlli, di analogo genotipo e simili il più possibile
per età e peso corporeo, per effettuare, in uno studio caso-controllo, la valutazione dettagliata
dell’attività, in vivo, dell’ 11b-HSD1 genotipo correlata. L’ attività totale corporea dell’ 11b-HSD1
è stata valutata misurando la quantità di 9,12,12-2H3-cortisolo (d3-cortisolo) prodotta durante
l’infusione di 9,11,12,12-2H4-cortisolo. L’attività epatica di 11b-HSD1 è stata quantificata
attraverso la misurazione della generazione di cortisolo a seguito della somministrazione orale di
cortisone 25mg previa soppressione con desametazone, mentre l’attività dell’ 11b-HSD1 a livello
del tessuto adiposo sottocutaneo è stata quantificata, in vitro, attraverso la misurazione della
conversione di 1,2,6,7-3H-cortisolo a cortisone (attività deidrogenasica). Negli stessi omogenati
ottenuti dalle biopsie del tessuto adiposo è stato quantificato anche l’mRNA di 11b-HSD1.
Nell’intera coorte studiata abbiamo trovato una frequenza allelica di A per lo SNP1 del 4% e di G
per lo SNP5 del 15%, mentre nessun partecipate allo studio è risultato omozigote per l’allele A
dello SNP1. La frequenza dello SNP1 e SNP5 e degli aplotipi di entrambi gli SNPs GATT, GGTT,
GATG, e GGTG non differivano tra i casi di PCOS e i controlli. Inoltre, pochi soggetti
presentavano gli aplotipi GAGG (n= 1) e GGGG (n= 11) e questo ci ha portato ad escluderli dalle
analisi successive. Con interesse abbiamo riscontrato che, sebbene lo SNP considerato
singolarmente non avesse un impatto importante sul fenotipo della popolazione analizzata, tuttavia
era presente un effetto evidente dell’aplotipo, in particolare dell’aplotipo GATT. Infatti, i soggetti
eterozigoti per l’allele A dello SNP1 ed omozigoti per l’ allele T dello SNP5 (aplotipo GATT)
presentavano i valori più elevati di circonferenza vita, particolarmente nel gruppo di PCOS, livelli
più elevati di risposta insulinica alla curva da carico di glucosio, e maggiori valori circolanti delle
transaminasi e dei trigliceridi. L’associazione dei questo aplotipo del gene HSD11B1 con un quadro
metabolico peggiore veniva confermata dalla dimostrazione che la quantità di soggetti affetti da
sindrome metabolica in accordo ai criteri NCEP-ATPIII era significativamente maggiore entro
l’aplotipo GATT rispetto agli altri aplotipi (42.3% verso 18% nell’intera popolazione), senza
distinzione tra PCOS e controlli. Non erano invece evidenti importanti associazioni tra l’aplotipo
del gene HSD11B1 e il pattern ormonale. I soggetti con l’aplotipo GATT presentavano inoltre non
solo un aumentato rapporto urinario di (THF+-THF)/THE (studio sull’intera popolazione di 600
donne), suggerendo una aumentata conversione totale corporea del cortisone a cortisolo, ma anche,
durante il test di infusione del cortisolo tetradeuterato (studio sulla popolazione di 40 soggetti), una
aumentata produzione di cortisolo, riflesso della combinazione della secrezione surrenalica di
cortisolo e della rigenerazione di cortisolo ad opera della 11-HSD1, e di d3-cortisolo, espressione
esclusivamente del contributo dell’ 11-HSD1. La quantità di cortisolo e di d3-cortisolo prodotta
durante il test di infusione del cortisolo tetradeuterato non differiva tra PCOS e controlli. Tuttavia,
le donne con PCOS presentavano un maggiore livello di trascritto di 11b-HSD1 a livello del tessuto
adiposo sottocutaneo, particolarmente all’interno dell’ aplotipo GATT. L’attività epatica dell’ 11b-
HSD1, invece, non differiva tra gli aplotipi, ma era ridotta nelle PCOS. Inoltre, l’espressione intraadiposa
di 11b-HSD1 era significativamente correlata con i valori di insulina a digiuno e gli indici
di insulino-sensibilità. In conclusione, questo studio dimostra che l’ aplotipo GATT del gene
HSD11B1 è associato alla sindrome metabolica nella popolazione generale, verosimilmente
attraverso l’ aumentata attività totale corporea dell’ enzima 11-HSD1. Inoltre, lo stesso aplotipo
enfatizza la differenza tra PCOS e controlli in termini di espressione/attività dell’ 11-HSD1
tessuto-specifica, che risulta maggiore a livello intra-adiposo e minore a livello epatico. La
maggiore espressione dell’ 11-HSD1 intra-adiposa potrebbe essere uno dei meccanismi di
associazione tra PCOS e sindrome metabolica attraverso l’insulino-resistenza. Inoltre, nel presente
studio abbiamo valutato anche l’effetto di due polimorfismi del gene HSD11B1 a livello dell’
espressione di 11b-HSD1: lo SNP1 e lo SNP rs13306421, un raro polimorfismo identificato in una
popolazione giapponese situato in posizione -2 rispetto al sito di inizio della traduzione (SNP-2).
