Amelioration of osteopenia and hypovitaminosis D by 1alpha-hydroxyvitamin D3 in elderly patients with Parkinson''s disease

The utility of open chest conductance (COND) ventriculography is limited by artifacts altering the relationship between COND and left ventricular (LV) volume. Pressure-COND loops often lean to the left during LV volume reduction by caval occlusion. Time varying alterations in the pericardial-LV contact area affect electrical coupling in the open chest during the cardiac cycle, producing COND artifacts. In this study, an open-mediastinum model was constructed. Components represented the LV, blood, pericardium, and thoracic contents. Varying ventriculothoracic coupling was simulated by changing the volume of pericardial saline (0, 30, 60 ml). Raw dual field COND was repeatedly (n = 20) compared with volumes of normal saline from 60 to 120 ml at 5 ml intervals. Groups were compared by linear regression and repeated measures ANOVA. Artifacts significantly (p < 0.01) altered parallel COND, indicated by the y-intercept, with the exception of 0 versus 30 ml. The slope constant also changed significantly, with the exception of 30 versus 60 ml. These results suggest that variable pericardial-LV contact can cause time varying artifacts in COND in the open chest. Therefore, posterior insulation may reduce artifacts in COND ventriculography and should be tested for this effect.     

Relationship of thyroid states and serum thrombomodulin (TM) levels in patients with Graves' disease: TM, a possible new marker of the peripheral activity of thyroid hormones

Thrombomodulin (TM) is a thrombin receptor glycoprotein that functions as an anticoagulant on the surface of endothelial cells. Serum TM is regarded as a new marker of generalized endothelial cell damage. Serum TM concentrations were measured in 75 patients with Graves' disease and 75 age- and sex-matched healthy subjects. Serum TM levels in patients in the hyperthyroid state were significantly increased, while those in patients in the hypothyroid state due to treatment were significantly decreased compared with levels in control subjects. All patients with untreated Graves' disease had markedly elevated TM levels. Serum TM levels correlated closely with thyroid hormone concentration (TM vs. free T4, r = 0.858; P = 0.001). Serial measurement of individual patients revealed that serum TM levels paralleled thyroid hormone concentration, reaching normal control values upon attainment of euthyroidism. On the other hand, there was no significant correlation between serum TM concentration and titer of antithyroglobulin antibodies, titer of antimicrosomal antibodies, serum thyroglobulin level, or goiter size, and serum TM was not directly influenced by TSH receptor antibodies or resting pulse rates. The close correlation between serum TM and thyroid hormone concentration suggests that thyroid hormones might influence the synthesis or metabolism of TM on the surface of endothelial cells in patients with Graves' disease.     

Human thyroid adenyl cyclase-stimulating activity in immunoglobulin G of patients with Graves' disease

We have studied the characteristics of the stimulation of adenyl cyclase (AC) activity in human thyroid plasma membranes by thyroid-stimulating hormone (TSH) and by immunoglobulin G (IgG) from the sera of patients with Graves' disease. AC activity was measured as adenosine 3',5'-cyclic monophosphate (cAMP) generated by membranes in a 10 minute incubation. IgG from two patients with Graves' disease possessed particularly potent human thyroid AC-stimulating activity; the dose-response curves with these IgGs were essentially parallel to those obtained with TSH. As little as 30 mug of the IgG of one patient with Graves' disease or 8 muU of TSH caused significant AC stimulation. A Lineweaver-Burk plot of the data suggested similarity in the site of action of both TSH and human thyroid adenyl cyclase stimulator (HTACS) in Graves' IgG. Submaximal doses of HTACS and TSH had additive effects on AC stimulation, but a large dose of a Graves' IgG with potent AC stimulating activity did not enhance AC stimulation by a maximal dose of TSH. The effect of HTACS on AC was slower in onset and longer in duration than an equipotent dose of TSH. HTACS was detectable in IgGs of 9 of 15 untreated hyperthyroid Graves' disease patients; its concentration, however, did not correlate significantly with tests of thyroid function, nor with long-acting thyroid stimulator (LATS) activity. In another 11 treated patients with Graves' disease, selected for the presence of LATS, HTACS and LATS were significantly correlated. We observed no inhibition of LATS activity in a Graves' IgG chosen for such testing because of its high titer of HTACS and no detectable LATS. However, an inhibitor of HTACS was detected in 2 of 4 IgGs; one of these two IgGs also inhibited AC stimulation by TSH. Conclusions: 1) Some Graves' disease IgGs contain a human thyroid AC stimulator (HTACS), probably different from LATS. 2) HTACS may act via a common pathway with TSH; it differs from TSH, however, in having a slower onset and a greater effect during more prolonged incubation with plasma membranes. 3) There is also an inhibitor of HTACS activity in some Graves' disease IgGs.     

