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Biomedical subjects

A Sulli

Publications and source records attributed to A Sulli.

At least 19 recordsLinked to original sources
PubMed2006

Serum cytokines and steroidal hormones in polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

BACKGROUND: Polymyalgia rheumatica (PMR) may create some difficulties in the differential diagnosis of elderly-onset rheumatoid arthritis (EORA) and of EORA with PMR-like onset (EORA/PMR). AIM: To investigate possible differences between three groups of patients, with regard to serum levels of inflammatory cytokines and steroidal hormones at baseline and after 1 month of treatment with glucocorticoids (prednisone 7.5-12.5 mg/day). PATIENTS AND METHODS: 14 patients with PMR, 15 with EORA and 14 with EORA/PMR, as well as 15 healthy, matched controls were analysed. Tumour necrosis factor alpha (TNFalpha), interleukin (IL)6, IL1 receptor antagonist (IL1Ra), cortisol, dehydroepiandrosterone sulphate (DHEAS) and 17-hydroxy-progesterone (PRG) were evaluated. RESULTS: Serum levels of both TNFalpha and IL6 were significantly higher in all three groups of patients than in controls (p<0.01). Serum IL6 levels were significantly higher in patients with both PMR and EORA/PMR than in patients with EORA (p<0.05). IL1Ra serum levels were significantly higher in patients with EORA than in controls (p<0.001) and in patients with PMR and EORA/PMR (p<0.05). DHEAS was significantly lower in patients with EORA/PMR than in those with EORA (p<0.05). PRG was significantly higher in all patient groups (p<0.05). After glucocorticoid treatment, serum TNFalpha and IL6 levels significantly decreased in all patient groups; IL1Ra significantly increased in patients with PMR and in those with EORA/PMR; cortisol, DHEAS, and PRG significantly decreased in patients with PMR and in those with EORA/PMR (p<0.05). CONCLUSIONS: Different cytokine and steroidal hormone patterns suggest that patients with PMR and those with EORA/PMR seem to be have a more intensive inflammatory reaction and are more efficient responders to glucocorticoid treatment than patients with EORA.

17-alpha-Hydroxyprogesterone↗
PubMed2006

[Capillaroscopy and rheumatic diseases: state of the art].

Nailfold capillaroscopy (NVC) represents the best method for analyzing microvascular abnormalities in rheumatic diseases. Raynaud's phenomenon (RP) represents the most frequent clinical aspect of microvascular involvement and is a key feature of several such diseases. Under normal conditions or in primary RP (exclusion by the cold-exposure test), the normal nailfold capillaroscopic pattern shows a regular disposition of the capillary loops within the nail bed. However, in subjects suffering from secondary RP, one or more alterations in the capillaroscopic findings should alert the physician to search for an underlying connective tissue disease. Architectural disorganization, giant capillaries, hemorrhages, loss of capillaries and avascular areas characterize more than 95% of patients with overt systemic sclerosis (scleroderma, SSc). Therefore, the term "scleroderma pattern", includes all capillaroscopic changes typical of the microvascular involvement in SSc. The capillaroscopic aspects observed in dermatomyositis and in undifferentiated connective tissue disease are generally reported as "scleroderma-like patterns". This peripheral microangiopathy can be effectively detected early in the course of the disease and studied in detail by nailfold capillaroscopy or, better, with NVC. In addition, early differential diagnosis between primary and secondary RP is the greatest advantage NVC has to offer. In addition, interesting capillaroscopic changes have been observed in systemic lupus erythematosus, antiphospholipid syndrome and Sjögren's syndrome. However, further epidemiological and clinical studies are needed to better standardize NVC patterns.

Antiphospholipid Syndrome↗
PubMed2006

Nailfold capillaroscopy is useful for the diagnosis and follow-up of autoimmune rheumatic diseases. A future tool for the analysis of microvascular heart involvement?

