Mean Value Of Control Subjects Research Articles

Prevalence and Pathophysiologic Attributes of Ventricular Dyssynchrony in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

This study sought to investigate the prevalence and mechanisms underlying right ventricular (RV) dyssynchrony in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using tissue Doppler echocardiography (TDE). An ARVD/C is characterized by fibrofatty replacement of RV myocardium and RV dilation. These pathologic changes may result in electromechanical dyssynchrony. Echocardiography, both conventional and TDE, was performed in 52 ARVD/C patients fulfilling Task Force criteria and 25 control subjects. The RV end-diastolic and -systolic areas, right ventricular fractional area change (RVFAC), and left ventricular (LV) volumes and function were assessed. Mechanical synchrony was assessed by measuring differences in time-to-peak systolic velocity (T(SV)) between the RV free wall, ventricular septum, and LV lateral wall. An RV dyssynchrony was defined as the difference in T(SV) between the RV free wall and the ventricular septum, >2 SD above the mean value for control subjects. The mean difference in RV T(SV) was higher in ARVD/C compared with control subjects (55 +/- 34 ms vs. 26 +/- 15 ms, p < 0.001). Significant RV dyssynchrony was not noted in any of the control subjects. Based on a cutoff value of 56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). Patients with RV dyssynchrony had a larger RV end-diastolic area (22 +/- 5 cm(2) vs. 19 +/- 4 cm(2), p = 0.02), and lower RVFAC (29 +/- 8% vs. 34 +/- 8%, p = 0.03) compared with ARVD/C patients without RV dyssynchrony. No differences in QRS duration, LV volumes, or function were present between the 2 groups. An RV dyssynchrony may occur in up to 50% of ARVD/C patients, and is associated with RV remodeling. This finding may have therapeutic and prognostic implications in ARVD/C.

Hormone Allergy

Estrogen and progesterone have been associated in women with symptoms that include asthma, migraine, dermatitis and pain. We suggest a connection between symptoms associated with hormone changes to a hormone antibody response. For IgG, IgM and IgE antibodies to progesterone, blood samples were obtained from 288 healthy control subjects by a commercial lab in California. Blood from 270 patients in Texas with changes in symptoms associated with menstrual cycles was examined. For IgE antibodies to both progesterone and estrogen, blood samples were obtained from an additional 32 healthy control subjects who had no symptoms related to menses and from 98 patients with symptoms associated with menstrual cycles. The symptoms were asthma, migraines and joint pain. At 2 S.D. above the mean values of control subjects, a significant number of patients show high levels of IgG, IgM and IgE antibodies to progesterone and estrogen. This paper describes evidence of antibodies to the hormones estrogen and progesterone. Progesterone, estrogen and their metabolites, after binding to human tissue proteins, such as albumin or globulin, may act as antigens and promote Type 2 helper cell development, thereby regulating antibody synthesis and allergy. This leads to the possibility of treating a wide variety of disorders by determining hormone allergy and initiating desensitization. Two obvious applications for determination and treatment of hormone allergies are pre-menstrual asthma and menstrual migraines.

Simple non-invasive assessment of advanced glycation endproduct accumulation

The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age- and sex-matched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N(epsilon)-(carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine (CEL). Autofluorescence correlated with CLF, pentosidine, CML, and CEL ( r=0.47-0.62, p</=0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA(1)c of the previous year and creatinine levels. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation.

Low serum inhibin B levels as a marker of testicular damage after treatment for a childhood malignancy.

The aim of this study was to evaluate the role of inhibin B and the determination of its concentration to diagnose testicular damage after treatment for a childhood malignancy. Thirty-seven males treated for Hodgkin disease (n = 11) or non-Hodgkin lymphoma (n = 26) were examined at a mean age of 16.9+/-2.9 years. Mean age at the stop of therapy was 11.3+/-3.0 years and in most cases the chemotherapy regimen included gonadal damaging alkylating agents. Thirty-three normal males (mean age 17.9+/-4.1 years) were examined as controls. Serum samples were collected for determination of inhibin B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Median inhibin values were significantly lower in patients than in controls (96.0 vs. 225.0 pg/ml, P<0.0001) and a strong negative correlation was found between inhibin B and FSH (r = -0.86, P<0.0001), a weak correlation with LH (r = -0.32, P<0.05) and no correlation with testosterone. In post-pubertal patients (i.e., over 16 years) a positive correlation was found between testicular size and inhibin level (r = 0.53, P<0.05), but not between testicular size and testosterone level. Pathological low levels (values that differed by more than 2 SD from the mean value of control subjects) were found in 20 patients for inhibin B and 8 for testosterone (P<0.01) and pathological high values in 19 patients for FSH and 3 for LH. This study confirms the role that inhibin B plays in the regulation of FSH secretion and provides further evidence of the utility of its evaluation as a direct indicator of male gonadal dysfunction.