Increased serum vascular endothelial growth factor levels and intrathyroidal vascular area in patients with Graves' disease and Hashimoto's thyroiditis

Vascular endothelial growth factor (VEGF) is one of the angiogenic factors. We examined both thyroid volume and intrathyroidal vascular area by color flow Doppler ultrasonography in patients with Graves' disease (GD), Hashimoto's thyroiditis (HT), and subacute thyroiditis. The serum concentrations of thyroid hormones, TSH, TSH receptor antibodies, and VEGF were also examined. There was a significant increase in serum VEGF levels in patients with untreated GD and goitrous HT compared with those in healthy subjects. The serum VEGF levels in untreated patients with subacute thyroiditis were significantly higher than those in patients with untreated GD or HT. There was a significant correlation between serum VEGF levels and the ratio of intrathyroidal vascular area and thyroid area in untreated patients with GD who had a goiter larger than or equal to 40 cm3. There was also a significant correlation between serum VEGF and TSH levels in patients with HT who were hypothyroid and had a goiter. Serum VEGF levels decreased significantly in these patients after treatment; this was accompanied by a significant decrease in intrathyroidal vascular area and thyroid volume. Our study demonstrates that VEGF appears to play an important role in intrathyroidal angiogenesis in patients with GD and goitrous HT.     

25-hydroxycholecalciferol serum levels in patients with Crohn's disease

In 37 patients with Crohn's disease the 25-hydroxycholecalciferol (25-HCC) serum level, serum concentration of calcium and inorganic phosphate, and the enzyme activity of alkaline phosphatase were measured. Furthermore the activity index of Crohn's disease was determined in every patient. There was no statistically significant difference of 25-HCC serum levels in these patients compared to a healthy control group. Correspondingly most patients showed normal alkaline phosphatase enzyme activity and normal serum concentration of calcium and inorganic phosphate. No correlation between 25-HCC concentration and site of inflammation or activity index was found.     

TAP1 polymorphism identified in African-American Graves' disease patients

Polymorphism in transporter associated with antigen processing (TAP)1 gene has been observed in African American Graves' disease patients. Single strand conformational polymorphism has been used to identify variation for the locus. First-strand cDNA was generated from cell lines obtained by Epstein-Barr virus immortalization. Four variant alleles for TAP1 have been observed and the products have been sequenced to compare with the location of observed with SSCP position patterns. Variants were detected and compared with substitutions within TAP1 polypeptide which includes changing valine to leucine and three (3) silent substitutions for glycine, glutamic acid and alanine.     

Simultaneous radioimmunoassay of thyroid hormones in unextracted serum

Weekly atmospheric sampling in the Pocatello, Idaho, area and skin testing with a standard inland smut mixture of the smuts of common cereal grains and grasses have shown that smut is a prominent antigen and, used rationally in a mixture of related antigens, is useful in all seasons in the treatment of allergies. The history, agricultural aspects and medical significance of smuts are discussed.     

Outcome of differentiated thyroid cancer in Graves' patients

The clinical behavior and outcome was evaluated in 21 nonoccult differentiated thyroid carcinomas occurring in Graves' patients during the period 1982-94 and compared with that of matched tumors occurring in euthyroid controls (n = 70). At surgery, patients with Graves' disease showed distant metastases more frequently than euthyroid patients (3/21 = 14.3% vs. 1/70 = 1.4%, P = 0.0556). Graves' patients also showed a significantly higher cumulative risk of recurrent/progressive distant metastases or total adverse events (odd ratios = 3.14 and 2.07, respectively) as compared with euthyroid patients. At the last follow-up visit, persistence of distant metastases was also more frequent in the Graves' group (P = 0.007), although the cumulative individual dose of radioiodine administered was higher than in the control group (median dose = 805 mCi vs. 350 mCi). Two patients died in the Graves' group vs. none in the control group. Circulating thyroid stimulating antibodies were present in all patients but one and persisted as long as signs of disease were evident. These findings indicate that differentiated thyroid carcinomas in patients with Graves' disease are more aggressive than those occurring in matched euthyroid controls and should, therefore, be managed accordingly.     