Non abbiamo trovato nessun effetto dello SNP1. Questo risultato ci ha portato ad ipotizzare che
questo SNP possa essere in linkare disequilibrium con un polimorfismo funzionale. Abbiamo
invece trovato che il polimorfismo SNP-2 è in grado di alterare l’efficienza dell’ inizio della
traduzione di 11-HSD1, ed in particolare abbiamo rilevato che l’allele A è associato ad una attività
enzimatica maggiore e ad una maggiore quantità di enzima sintetizzato in vitro. Tuttavia, la
frequenza allelica di G per lo SNP-2 è risultata del 100% nella nostra popolazione, sollevando il
dubbio se questo sia realmente un polimorfismo, oppure se possa essere più propriamente
considerato una mutazione. Infatti, sebbene l’allele A sia stato descritto originariamente in un 5%
della popolazione giapponese, in uno studio recente in cui sono stati genotipizzati per lo SNP-2 210
soggetti appartenenti a quattro diverse popolazioni (Nigeriana, Giapponese, Cinese e Caucasica)
nessuno è stato rivelato essere portatore dell’allele A. Pertanto, sono necessari ulteriori studi
finalizzati a dimostrare se l’ allele A sia di fatto un polimorfismo.HSD11B1 encodes the enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) which
catalyses regeneration of cortisol from its inactive metabolite cortisone, thereby amplifying
glucocorticoid receptor activation, e.g. in liver and adipose tissue. Both increased and decreased
11b-HSD1 activity has been associated with common disease. Glucocorticoid excess, e.g. in
Cushing’s syndrome, is associated with features of the Metabolic Syndrome, including central
obesity, hypertension and glucose intolerance. Transgenic overexpression of 11b-HSD1 in liver or
adipose tissue in mice induces elevated local glucocorticoid concentrations and features of
Metabolic Syndrome, while inhibition or disruption of 11b-HSD1 ameliorates features of the
Metabolic Syndrome. In human obesity, 11b-HSD1 expression is increased in adipose tissue. In
contrast, decreased 11b-HSD1 results in impaired regeneration of cortisol and hence increased
metabolic clearance rate for cortisol; the resulting compensatory activation of the hypothalamicpituitary-
adrenal axis may be responsible for adrenal androgen excess in some patients with
polycystic ovary syndrome (PCOS). The few studies performed until now to estimate 11b-HSD1
activity in vivo in PCOS rely on the ratio of metabolites of cortisol and cortisone in urine. There are
many flaws to this, which can explain the lack of consistency between the studies. This assay, in
fact, reflects not just 11b-HSD1 activity, but the balance between opposing activities of 11b-HSD1
and 11b-HSD type 2, and changes in A ring reductases. In addition, urinary ratios are not able to
determine tissue-specific changes in 11b-HSD1, as has been recently observed in human obesity. A
variety of hormonal and nutritional factors regulate 11b-HSD1 expression. In addition, common
non-coding single nucleotide polymorphisms (SNP) in HSD11B1 exist, allowing investigation of
the genetic contribution to inter-individual variation in cortisol regeneration. SNPs in the 5’
flanking region (rs846910, A to G, ‘SNP 1’) and in an enhancer region in intron 3 (rs12086634, G
to T, ‘SNP5’) have been associated independently with insulin resistance, type 2 diabetes and/or
hypertension, but not with obesity in several, but not all, populations. Conversely, the G allele of
SNP5, which causes lower 11b-HSD1 expression in vitro, is associated with hyperandrogenism
amongst lean women with PCOS, although it is not more common amongst PCOS cases as a whole.
