Cushing's disease with cure by resection of a pituitary adenoma. Evidence against a primary hypothalamic defect

A patient with Cushing's disease was treated by transphenoidal resection of a pituitary adenoma. Pituitary-adrenal suppressibility, responsiveness to metyrapone and circadian rhythm were observed postoperatively. Reversion to physiologic regulation after resection of an adenoma implies that the lesion secreted ACTH autonomously (primary hyperpituitarism). Current evidence favors the pituitary adenoma, when present, as the primary etiologic factor in pituitary-dependent Cushing's syndrome. Since adenomas occur in a majority of cases, initial therapy is best directed at the pituitary.     

Serum antibodies to mycobacterial antigens in active Crohn's disease

Infection with a species of Mycobacterium has been implicated in the pathogenesis of Crohn's disease. Therefore, we attempted to determine whether a specific serum antibody response to mycobacteria occurs in patients with the disease. We tested sera of patients with active Crohn's disease and several control groups in an enzyme-linked immunosorbent assay for reactivity with two mycobacterial antigens: (a) lipoarabinomannan, a highly immunogenic somatic lipopolysaccharide present in the cell walls of all species of the Mycobacterium genus, and (b) a protoplasmic antigenic preparation from M. sp strain linda, the mycobacterium that has been specifically implicated in Crohn's disease. We found no significant elevation in immunoglobulin A, immunoglobulin G, or immunoglobulin M antibody levels to these two antigen preparations in the Crohn's disease patients. Moreover, no subset of patients (sex, age, Crohn's disease activity index, location of disease, duration of disease, operations, or response to treatment) had elevated antibody levels. As virtually all known chronic infectious diseases have an associated serologic response to the etiologic agent, our findings greatly diminish the likelihood that Crohn's disease is caused by an infection with a mycobacterium.     

Analysis of the in vitro lymphoproliferative responses and antibody levels to the arc-5 antigen in patients with cystic hydatid disease.

Using a commercially-available, purified, arc-5 antigen, we examined the in vitro proliferative responses of peripheral blood mononuclear cells from hydatid patients and from healthy controls. Antibody levels of different immunoglobulin classes were also measured against the same antigen, in sera of both groups. Our findings indicate that lymphocytes from healthy controls do not proliferate to the arc-5 antigen, whereas lymphocytes from the majority of patients do. The negative or weak responses observed among a few patients were not due either to increased release of prostaglandins in culture or to a lack of responsiveness to Interleukin-2. Antibodies of all three classes, G, M and A, measured by an ELISA, were elevated in sera of patients when compared with controls. However, only levels of specific IgG antibodies gave an excellent discrimination of the disease state and these were of diagnostic value. No direct or inverse correlations between lymphoproliferative responses and antibody levels were observed in either group, although a few patients with relatively low antibody titres demonstrated very high proliferative responses. The possible use of the proliferative assay as an adjunct to serology in the diagnosis of hydatid disease is indicated.     

Interleukin 2 production and responsiveness in active and inactive rheumatoid arthritis

The interleukin 2 (IL-2) production and responsiveness of peripheral blood lymphocytes from patients with rheumatoid arthritis (RA) with active or inactive disease was compared with that of normal control donors. IL-2 production was assessed using a cellular interleukin assay in which an IL-2 dependent cell line was cocultured with varying numbers of irradiated IL-2 producing lymphocytes from the different donor sources. Cells from patients with active disease showed a significantly different pattern of IL-2 production from that of control or inactive RA patients in that a lower number of cells supported growth of the IL-2 dependent cell line. In one patient this shift in pattern was shown to correlate with change in disease activity. Lymphocyte responsiveness to IL-2 as determined by limiting dilution analysis did not differ significantly between the different groups. The results are consistent with a hyperproduction of IL-2 in RA during active disease.     

Adrenocorticotropin and cortisol responsiveness to thyrotropin-releasing hormone and luteinizing hormone-releasing hormone discloses two subsets of patients with Cushing's disease