Raynaud's phenomenon (RP) represents the most frequent clinical aspect of cardio/microvascular involvement and is a key feature of several autoimmune rheumatic diseases. Moreover, RP is associated in a statistically significant manner with many coronary diseases. In normal conditions or in primary RP (excluding during the cold-exposure test), the normal nailfold capillaroscopic pattern shows a regular disposition of the capillary loops along with the nailbed. On the contrary, in subjects suffering from secondary RP, one or more alterations of the capillaroscopic findings should alert the physician of the possibility of a connective tissue disease not yet detected. Nailfold capillaroscopy (NV) represents the best method to analyse microvascular abnormalities in autoimmune rheumatic diseases. Architectural disorganization, giant capillaries, haemorrhages, loss of capillaries, angiogenesis and avascular areas characterize >95% of patients with overt scleroderma (SSc). The term 'SSc pattern' includes, all together, these sequential capillaroscopic changes typical to the microvascular involvement in SSc. The capillaroscopic aspects observed in dermatomyositis and in the undifferentiated connective tissue disease are generally reported as 'SSc-like pattern'. Effectively, and early in the disease, the peripheral microangiopathy may be well recognized and studied by nailfold capillaroscopy, or better with nailfold video capillaroscopy (NVC). The early differential diagnosis between primary and secondary RP is the best advantage NVC may offer. In addition, interesting capillaroscopic changes have been observed in systemic lupus erythematosus, anti-phospholipid syndrome and Sjogren's syndrome. Further epidemiological and clinical studies are needed to better standardize the NCV patterns. In future, the evaluation of nailfold capillaroscopy in autoimmune rheumatic diseases might represent a tool for the prediction of microvascular heart involvement by considering the systemic microvascular derangement at the capillary nailfold.

Autoimmune Diseases↗
PubMed2005

Anti-inflammatory effects of leflunomide in combination with methotrexate on co-culture of T lymphocytes and synovial macrophages from rheumatoid arthritis patients.

OBJECTIVES: To investigate the anti-inflammatory effects of the active leflunomide metabolite A771726 (Lef-M) in combination with methotrexate (MTX) on synovial macrophages (SM) from rheumatoid arthritis (RA) patients co-cultured with an activated T cell line (Jurkat cell line). METHODS: Pro-inflammatory cytokines (TNFalpha, IL1beta, IL6), adhesion molecule ICAM-1, cyclooxygenase isoenzymes (COX1, COX2), and the nuclear factor kappaB (NF-kappaB) complex were analysed on SM co-cultured with a T cell line, as intracellular protein expression by immunocytochemistry (ICC) and western blot analysis, as extracellular protein expression by ELISA assay, and as mRNA expression by reverse transcriptase-multiplex PCR (RT-MPCR) after treatment with Lef-M (1, 10, 30 micromol/l) alone or in combination with MTX (50 ng/ml). RESULTS: The most significant intracellular decrease in cytokines was observed by ICC in SM treated with the combination of Lef-M (1, 10, 30 micromol/l) and MTX (50 ng/ml) versus untreated SM (TNFalpha 29%, 37%, 49%, IL1beta 56%, 43%, 50%, and IL6 59%, 62%, 71%, respectively). Furthermore, a significant decrease was confirmed concerning cytokine levels evaluated by ELISA in the medium of SM treated with the combination Lef-M+MTX (TNFalpha 40%, 41%, 44%; IL1beta 10%, 20%, 60%; IL6 37%, 41%, 49%, respectively). Western blot and RT-PCR analysis confirmed these results. Concordant decreased expression was observed for ICAM-1, COX1, COX2, and the NF-kappaB complex after Lef-M+MTX treatment. CONCLUSIONS: The combination of MTX and Lef-M shows additive inhibitory effects on the production of inflammatory mediators from SM co-cultured with a T cell line. These observations might support the positive results obtained in RA clinical studies by combination therapy.

Analysis of Variance↗
PubMed2005

Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease's symptoms.

The circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids (reduction) observed in rheumatoid arthritis (RA) patients are responsible, in part, for the time-dependent changes that are observed in the inflammatory response and related early morning clinical symptoms of the disease. Melatonin (MLT), another circadian nocturnal hormone that is the secretory product of the pineal gland, has been implicated in the time-dependent RA inflammatory reaction with effects that are opposite to those of corticosteroids. As a consequence, altered functioning of the HPA axis (early morning reduced corticosteroid production) and of the pineal gland (night increased MLT production) found in RA patients, seem to be important factors in the appearance and perpetuation of the clinical circadian symptoms of the disease. Consistently, human proinflammatory Th1-type cytokine production (related to MLT stimulation) exhibits a diurnal rhythmicity with peak levels during the night and early morning, at a time when plasma cortisol (inducing the Th2-type cytokine production) is lowest and MLT is highest. Reduced daily light exposure as observed in northern Europe (Estonia), at least during the winter, might explain the higher and more prolonged serum MLT concentrations that were observed in northern RA patients, as well as some epidemiological features versus southern Europe patients.

Arthritis, Rheumatoid↗
PubMed2005

White matter hyperintensities on brain magnetic resonance in systemic sclerosis.

OBJECTIVE: To evaluate the brain status of patients with systemic sclerosis (SSc). METHODS: Fourteen female patients with SSc aged 24-74, with a disease duration of 1-12 years and without other relevant systemic diseases, were enrolled. All patients and an age matched female control group (CG) of 14 clinically normal subjects, underwent brain magnetic resonance examination at 1.5 T; spin echo proton density weighted images were evaluated. Mann-Whitney U and Spearman rank correlation tests were used for statistical analysis. RESULTS: 170 white matter hyperintensities >/=2 mm in diameter were counted in the patient group (range 0-75, mean 12.1, median 4.5), only 13 in the CG (0-2, 0.9, 1, respectively), with a significant difference (p = 0.011). Moreover, 208 white matter hyperintensities <2 mm were found in the patient group (0-38, 14.9, 8, respectively), only 31 in the CG (0-7, 2.0, 1, respectively), with a significant difference (p = 0.006). No statistically significant correlation between the number of hyperintensities and either patient's age or disease duration was observed. CONCLUSION: White matter hyperintensities are more common in patients with SSc than in a CG. These findings might be related to obliterative microvascular processes due to the disease. Early brain involvement in patients with SSc may occur.

Adult↗
PubMed2005

Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison.

BACKGROUND: Altered functioning of the hypothalamic-pituitary-adrenal axis and altered melatonin production might modulate the circadian symptoms in patients with rheumatoid arthritis. OBJECTIVE: To investigate the influence of different winter photoperiods on the circadian rhythms of serum melatonin, cortisol, tumour necrosis factor alpha (TNFalpha), and interleukin 6 (IL6) in patients with rheumatoid arthritis from a north Europe country (Estonia) and a south Europe country (Italy). METHODS: The patients from Estonia (n = 19) and Italy (n = 7) had similar disease severity and duration and were compared with healthy age and sex matched controls in the two countries. Blood samples were collected during the period January to February at 8 pm, 10 pm, midnight, 2 am, 4 am, 6 am, 8 am, and 3 pm. Melatonin was measured by radioimmunoassay using (125)I-melatonin. Serum cortisol, TNFalpha, and IL6 cytokines were assayed by standard methods. RESULTS: Higher circadian melatonin concentrations from 10 pm and an earlier peak were observed in Estonian patients than in their age and sex matched controls (p<0.01). Starting from midnight, melatonin concentrations were significantly higher in the Estonian patients than in the Italian patients. No significant differences were observed for serum cortisol. Serum TNFalpha was higher (p<0.05) in Estonian patients than in their controls and was correlated with the melatonin levels. CONCLUSIONS: In a north European country (Estonia), the circadian rhythm of serum concentrations of melatonin and TNFalpha in patients with rheumatoid arthritis were significantly higher than in matched controls or in rheumatoid patients from a south Europe country (Italy).

Adult↗
PubMed2005

Estrogens, autoimmunity and the heart.