Increased serum concentration of soluble CD30 in patients with Graves' disease and Hashimoto's thyroiditis

This study investigated serum levels of the soluble form of CD30 (sCD30), which is mainly secreted from T helper 2(Th2) cells, in autoimmune thyroid diseases. The possible relationship of sCD30 to autoantibody production was also evaluated. Serum levels of sCD30 were determined by an enzyme-linked immunosorbent assay in 71 patients with Graves' disease, 37 patients with Hashimoto's thyroiditis, and 21 normal donors. Compared with normal subjects (7.1 +/- 4.5 U/mL), sCD30 was increased in patients with Graves' disease (29.2 +/- 25.2 U/mL, P < 0.0001) and in patients with Hashimoto's thyroiditis (29.9 +/- 26.9 U/mL, P < 0.0001). In Graves' disease, sCD30 levels were higher in thyrotoxic patients (41.7 +/- 31.2 U/mL, P < 0.001) than in remission patients (15.8 +/- 11.0 U/mL), and a significant correlation was observed between sCD30 levels and serum activities of TSH receptor antibody (r = 0.444, P < 0.0001). In Hashimoto's thyroiditis, sCD30 levels were higher in patients with transient destructive thyrotoxicosis caused by the aggravation of the disease (48.8 +/- 34.4 U/mL, P < 0.05) than in euthyroid patients (24.2 +/- 19.4 U/mL). These data suggest that serum sCD30 is a valuable marker of disease activity and support an important role of the Th2-type immune response in the pathogenesis in Graves' disease and Hashimoto's thyroiditis.     

F-qi-FDG PET of the thyroid gland in Graves' disease

AIM: This study evaluates F-18-FDG PET of the thyroid in Graves' disease. METHODS: Thirty patients were investigated the day before radioiodine therapy, 15 patients 3-10 days after radioiodine therapy. Twenty patients with cancer of the head or neck and normal thyroid function served as controls. RESULTS: F-18-FDG uptake was higher in Graves' disease patients than in controls. Negative correlations of F-18-FDG uptake with half-life of radioiodine and absorbed radiation dose due to radioiodine therapy were found along with a positive correlation to autoantibody levels. CONCLUSION: Thus F-18-FDG PET is likely to give information on the biological activity of Graves' disease as well as on early radiation effects.     

Thyroxine and triiodothyronine levels in hyperthyroid patients during treatment with propranolol

In the last few years, there has been an active effort in Italy to involve the population in solving health problems at the community level. This movement had its origin in the industrial setting, where workers succeeded in promoting legislation which gives them control over matters affecting their health. This experience lead to the development of a health education methodology based on the following principles: (a) the assessment of health needs must be based on the subjective experience of the people who have acquired knowledge and interest in health problems; (b) the evaluation of health needs by professionals serves to complement and integrate the assessment of needs as experienced by the community; (c) the self-diagnosis of the community -- in particular of homogenous community groups exposed to similar health risks and experiencing the same needs--and the diagnosis of the professionals must undergo cross-validation and be accepted by both parties; (d) on the basis of this mutual agreement, community health programmes should be planned and carried out jointly by the professionals and the people.     