In 23 consecutive patients with Cushing's disease and 52 control subjects, the responses of ACTH and cortisol to TRH and LRH were investigated. From the pattern of cortisol levels after the administration of the releasing hormone in the controls, a criterion for paradoxical responsiveness could be derived (maximum cortisol increase, greater than 6.0 micrograms/100 ml). According to this criterion, 9 patients with Cushing's disease showed a paradoxical responsiveness to one or both releasing hormones (3 to both TRH and LRH, 3 to TRH alone, and 3 to LRH alone; group I). In all patients tested, paradoxical responses of cortisol were preceded by paradoxical increments in ACTH. The remaining 15 patients showed no paradoxical increments in ACTH or cortisol after TRH or LRH (group II). ACTH levels in group I (89 +/- 28 pg/ml) were significantly lower than those in group II (185 +/- 164 pg/ml; P less than 0.02). Nevertheless, in both groups, a similar plasma cortisol level was found, suggesting a relatively higher bioactivity of ACTH in group I. A second difference between both groups was a lower amplitude of cortisol variability during the day in group I. The 2 groups did not differ in clinical data, such as age, sex distribution, sellar volume, and duration of disease, or dexamethasone suppressibility, bromocriptine sensitivity, and basal PRL levels. These latter findings do not favor an intermediate lobe origin of Cushing's disease in patients with paradoxical responses to TRH/LRH. To conclude, TRH/LRH responsiveness of ACTH/cortisol discloses two subsets of patients with Cushing's disease.     

IgM anti-P1 immunoblotting. A standard for the rapid serologic diagnosis of Mycoplasma pneumoniae infection in pediatric care.

STUDY OBJECTIVE: To prospectively evaluate the use of an IgM anti-P1 immunoblotting assay for the rapid diagnosis of Mycoplasma pneumoniae infection in a pediatric setting. PATIENTS AND METHODS: Blood specimens from 107 children representing 108 predominantly respiratory illnesses were obtained for a prospective evaluation of the IgM anti-P1 assay. Primary patient diagnoses were determined by a combination of the complement fixation test and supplementary microbiologic and nonmicrobiologic diagnostic tests. The potential effect of the assay results on antibiotic therapy was assessed by observing concurrent therapy. RESULTS: M pneumoniae was the primary etiologic agent of disease in 19 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of the IgM test to determine a case of primary M pneumoniae disease was 84.2 percent, 95.5 percent, 80.0 percent, and 96.6 percent, respectively. Twenty-seven children may have had antimicrobial therapy appropriately modified if results of the assay were directly utilized. Three of four patients with positive assays, which would have been falsely indicative of primary disease, had evidence of a recent probable M pneumoniae infection shortly preceding the acute illness. CONCLUSION: The rapid IgM anti-P1 assay is reasonably specific for the diagnosis of M pneumoniae infection. Apart from establishing prompt and accurate diagnosis, the results have the potential to change treatment measures in a significant proportion of patients.     

Pituitary function after removal of pituitary microadenomas in Cushing's disease.

Pituitary function has been studied sequentially after transsphenoidal removal of pituitary microadenomas in two men with Cushing's disease. Patient 1 gradually regained normal glucocorticoid levels with normal diurnal variation, metyrapone responsiveness, and low dose dexamethasone suppressibility (17-hydroxycorticosteroid, 6.5-0.9 mg/24 h). GH levels rose from 1 to 35 ng/ml during insulin hypoglycemia and from 2.3 to 27 ng/ml during arginine infusion. PRL secretion rose normally in response to thorazine, and gonadotropin and TSH levels remained normal. Patient 2 regained significant metyrapone responsiveness by 9 months postoperatively (11-deoxycortisol rose to 11.7 micrograms/dl), had a normal spontaneous nocturnal rise in PRL secretion, and normal levels of testosterone and thyroid hormones. The return to normal of cortisol-ACTH dynamics and GH responsiveness in Patient 1 and the normal nocturnal surge in PRL secretion in Patient 2 imply that in these patients the etiology of Cushing's disease was not related to hypothalamic dysfunction.     

Immune status in Crohn's disease. 2. Originally unimpaired primary cell mediated immunity in vitro.

One-way mixed lymphocyte cultures (MLC) were performed with peripheral blood lymphocytes of 21 patients with Crohn's disease (CD) not receiving salizylazosulphapyridine, steroids or azathioprine, seven patients with inflammatory bowel disease other than CD and ulcerative colitis, and 46 age- and sex-matched normal control subjects. The group of CD patients consisted of 11 patients with newly diagnosed, short-standing and so far untreated CD (group CD 1) and 10 patients previously treated with drugs and with mostly long-standing CD (group CD 2). Results showed that the MLC responsiveness was similar in all Crohn's disease groups, normal subjects and diseased controls. While there was no correlation between MLC responsiveness and either disease activity or disease duration when compared singly, those CD 2 patients who had highly active and/or very long-standing disease did exhibit a depressed MLC responsiveness as compared with that of normal subjects (p less than 0.001), CD 1 patients who had both inactive and short-standing disease (P less than 0.05), and diseased controls (0.1 greater than or equal to P greater than 0.05). The stimulatory capacity did not differ significantly between the CD groups and normal subjects or diseased controls; the latter, however, stimulated poorly compared with normal subjects (P less than 0.05). In accordance, an inverse relationship between the magnitude of the stimulatory capacity and the disease activity was found in the CD patients as a whole. These data suggest that there is no depression of the in vitro primary cell mediated immune response as a predisposing factor for CD or as an early event associated with the pathogenesis of CD.     