PCOS is characterized by a high prevalence of all features of the Metabolic Syndrome, but the role
played by HSD11B1, although attractive, is unknown. In addition, the consequences of the nonexonic
polymorphisms for 11b-HSD1 expression and function in vitro (with the exception of SNP5)
or in vivo have not been determined. In subcutaneous adipose tissue biopsies, SNP5 G allele was
associated with low 11b-HSD1 mRNA in one patient, but neither SNP1 nor SNP5 genotype
predicted 11b-HSD1 mRNA in adipocytes in 61 subjects from a native N American cohort. Urinary
ratios of cortisol:cortisone metabolites are not associated with SNP5 genotype. In the present study
we aimed to establish the consequences of SNP1 and SNP5 polymorphisms on features of
Metabolic Syndrome and of PCOS, and further to define their influence on whole-body and liver or
adipose tissue 11b-HSD1 activities. We genotyped a cohort of 600 women in whom metabolic and
endocrine variables were carefully assessed, half of whom have PCOS, and selected 40 participants
for a nested study in which we undertook detailed measurements of 11b-HSD1 activity in vivo.
Whole-body 11b-HSD1 activity was assessed by measuring rate of appearance of 9,12,12-2H3-
cortisol (d3-cortisol) during 9,11,12,12-2H4-cortisol infusion. Hepatic 11b-HSD1 activity was
quantified by measuring the generation of plasma cortisol following an oral dose of cortisone 25mg
after overnight dexamethasone suppression, whereas subcutaneous adipose 11b-HSD1 activity was
assessed, in vitro, by measuring the conversion of 1,2,6,7-3H-cortisol to cortisone. In the same
homogenates, obtained by sc abdominal fat biopsy, 11b-HSD1 mRNA was quantified. In the whole
cohort, allele frequencies were 4% for SNP1 A and 15% for SNP5 G. No participants were
homozygous for SNP1 A. There were no differences in the frequency of either SNP, or of
haplotypes of both SNPs, between PCOS cases and controls. Very few participants had haplotypes
GAGG (n=1) or GGGG (n=11) so they were not included in further analyses. Strikingly, neither
SNP had independent effects on phenotype. However, there were differences between individuals of
different haplotype. Individuals heterozygous for SNP1 A and homozygous for SNP5 T (GATT)
had the highest waist circumference and, particularly amongst the PCOS group, higher plasma
transaminase and triglyceride levels, and higher insulin response to the oral glucose tolerance test,
as AUC. The proportion meeting the NCEP-ATPIII criteria for Metabolic Syndrome was also
substantially higher in women with GATT haplotype (42.3% versus 18% in the whole cohort). The
association between GATT haplotype and the Metabolic Syndrome was also observed by analysing
PCOS women and controls separately. There were weaker associations between HSD11B1
genotype and hormonal features. Cortisol metabolites were measured in urine of the entire cohort of
600 women to assess relationships between HSD11B1 haplotypes and in vivo 11b-HSD1 activity.
As previously reporter, individual SNPs did not predict urinary (5a-THF + 5b-THF)/5b-THE ratio.
However, the GATT haplotype was associated with a higher ratio amongst women with PCOS,
suggesting higher conversion of cortisone to cortisol. In the nested study, the group with the GATT
haplotype had higher whole body rates of appearance of cortisol, reflecting the combination of
adrenal cortisol secretion and net regeneration of cortisol by 11b-HSD1, and d3-cortisol, reflecting
exclusively the contribution of 11b-HSD1. Rate of appearance of cortisol and d3-cortisol did not
differ between PCOS and controls. Women with the GATT haplotype had higher transcript levels
of 11b-HSD1 in subcutaneous adipose tissue only if they also had PCOS. Liver 11b-HSD1,
measured as appearance of cortisol on first pass conversion after an oral dose of cortisone, was not
significantly different between haplotypes, but was significantly lower in PCOS with respect to
controls. Subcutaneous adipose tissue 11b-HSD1 trascript levels were positively and significantly
correlated with insulin-resistance state and insulin levels. In conclusion, these data demonstrate that
the GATT haplotype of HSD11B1 is associated with the Metabolic Syndrome and with increased
whole body activity of 11b-HSD1, which appears to be independent of PCOS status. In addition,
the whole-body activity is not altered in PCOS, suggesting that any differences which occur in 11b-
HSD1 in one tissue are cancelled out by differences in other tissues. The role of tissue-specific
dysregulation of 11b-HSD1 in PCOS must be clarified. However, we can speculate that upregulation
of adipose 11b-HSD1 can be a key contributor to metabolic dysfunction in women with
PCOS. In addition, in the present study we investigated the effect of two polymorphisms upon
expression of 11b-HSD1; SNP1 and rs13306421, a rare polymorphism identified in a Japanese
population, situated at -2 with respect to the translation start site (SNP-2). We did not find any
effect of SNP1, thus suggesting that this SNP can be in linkage disequilibrium with another,
functional, polymorphism. At variance, we found that SNP-2 modulates translation of the enzyme,
with the A allele resulting in greater enzyme activity and a higher proportion of full-length enzyme
synthesised in vitro. However, whether the SNP-2 is truly a polymorphism or may more properly be
called a mutation is an open question. In fact, we did not find the A allele in our population of 300
PCOS patients, nor in the case controls. Furthemore, although the A allele was reported at 5% in the
original Japanese population, in a further study, genotyping of a total of 210 individuals in four
different populations detected only the G allele, as we did. Thus, further studies are required to
confirm whether the A allele is indeed a polymorphism. Nevertheless, our studies show the clear
potential to influence levels of active 11b-HSD1
MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects.