Evidence for the effect of antibodies to TSH receptors on the thyroid ultrasonographic volume in patients with Graves' disease

OBJECTIVE: It has been demonstrated that antibodies (Ab) to thyroid-stimulating hormone receptors (R), which stimulate the thyroid gland, induce hyperthyroidism in patients with Graves' disease. Furthermore, it has been shown in thyroid cells in culture that thyroid-stimulating hormone receptor Ab acts through the adenosine 3', 5'-monophosphate pathway which stimulates both thyroid hormonogenesis and growth. We investigated the relations between thyroid autoimmunity expression and thyroid ultrasonographic parameters or thyroid hormonal status in patients with Graves' disease. PATIENTS: A prospective study of 53 consecutive patients referred with untreated Graves' disease. MEASUREMENTS: Measurements were made of serum TSH-R, peroxidase (TPO) and thyroglobulin (Tg) Ab and basal plasma free T4 (FT4), free T3 (FT3) and TSH. Thyroid morphological characteristics (number and total volume of nodule(s), total volume of lobes and total thyroid volume) were determined by ultrasonography. RESULTS: There were significant correlations (P < 0.001) between TSH-RAb levels and FT4 values (r = 0.48) or FT3 levels (r = 0.46). Likewise, significant correlations were found between TSH-RAb levels and total lobe volume values (r = 0.56, P < 0.001), total nodular volume values (r = 0.59, P < 0.01) or total thyroid volume values (r = 0.63, P < 0.001). By contrast, no correlation was found between TSH-RAb levels and the number of nodules or between any of the ultrasonographic parameters and TPOAb levels or TgAB values. CONCLUSIONS: This study demonstrates, in vivo, that TSH receptor antibodies modulate the thyroid ultrasonographic extranodular and nodular volumes in patients with Graves' disease.     

Cytokines serum levels as the markers of thyroid activation in Graves'' disease

We examined whether central somatostatin prevents an inhibitory effect of central calcitonin-gene related peptide (CGRP) on pancreatic secretion in conscious male Wistar rats (330-330 g). Rats were prepared with separate cannulas for draining bile and pancreatic juice and with a duodenal cannula and an extrajugular vein cannula. In addition, another cannula was stereotactically implanted into the left lateral cerebral ventricle. Rats were placed in restraint cages and experiments were conducted 4 days after the operation without anesthesia. An injection of CGRP (0.1, 1.0 nmol/10 microl) into the left lateral cerebral ventricle (i.c.v.) inhibited pancreatic secretion dose-dependently. To confirm the inhibitory effect of CGRP (i.c.v.) was mediated via sympathetic nerves, phentolamine was injected intravenously (i.v.) bolus (0.5 mg kg(-1)) 0.5-h before CGRP (i.c.v.), followed by continuous infusion of 0.2 mg kg(-1) h(-1). Phentolamine (i.v.) reversed the inhibition produced by CGRP (i.c.v.). An injection of 4 nmol/10 microl somatostatin (i.c.v.) 5 min prior to CGRP injection diminished the inhibitory effect of CGRP (i.c.v.). It is concluded that centrally administered somatostatin diminished the inhibitory action of CGRP (i.c.v.) on pancreatic secretion, probably via inhibiting autonomic (sympathetic) nerve excitation at the central site.     

MHC-extended haplotypes in families of patients with Graves' disease

MHC-extended haplotypes were investigated in multiplex families of patients with hyperthyroid GD. Using a combination of both phenotypic (serology and protein electrophoresis) and genotypic (DNA-RFLP) markers, 159 MHC-extended haplotypes extending from HLA-A across the MHC class III (C2, Bf, C4A, and C4B) toward the HLA-DR/DQ complex were deduced from 217 (51 and 166 affected and unaffected) members of 21 families of patients with GD. Thyroid autoantibodies were measured and found positive in 27.1% of 166 clinically euthyroid unaffected members. Extended haplotypes were classified into four categories--affected (n = 40), Aff/Ab + ve (shared haplotype between affected and Ab + ve members, n = 31), Ab + ve (n = 29), and Ab - ve (n = 59)--based on the presence and absence of these haplotypes in 51 affected members with GD and 45 and 121 unaffected members who were respectively positive and negative for thyroid autoantibodies. Five recombinations were detected: three were found between HLA-A and B and two between HLA-B and the MHC class III. No recombination was found between or within the MHC class III and class II complex. Though the HLA-DR17 (DR beta 17(1) and DR beta 17(2)) allele was found to be significantly increased in both the affected and the Aff/Ab + ve when compared with the Ab - ve haplotypes (p < 0.042 and p < 0.018), the frequency of the HLA-B8, 2.7-kb SstI-4.5-kb TaqI/C2 Bf*S, 6.4-kb TaqI/C4A*Q0C4B*1, HLA-DR beta 17(1)/DQ alpha 2-DQ beta 2a extended haplotype was found to be significantly increased only in the affected haplotype (p < 0.05). These results suggest that while HLA-DR17 is a susceptibility allele shared between GD and individuals with positive thyroid autoantibodies, the HLA-B8, 2.7-kb SstI-4.5-kb TaqI/5'-3'C2 Bf*S, 6.4-kb TaqI/C4A*Q0B*1, DR beta 17(1)/DQ alpha 2-DQ beta 2a is a disease susceptibility-extended haplotype for Graves' disease.     