Cellular immune findings in Lyme disease. Correlation with serum IgM and disease activity

Cellular immune findings were studied in 48 patients with various stages of Lyme disease. At each stage, some patients, particularly those with neuritis or carditis, had elevated serum IgM levels and lymphopenia. During early disease, mononuclear cells tended to respond normally to phytohemagglutinin, and spontaneous suppressor cell activity was greater than normal. Later, during active neuritis, carditis, or arthritis, the trend was toward heightened phytohemagglutinin responsiveness and less suppression than normal. By multiple regression analysis, serum IgM levels correlated directly with disease activity (p = 0.025) and inversely with the number of T cells (p = 0.02); during acute disease only, elevated IgM levels correlated with increased phytohemagglutinin responsiveness (p = 0.004) and decreased suppressor cell activity (p = 0.03). Decreased suppression, observed later in the disease, may permit damage to host tissues because of either autoimmune phenomena or a heightened response to the Lyme spirochete.     

IDDM自身抗体与胰岛功能的研究

本文测定了36例新诊断、未使用过外源胰岛素的IDDM患者的血清胰岛细胞抗体(ICA)、血清胰岛素自身抗体(IAA)及血清C肽和胰岛素水平,并以72例新诊断的NIDDM和36例正常人作为对照。研究表明:自身免疫在IDDM病因中占有重要地位;临床发病时ICA、IAA阳性可以作为IDDM自身免疫的标志,但不能反映胰岛β细胞功能损害的程度。     

Hormonal profile in benign breast disease. Endocrine status of cyclical mastalgia patients

Plasma levels of prolactin, before and after TRH stimulation, progesterone, estradiol, sex-hormone-binding-globulin, androstenedione, testosterone and dehydroepiandrosterone-sulphate were determined in a group of women with benign breast disease and in control group, in order to correlate a possible hormonal disorder to breast pathology. The hormonal pattern in the patients with benign breast disease was characterized by an increased responsiveness of lactotrophes to TRH stimulation and by higher levels of sex hormone binding globulin, probably sustained by an underlying hyperestrogenism.     

Low HCV replication levels in end-stage hepatitis C virus-related liver disease.

BACKGROUND/AIMS: The relationship between HCV RNA levels and the severity of HCV-related liver disease has been addressed in a few studies, which has led to conflicting results. To clarify this point, we studied serum HCV RNA levels in patients with HCV liver disease at various stages, using a second-generation branched DNA (bDNA) assay. METHODS: One hundred and forty-eight patients with chronic HCV infection were classified into 3 groups: group A included 92 patients with chronic active hepatitis (CAH) without cirrhosis; group B included 30 patients with CAH and compensated cirrhosis; group C included 26 patients with end-stage cirrhosis. In all patients, serum HCV RNA was sought by qualitative PCR and quantified using second-generation bDNA assay. HCV RNA was also quantified after liver transplantation in 22 patients from group C. HCV genotype was determined in all patients. RESULTS: HCV RNA was detected by PCR in 100%, l00% and 92% of the patients from groups A, B and C, respectively (NS). The proportion of patients with HCV RNA levels higher than the cut-off of bDNA assay was significantly lower in patients from group C than in patients from groups A and B (50% vs 94% and 93% respectively, p<0.0001). The mean HCV viremia was lower in group C than in groups A and B (1.35+/-0.24 MEq/ml vs 5.00+/-6.04 MEq/ml and 5.85+/-7.70 MEq/ml, respectively, p<0.0001). This difference was independent of HCV genotype. In the patients from group C, post-transplant HCV RNA levels were significantly higher than pretransplant HCV RNA levels (14.90+/-26.40 vs 1.35+/-0.24 MEq/ml, p=0.0065). CONCLUSIONS: HCV RNA levels do not appear to differ significantly among patients with CAH with or without compensated cirrhosis. In contrast, HCV RNA levels seem to be significantly lower in patients with end-stage HCV-related liver cirrhosis. In these patients, high levels of replication are restored after liver transplantation, suggesting that low pretransplant viral loads are not due to the intrinsic characteristics of the infective viral strains, but rather to the severity of liver disease.     