No full textPCOS is a clinical heterogeneous entity of female androgen excess diagnosed by exclusion of other disorders responsible for androgen excess. The concept of secondary PCOS implies that there is a primary well-defined cause leading to the PCOS phenotype with underlying androgen overproduction, regardless of the origin. In these cases, we presume the term of 'secondary PCOS' could be used. In all these conditions, the potential complete recovery of the hyperandrogenemic state as well as the remission of the PCOS phenotype should follow the removal of the cause. If accepted, these concepts could help clinicians to perform in-depth investigations of the potential factors or disorders responsible for the development of these specific forms of secondary PCOS. Additionally, this could contribute to develop further research on factors and mechanisms involved in the development of the classic and the nonclassic PCOS phenotypes
Atypical Presentations of IPEX: Expect the Unexpected
No full textImmune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life
IL-2 Signaling Axis Defects: How Many Faces?
No full textCD25, Signal transducer and activator of transcription 5B (STAT5B) and Forkhead box P3 (FOXP3) are critical mediators of Interleukin-2 (IL-2) signaling pathway in regulatory T cells (Tregs). CD25 (i.e., IL-2 Receptor α) binds with high affinity to IL-2, activating STAT5B-mediated signaling that eventually results in transcription of FOXP3, a master regulator of Treg function. Consequently, loss-of-function mutations in these proteins give rise to Treg disorders (i.e., Tregopathies) that clinically result in multiorgan autoimmunity. Immunodysregulation, Polyendocrinopathy Enteropathy X-linked (IPEX), due to mutations in FOXP3, has historically been the prototype of Tregopathies. This review describes current knowledge about defects in CD25, STAT5B, and FOXP3, highlighting that these disorders both share a common biological background and display comparable clinical features. However, specific phenotypes are associated with each of these syndromes, while certain laboratory findings could be helpful tools for clinicians, in order to achieve a prompt genetic diagnosis. Current treatment strategies will be outlined, keeping an eye on gene editing, an interesting therapeutic perspective that could definitely change the natural history of these disorders
Role of regulatory T cells and FOXP3 in human diseases
No full textImmune regulation and tolerance are specific functions ofthe immune system, meaning at prevention or limitation ofeffector immune responses against inner and external insults.Regulatory T (Treg) cells are crucial players in this immunebalance network. Research over the last 10 years hassignificantly contributed to characterizing Treg cell features,their mechanisms of function, and their role in humanpathologies. The discovery of FOXP3 as an essentialtranscription factor not only for differentiation and functionof naturally occurring Treg cells but also for regulationof intracellular molecules related to effector T-cellresponses has provided new insights into the pathogenesisof immune-mediated diseases. Interestingly, there is increasingevidence that the individual signature of genes relevantfor immune regulation definitely influences the final outcomeof an immune response
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Author, publisher and bookseller : a tripartite synergy in Nigerian book industry
No full textThis work is about the roles of Author, Publisher and Bookseller in Book development in
Nigeria. The paper started by delving into the history of Book Publishing in Nigeria after
which it proceeded by defining who an author, a publisher, and a bookseller is and
expatiated on the indispensable roles of these key actors in Nigerian Book Industry and in
the emerging Information Society. Furthermore, the various constraints to book
development were identified while the paper advised on how the Book Industry can be
further promoted in Nigeria. However, the paper concluded and made recommendations
on how the Book sector can help in enhancing scholarship in the country
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