Soluble interleukin-1 receptor antagonist serum levels in smokers and nonsmokers with Graves' ophthalmopathy undergoing orbital radiotherapy

Interleukin-1 (IL-1) plays an important role in the pathogenesis of Graves' ophthalmopathy (GO). Impaired antagonism of the proinflammatory cytokine IL-1 by the naturally occurring IL-1 receptor antagonist (IL-1RA) has been implicated in the initiation and perpetuation of various autoimmune diseases and may play a role in the evolution of GO. Cigarette smoking appears to adversely affect the course of GO. We have evaluated the course of IL-1 alpha, IL-1 beta, and soluble IL-1RA (sIL-1RA) serum levels in smokers and nonsmokers with GO undergoing orbital radiotherapy (OR). We prospectively studied the eye status of 27 randomly selected patients (mean age 47.3 +/- 11.0 yr; 20 females; 18 smokers) with active, moderately severe GO before and 3 and 6 months following OR, respectively. None had received any previous treatment for GO, and all patients were kept euthyroid on carbimazole. Serum concentrations of IL-1 alpha, IL-1 beta, and sIL-1RA were measured using highly sensitive enzyme linked immunosorbent assay systems. Baseline sIL-1RA levels were negatively correlated with the number of cigarettes smoked before and following OR (P < 0.0001). Patients with no or minor therapeutic response to OR (n = 8), all of whom were smokers, revealed mean baseline sIL-1RA levels of 114 +/- 85 pg/mL, which increased to 172 +/- 103 pg/mL at 3 months and 149 +/- 96 pg/mL at 6 months after initiation of OR, respectively. By contrast, patients with a good clinical response (n = 19, 9 nonsmokers), revealed significantly higher baseline sIL-1RA levels at 294 +/- 148 pg/mL (P = 0.004), which increased to 845 +/- 668 pg/mL at 3 months (P = 0.01) and 634 +/- 337 pg/mL at 6 months (P < 0.001), respectively, following initiation of OR. Serum concentrations of IL-1 alpha IL-1 beta were below 3.9 pg/mL in all patients with GO who were studied, and were not correlated with gender, age, smoking status, clinical course, or outcome. Low baseline levels and impaired surge of sIL-1RA serum levels following OR were strongly correlated with smoking status and a less favorable therapeutic outcome in patients with active, moderately severe GO. Measurement of sIL-1RA may contribute to predict the therapeutic response to OR in patients with active, moderately severe GO. Strategies designed to raise local or systemic concentrations of sIL-1RA may be of benefit to patients with GO.     

Elevated C3-proactivator serum levels in patients with chronic polyarthritis

The C3-Proactivator (C3-PA) and the C3 and C4 complements were determined by radio-immuno diffusion in the serum of 72 patients with definite or classical rheumatoid arthritis, 51 patients with osteoarthrosis and 42 healthy subjects. C3-PA and C4 levles were significantly higher in the serum of patients with rheumatoid arthritis than in the control group (C3-PA in 72%, C4 in 37% of the RA patients). There was also a significant difference between seropositive und seronegative cases. Elevation of both components was more frequently found in patients with seronegative rheumatoid arthritis than in the seropositive cases. However, the C3-PA serum level is not correlated with the ESR. Also an elevation of the C3-PA serum level is not specific for rheumatoid arthritis, it is also found in other inflammatory diseases as well as after surgery.     