Systemic inflammatory/autoimmune rheumatic diseases are associated with a significantly increased rate of atherosclerosis and cardiovascular disease. Several mechanisms of accelerated atherosclerosis have been proposed, including abnormal lipid and lipoprotein profiles, oxidative stress, enhanced apoptosis, thrombophilia, immune complexes and increased mononuclear cell infiltration of atherosclerotic lesions, local generation of cytokines and female estrogen deficiency. However, the widely shared enthusiasm about the cardioprotective potential of hormone replacement therapy (HRT) with estrogens, has come to an abrupt halt since very recent randomized trials failed to show a cardiovascular risk reduction in postmenopausal women. Several factors might play a role in these discrepancies, in particular, parts of the striking discrepancy between observational and randomized data have been attributed to an estrogen-mediated adverse effect on inflammation (enhancement, possibly dose-related). In fact, estrogens potentially increase the inflammatory/immune response in autoimmune rheumatic diseases. New roles for estrogen peripheral metabolites (hydroxylated) and their increased formation in inflammatory sites, might partially introduce some explanations for several apparently contrasting evidences.

Animals↗
PubMed2004

Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic sclerosis.

BACKGROUND: Microvascular lesions are a predominant feature in systemic sclerosis (SSc) and seem to play a central pathogenetic role. Recently, we graded scleroderma microangiopathy by nailfold videocapillaroscopy (NVC) into three NVC patterns (early, active and late). The aim of the present study was to confirm, in a larger number of SSc patients, the presence of three patterns of microvascular damage, and to detect any possible relationship between these patterns and both specific serum autoantibodies and the subsets of cutaneous involvement. METHODS: Two hundred and forty-one consecutive patients (227 women and 14 men) affected by SSc were recruited. One hundred and forty-eight patients were affected by limited cutaneous SSc (lSSc) and 93 patients by diffuse cutaneous SSc (dSSc). The ages at onset of Raynaud's phenomenon (RP) and SSc, the durations of RP and SSc, ANA and antitopoisomerase I (anti-Scl70) and anticentromere (ACA) antibodies were investigated in all patients. The SSc patients were subdivided on the basis of the NVC pattern into three groups. RESULTS: A statistically significant correlation was found between the NVC patterns and the durations of both RP and SSc (P<0.001). Enlarged and giant capillaries, together with haemorrhages, constituted the earliest NVC finding in SSc (early NVC pattern). These abnormalities were mostly expressed in the active NVC pattern. Loss of capillaries, ramified capillaries and vascular architectural disorganization were increased in the late NVC pattern. Age and the duration of both RP and SSc were lower in 24 patients complaining of RP alone. Anti-Scl70 antibodies were statistically less frequent in the early vs both the active and the late NVC pattern, whereas no significant correlation was found between the presence of anti-Scl70 antibodies and the duration of either RP or SSc. ACA positivity was more frequent in patients with longer RP duration. Patients with lSSc had shorter SSc duration and showed the early or active NVC pattern more frequently. Conversely, patients with dSSc showed longer disease duration and mostly showed the late NVC pattern. CONCLUSIONS: NVC is an appropriate tool for differential diagnosis between primary and secondary RP through the clear recognition of the early NVC scleroderma pattern. This study confirms, in a large number of SSc patients, the existence of three distinct NVC patterns that might reflect the evolution of SSc microangiopathy. The presence of anti-Scl70 antibodies seems be related to earlier expression of the active and late NVC patterns of SSc microvascular damage. The presence of ACA seems to be related to delayed expression of the late NVC pattern.

Adult↗
PubMed2004

Blunted coronary flow reserve in systemic sclerosis.