Serum Vasopressinase and Platelet Responses to Arginine Vasopressin in Normal Pregnancy, Pregnancy-induced Hypertension and Pre-eclampsia

Pregnancy is marked by the placental production of vasopressinase, an enzyme which accelerates the metabolic clearance of arginine vasopressin (AVP), and serum vasopressinase is reported to be abnormally elevated in hypertensive pregnancy. Since platelet AVP binding capacity is influenced by the plasma AVP concentration, we sought to determine whether alterations in vasopressinase and AVP concentrations affect platelet responsiveness to AVP in normotensive and hypertensive pregnancy. Four groups of 10 women were studied: non-pregnant subjects, normotensive pregnancy, hypertensive pregnancy, and pre-eclampsia (PE). AVP-induced platelet aggregation was measured turbidometrically, serum vasopressinase by chromogenic assay and plasma AVP by radioimmunoassay. Platelet responses to AVP were similar in all groups, as were plasma concentrations of AVP. Vasopressinase was raised in all pregnant patients compared with non-pregnant subjects, and levels were significantly higher in pregnancy-induced hypertension than in either the normotensive or PE groups (p<0.05). No significant correlation was observed between platelet responsiveness to AVP and circulating concentrations of either AVP or vasopressinase. Thus circulating vasopressinase is increased in pregnancy and abnormally so in hypertensive pregnancy. This does not, however, appear to influence ex vivo platelet responsiveness to AVP.     

Effect of pravastatin on responsiveness to N-monomethyl-L-arginine in patients with hypercholesterolaemia.

Improvement of endothelial function in hypercholesterolaemia is attributed to lipid lowering and to pleiotropic effects of statin therapy. We investigated whether responsiveness to inhibition of constitutive NO formation with N-monomethyl-L-arginine (L-NMMA) is improved after 7 and 28 days of pravastatin. Twelve female and four male subjects with mild or moderate primary hypercholesterolaemia were randomized to pravastatin (20 mg per oral (p.o.) n=8) or placebo (n=8) in a double blind parallel group design. Vascular responsiveness was studied by intravenous bolus infusions of L-NMMA (cumulative doses of 3 and 6 mg/kg). Mean arterial blood pressure (MAP) and pulse rate (PR) were measured noninvasively, pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation amplitudes (FPA) and renal plasma flow (RPF) was measured by the PAH clearance method. Pravastatin lowered plasma cholesterol levels by 16 and 24% after 7 and 28 days of treatment, respectively (P<0.01). L-NMMA caused comparable changes in MAP, PR and RPF between groups. L-NMMA reduced FPA to a similar extent in both groups before and after 7 days of treatment, but the response to L-NMMA was significantly enhanced after 28 days of pravastatin (21%; P<0.001 vs baseline) and greater than after placebo (15%; P<0.01 vs pravastatin). Pravastatin enhances responsiveness to L-NMMA in the ocular microvasculature. Improved responsiveness is associated with changes in total cholesterol levels.     

Raynaud's phenomenon.

Raynaud's phenomenon is episodic digital ischemia provoked by cold and emotion; it is associated with other disorders, such as Raynaud's syndrome, especially the connective tissue diseases. Recent information suggests links with Sj?gren's syndrome, malignancy, and obstructive vascular disease. The vasospasm can affect areas outside the periphery such as the inner ear in vibration white finger syndrome and the placental vessels in pregnancy. The initial presence of autoantibodies increases the chance by 63-fold of developing connective tissue diseases, and such immunologic testing can be usefully combined with nailfold vessel microscopy. Several factors are considered to be of etiologic importance in Raynaud's phenomenon, such as the augmenting effect of cold on the responsiveness of alpha 2-adrenoceptors to agonists. Deficiency in the vasodilator neuropeptide calcitonin gene-related peptide has been detected, as have excess amounts of the vasoconstrictor endothelin. Treatment of vasospasm remains symptomatic, and directed towards the vasospasm and altered blood constituents.     

Modification of the plasma cortisol response to stress in rainbow trout by selective breeding.

Male and female rainbow trout were segregated into high- and low-responding individuals (HR, LR) on the basis of their plasma cortisol response to a 3-h period of confinement imposed at monthly intervals for 5 months. Consistent divergence was obtained in the responsiveness of the two groups, although the difference between LR and HR groups was greater in female fish (56 c.f. 116 ng ml(-1)) than in males (45 c.f. 69 ng ml(-1)). Progeny groups (full-sib families) were obtained from the pairing of HR males and females and LR males and females. A third progeny group (US) was obtained by random pairing of parents which were not selected as HR or LR. Poststress plasma cortisol levels in the progeny were first tested at 6 months after hatch and were significantly correlated with the response of the corresponding parental groups, HR > US > LR (178, 126, 81 ng ml(-1), respectively). The difference in responsiveness between LR and HR groups was demonstrated in all four subsequent tests over a 12-month period. There were no significant differences in baseline plasma cortisol levels in LR and HR groups prior to confinement. During a 4-h period of confinement, the differences in plasma cortisol levels between LR and HR fish were sustained throughout, indicating that the trait upon which the fish were selected was related to absolute maximum levels of circulating cortisol and not to the rate of change of cortisol levels during exposure to a stressor. A moderately high heritability (h(2)) for confinement-induced plasma cortisol of 0.41 was obtained by a parent-progeny regression. Manipulation of stress responsiveness in fish by selective breeding offers scope for optimizing performance under intensive rearing conditions but also provides a useful research tool for investigating the operation of the endocrine stress response.     