Increase in femoral bone mass by ipriflavone alone and in combination with 1 alpha-hydroxyvitamin D3 in growing rats with skeletal unloading

We assessed the possibility that ipriflavone treatment might result in bone restoration in immobilized rats. We also investigated the effect of combined treatment with ipriflavone and vitamin D3 on the bone. Male Sprague-Dawley rats, 6 weeks of age, were subjected to unilateral sciatic neurectomy. Three weeks after the operation, ipriflavone (100 mg/kg), 1 alpha-hydroxyvitamin D3 [1 alpha (OH)D3, 25 ng/kg], or both ipriflavone and 1 alpha (OH)D3 were orally administered every day for 12 or 24 weeks. After 12 weeks of treatment, only the group receiving combined treatment with ipriflavone and 1 alpha (OH)D3 showed increases in total femur calcium content (+16.4%, compared with the control). After 24 weeks, both animals treated with ipriflavone alone and those that had received the combination of ipriflavone and 1 alpha (OH)D3 showed significant increases in femur calcium content (+18.0% and +23.8%, respectively). In these treatment groups, X-ray analysis revealed an increase in bone mineral density over the entire length of the femur, and an increase in cortical diameter at the midshaft without affecting medullary width. Administration of 1 alpha (OH)D3 (25 ng/kg) alone had no effect. Body weight, femur length, and serum markers of calcium and bone metabolism were not affected in any group. We evaluated the relationship between ipriflavone and vitamin D3 in bone cells in a culture system using rat bone marrow stromal cells in which the cells subsequently form mineralized bone-like tissue. Continuous treatment with ipriflavone (10(-5) M) for 21 days resulted in an increase in osteocalcin secretion, and enhanced its response to 1 alpha, 25-dihydroxyvitamin D3 (10(-11) M-10(-8 M)). These findings indicate that ipriflavone treatment increases the femoral bone mass in immobilized rats. In addition, a low dose of 1 alpha (OH)D3, which did not induce hypercalcemia, in combination with ipriflavone, augmented the stimulatory effect of ipriflavone alone on the bone mass, possibly due to a direct effect of each agent on osteoblastic cells.     

An elevation of stem cell factor in patients with hyperthyroid Graves'' disease

The dose of cells expressing the surface antigen CD34 (CD34+) has been shown to be a reliable predictor of the time to engraftment following transplantation of PBPC to support high-dose chemotherapy. However, evaluation of rare cells is complicated by a number of factors, including the variability in operator and technical procedures. Recently, Becton Dickinson Immunocytometry Systems introduced a new CD34+ cell analysis system, the ProCOUNT cell enumeration kit, which automates the analysis of CD34+ cells and minimizes the variabilities of this procedure. We have evaluated the ProCOUNT system in comparison to a standard CD34 cell analysis (based on the Milan approach) using leukapheresis products from patients and normal donors mobilized with chemotherapy plus recombinant human G-CSF (rhG-CSF) or with rhG-CSF alone. In addition, we compared these analyses using CD34+ cell-selected mobilized leukapheresis products with purities of 75% or greater. The standard CD34 cell analysis methodology quantitated the frequency of cells identified as CD45+, low side scatter, and CD34+. A high correlation coefficient was obtained between the ProCOUNT methodology and the standard CD34 cell analysis methodology for cells obtained from leukapheresis products mobilized with chemotherapy plus rhG-CSF (r = 0.98), rhG-CSF alone (r = 0.96), and CD34+-selected mobilized leukapheresis products (r = 0.83). A comparison was also made between technicians using both analysis methods. Whereas the correlation coefficient between two technicians using the standard methodology was r = 0.77, the correlation coefficient was much higher when using ProCOUNT (r = 0.99). These data demonstrate that the use of ProCOUNT is associated with less variability between data analyzed by different operators. Also, ProCOUNT is consistent with existing CD34+ cellular analysis methodologies. An additional advantage is the ability to determine the absolute concentration of CD34+ cells, thereby allowing calculation of total CD34+ cell numbers without using WBC counts, which also have inherent errors. The ProCOUNT system provides an automated analysis procedure that minimizes the variables in CD34+ cell analysis and may be useful for standardization of methodology between laboratories.