OBJECTIVES: We investigated whether the non-invasive determination of coronary flow reserve (CFR), as evaluated by transthoracic Doppler echocardiography, might be a potential method to detect early dysfunction of cardiovascular system in patients affected by systemic sclerosis (SSc) without clinical signs or symptoms of cardiac impairment. The possible correlations between the CFR values and the duration of the disease, specific autoantibodies and cutaneous involvement subsets were investigated. METHODS: Forty-four consecutive patients affected by SSc were analysed. The CFR was detected in the distal left anterior descending coronary artery by contrast-enhanced transthoracic second harmonic Doppler in all SSc patients and in 16 healthy controls. CFR was assessed at rest and during hyperaemia induced by administration of adenosine at 0.14 mg/kg/min over 5 min. The CFR was calculated as the ratio between hyperaemic (peak adenosine infusion) and resting peak diastolic velocity (PdvCFR) and resting velocity time integral (VtiCFR). Past medical history was carefully investigated. RESULTS: Both PdvCFR and VtiCFR were significantly reduced in SSc patients when compared with controls (P<0.0001). In particular, both PdvCFR and VtiCFR were significantly lower in patients with dSSc when compared with patients affected by lSSc (P<0.02 and P<0.04 respectively). No statistically significant correlation was found between CFR values and history of smoking, serum levels of cholesterol or triglycerides, blood pressure, age of patients, duration of SSc and serum autoantibody positivity for ANA, ACA and Scl70. CONCLUSIONS: CFR is often reduced in SSc patients. CFR was lower in patients with dSSc than in those affected by lSSc. A reduced CFR value should be considered an indirect sign of heart involvement in scleroderma, but its clinical and prognostic implications need to be clarified.

Adult↗
PubMed2004

Nailfold video-capillaroscopy in systemic sclerosis.

The Raynaud's phenomenon (RP) is the most common and significant clinical condition supporting microvascular analysis as soon as possible. Microvascular involvement is a key feature of RP, and several rheumatic diseases are characterized by the presence of the RP. Nailfold capillary microscopy shows an impressive cost/effectiveness ratio: it is simple, noninvasive and inexpensive.Well-recognized videocapillaroscopic patterns (NVC) have been described mainly in scleroderma (SSc) patients complaining of a secondary RP. The peripheral microvascular damage in SSc is characterized by increasing structural alterations of the capillaries (giant capillaries and microhemorrhages) with progressive decrease of their density. The detection of the scleroderma NCV allows early differentiation between primary RP (functional, not disease associated), and secondary RP (disease associated). Other major NVC patterns have been described in the field of rheumatic diseases. Interestingly, correlations are evident between the NCV and the clinical symptoms, severity of the disease and the laboratory findings. Further clinical and epidemiological studies, as well as a standardized and computerized quantitation of the observed damages are required.

Capillaries↗
PubMed2004

Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity.

Sex hormones seem to play an important role as modulators of the autoimmune disease onset/perpetuation. Generally, steroid hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immunosuppressors. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female rheumatoid arthritis (RA) patients, as compared to controls, which is most probably due to increase of local enzymatic aromatase activity. Serum levels of estrogens have been found altered in RA patients, particularly estradiol in man. Thus, available steroid prehormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e., TNFalpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular, 16alpha-hydroxyestrone, showing a mitogenic tumor growth stimulating role. Altered serum hydroxylated estrogens have been found also in serum of systemic lupus erythematosus (SLE) patients. As a matter of fact, our recent studies indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase of markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on immune/inflammatory response is exerted by activating the NFkB complex pathway. In conclusion, locally increased estrogens (i.e., synovial tissue in RA or skin in SLE) might exert activating effects on cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in autoimmunity.

Androgens↗
PubMed2003

Hypothalamic-pituitary-adrenocortical and gonadal functions in rheumatoid arthritis.

Rheumatoid arthritis (RA) as well as most autoimmune disorders results from a combination of several predisposing factors including the relations between epitopes of the trigger agent (i.e., virus, self-antigens) and histocompatibility epitopes (i.e., HLA), the status of the stress response system including the hypothalamic-pituitary-adrenocortical axis (HPA) and the sympathetic nervous system (SNS), as well as the gonadal hormones (hypothalamic-pituitary-gonadal axis, HPG), with estrogens implicated as enhancers of the immune response and androgens and progesterone as natural suppressors. The regular observation of reduced cortisol and adrenal androgen secretion during testing in RA patients not treated with glucocorticoids should clearly be regarded as "relative adrenal insufficiency" in the setting of a sustained inflammatory process, as shown by high interleukin (IL)-6 levels. In polymyalgia rheumatica, several pathogenetic and clinical aspects of the disease might well overlap RA, at least with elderly onset RA (EORA). Therefore, reduced production of adrenal hormones (i.e., cortisol, DHEAS) at baseline in active and untreated patients with polymyalgia rheumatica was detected. The defect was mainly related to altered adrenal responsiveness to ACTH stimulation (i.e., increased 17-OHP), at least in untreated patients with polymyalgia rheumatica. Finally, normal serum estrogen and low androgen levels, but high synovial fluid estrogen and much lower androgen levels, have been found in RA patients, supporting the fundamental role of the peripheral sex hormone metabolism in the manifestations of the disease.