Platelet reactivity in stable cardiovascular patients with chronic kidney disease

The study aimed to evaluate antiplatelet drug responsiveness in stable outpatients with cardiovascular disease and chronic kidney disease (CKD) and examine whether impaired antiplatelet drug responsiveness is associated with worse clinical outcomes in this population. Stable cardiovascular patients (n = 771) were enrolled at least one month after an acute ischemic atherothrombotic event. Antiplatelet drug responsiveness was assessed with specific assays (serum TxA₂ for aspirin, the VASP assay for clopidogrel) and other aggregation-based assays using different agonists. All patients were followed until the first occurrence of a major adverse cardiovascular event. The 133 CKD patients were found to have higher activity of von Willebrand factor and higher fibrinogen levels. After a median follow-up of 33 months, 88 events occurred in patients without CKD and 31 events in patients with CKD (5.0 events and 8.7 events per 100 patient years, respectively, HR = 1.75 (95% CI 1.16–2.63; p = 0.008). The prevalence of poor aspirin and clopidogrel responsiveness and high platelet reactivity as assessed with different aggregation-based assays was similar in patients with estimated GFR ≥ 60 ml/min, 45–59 ml/min, and < 45 ml/min. No significant interaction for CKD vs. non-CKD was observed for events occurrence in patients with or without high platelet reactivity on several assays, with the exception of collagen-induced aggregation. In stable cardiovascular patients, CKD is not associated with higher platelet reactivity. Decreased antiplatelet drug responsiveness is not associated with worse clinical outcomes in CKD patients.     

TTV infection in children with and without liver disease.

BACKGROUND: TTV DNA has been reported in patients with a broad spectrum of hepatic disorders as well as in healthy people. AIM: To clarify the role of TTV in children with liver disease and in healthy children. METHODS: Degenerate primers designed to amplify a target sequence from the ORF 1 region of TTV genome were used for nested PCR, to detect TTV DNA in sera. RESULTS: TTV was detected in 3 of 18 children with chronic hepatitis B (16.7%), 2 of 17 hepatitis B carriers (11.8%), 2 of 17 children with cryptogenic chronic liver disease (11.8%), and 1 of 40 (2.5%) children without liver disease. The infection rate was similar among the various study groups and in the various age groups. There was no difference between TTV positive and negative children in respect to gender, history of surgery, parenteral treatment, transfusion of blood and blood products, presence of hepatomegaly, splenomegaly, jaundice, and transaminase values. CONCLUSION: TTV does not seem to have an etiologic role in cryptogenic liver disease in children and does not seem to influence the clinical course of liver disease.     

The relationship of nonspecific bronchial responsiveness to the occurrence of respiratory symptoms and decreased levels of pulmonary function. The Normative Aging Study

Nonspecific bronchial responsiveness was assessed by an abbreviated methacholine challenge test in 458 male participants of the Normative Aging Study, who also completed a respiratory questionnaire and spirometry. A positive response to the methacholine challenge test was defined as a greater than or equal to 20% decline in FEV1 during the test. Cigarette smoking was significantly associated with a positive methacholine response (p less than 0.001). Logistic regression analyses indicated that there was a significant association between a positive response to methacholine and both any wheeze (p = 0.002) and persistent wheeze (p less than 0.001) after taking into account smoking status and age; an association between responsiveness and chronic cough was of borderline significance (p = 0.06). Multiple linear regression analyses indicated that positive methacholine responsiveness was independently associated with lower levels of FEV1 (p less than 0.001) and FEF25-75 (p less than 0.001). Using the log of the dose-response slope rather than a dichotomous variable to characterize responder status yielded very similar results in the linear and logistic models. The findings of this cross-sectional study suggest that increased level of nonspecific responsiveness is significantly associated with wheeze and cough symptoms and decreased levels of pulmonary function in adult men. Longitudinal follow-up of these men should shed light on the importance of nonspecific responsiveness as a risk factor for the subsequent development of chronic obstructive pulmonary disease.