Animals↗
PubMed2003

Anti-inflammatory effects of leflunomide on cultured synovial macrophages from patients with rheumatoid arthritis.

BACKGROUND: Leflunomide and its active metabolite A77 1726 reversibly inhibits the enzyme dihydro-orotate dehydrogenase, the rate limiting step in de novo synthesis of pyrimidines and progression of the cell cycle in different cell lines, mainly activated T lymphocytes. OBJECTIVE: To analyse in vitro the possible anti-inflammatory effects exerted by A77 1726, on cultured macrophages, obtained from the synovial tissues of patients with rheumatoid arthritis (RA). METHODS: The effects of different doses of A77 1726 on intracytoplasmic expression and extracellular concentration of inflammatory cytokines (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6), as well as the influence on production and expression of intercellular adhesion molecule-1 (ICAM-1) and cyclo-oxygenase 2 (COX-2) by primary cultures of synovial macrophages from patients with RA, were evaluated by immunocytochemistry and western blot analysis. The observations were made at four and 24 hours. RESULTS: A progressive and significant time and dose dependent decrease of the number of positive macrophages for intracellular TNFalpha and IL1beta, treated with different doses of A77 1726, was found in comparison with untreated cells. The extracellular concentration of TNFalpha was found to be significantly decreased in media containing cultured macrophages at 24 hours for all tested doses of A77 1726. At 24 hours, a significant time and dose dependent decrease of ICAM-1 and COX-2 expression by cultured macrophages after A77 1726 treatment was found. CONCLUSIONS: In conclusion, the mechanism of antiproliferative activity exerted by leflunomide on activated T lymphocytes seems to be the same mechanism (alteration of the cell cycle progression) which interferes with the functions of other activated cells-namely, the monocytes/macrophages, which are strongly involved in the inflammatory reaction in RA synovial tissue. The positive clinical results seem to confirm that leflunomide exerts an anti-inflammatory action on phagocytic cells in short and long term treatment of RA.

Aniline Compounds↗
PubMed2003

[Rheumatoid arthritis and atherosclerosis].

Evidence continue to accumulate indicating that patients with rheumatoid arthritis (RA) present an increased risk of cardiovascular disease (and death). The risk factors for coronary artery disease (CAD) in RA are not fully understood. However, a number of possible factors have been described, but more than one may be efficient, such as homocysteine, presence of antiphospholipid antibodies, altered serum levels of selected lipoproteins, and all together may have implications for the atherogenesis observed in these patients. Other factors that may facilitate this process, include corticosteroid use, methotrexate therapy and hormonal factors. However, the relative importance of these specific risk factors for the atherogenesis in this disease is poorly known. Recent findings indicate that cardiac death is increased in RA patients when compared with subjects without arthritis and that generally, the inflammatory process may contribute to atherosclerosis. In addition, other studies indicate that serum concentration of pro-inflammatory cytokines are found elevated at baseline, among patients at risk for future coronary occlusion.

Antiphospholipid Syndrome↗
PubMed2002

Cortisol, dehydroepiandrosterone sulfate, and androstenedione levels in patients with polymyalgia rheumatica during twelve months of glucocorticoid therapy.

This paper aims to evaluate adrenal gland hormone levels in patients with polymyalgia rheumatica (PMR) during glucocorticoid (GC) therapy. A lower than expected basal production of cortisol was found in active and glucocorticoid-untreated PMR patients, particularly females. The abrupt onset of PMR with clinical features similar to those of the steroid-withdrawal syndrome or adrenal insufficiency, as well as the clinical response to GC therapy in elderly people already age-disposed to an inadequate adrenal and anti-inflammatory response, might represent the most significant pathophysiological basis of the disease.

Adrenal Cortex↗