Striatal uptake of the dopamine reuptake ligand [11C]beta-CFT is reduced in Alzheimer's disease assessed by positron emission tomography.

Striatal dopamine reuptake sites were studied with PET in Alzheimer's disease (AD). A cocaine analogue, [11C]beta-CFT was used as a radioligand. In patients with AD, the reduction in [11C]beta-CFT uptake was about 20% from the age-adjusted mean value in control subjects, both in the putamen (p = 0.002) and in the caudate nucleus (p = 0.002). Thus, the putamen and the caudate nucleus were equally affected, in contrast to Parkinson's disease, which shows predominantly putaminal reduction. We found that the smaller the [11C]beta-CFT uptake in the putamen or in the caudate nucleus, the more severe the extrapyramidal symptoms. In healthy volunteers (nine women, six men; aged 23 to 70 years), [11C]beta-CFT uptake was reduced with age, both in the putamen (r = -0.70, p < 0.01) and in the caudate nucleus (r = -0.77, p < 0.001). The average decline per decade was 4.4% in the putamen and 4.7% in the caudate nucleus. We conclude that the brain dopaminergic system is affected in AD because the striatal uptake of the dopamine reuptake ligand [11C]beta-CFT is decreased. This reduction in [11C]beta-CFT uptake correlates with the severity of the extrapyramidal symptoms of the patients.

Mapping of ventricular repolarization potentials in patients with arrhythmogenic right ventricular dysplasia: principal component analysis of the ST-T waves.

Nonuniform recovery of ventricular excitability has been demonstrated to facilitate the reentry circuits leading to the development of ventricular tachyarrhythmias. This can also occur in arrhythmogenic right ventricular dysplasia (ARVD). In fact, in patients with ARVD, abnormalities of ventricular repolarization are often observed on 12-lead ECGs, but their predictive value for the occurrence of malignant arrhythmias is yet to be established. Because body-surface potential mapping has been proved to be useful for the detection of heterogeneities in ventricular recovery even though they are not revealed by conventional 12-lead ECGs, we attempted to analyze repolarization potentials on the entire chest surface to find abnormalities that can be predictive of ventricular arrhythmias. Body-surface potential maps were recorded from 62 anterior and posterior thoracic leads in 22 patients affected by ARVD, 9 with episodes of sustained ventricular tachycardias (VT) and 13 without. Thirty-five healthy subjects were also studied as control subjects. The 62 chest ECGs were simultaneously recorded, digitally converted at a rate of 2000 Hz, and stored on a hard disk of a body-surface mapping computer system. In each subject, the QRST integral map was obtained by calculating at each lead point the algebraic sum of all instantaneous potentials, from the QRS onset to the T-wave end, multiplied by the sampling interval. In most ARVD patients, we observed a larger-than-normal area of negative values on the right anterior thorax. This abnormal pattern could be explained by a delayed repolarization of the right ventricle. Nevertheless, it was not related to the occurrence of VT in our patient population. To detect minor heterogeneities of ventricular repolarization, the principal component analysis was applied to the 62 ST-T waves recorded in each subject. We assumed that a low value of the first or of the first three components (components 1, 2, and 3) indicates a greater-than-normal variety of the ST-T waves, a likely expression of a more complex recovery process. The mean values of the first three components were not significantly different in ARVD patients and control subjects. Nevertheless, considering the two subsets of patients with and without VT, the values of component 1, components 1 + 2, and component 1 + 2 + 3 were significantly lower in the group of ARVD patients with VT. Values of component 1 < 69% (equal to 1 SD below the mean value for control subjects) were found in 6 of 9 VT patients and in 1 patient without VT (sensitivity, 67%; specificity, 92%). A low value of component 1 was the only variable significantly associated with the occurrence of VT. Principal component analysis provides a better quantitative assessment of the complexity of repolarization than other ECG measurements. When applied to ARVD patients, principal component analysis of the ST-T waves recorded from the entire chest surface revealed abnormalities not detected by conventional ECG that can be considered indexes of arrhythmia vulnerability.

Depletion of mitochondrial DNA in the liver of a patient with lactic acidemia and hypoketotic hypoglycemia

An infant with feeding difficulties, hypotonia, lactic acidemia, and severe hypoketotic hypoglycemia died at the age of 7 months of liver disease. Electron microscopy revealed abnormal mitochondria. Biochemical studies of mitochondrial enzymes in liver showed a decreased activity of complexes I, III, and IV. Mitochondrial DNA (mtDNA) content was reduced in liver 7% of the mean value in control subjects) and in muscle (50%). In kidney, brain, and heart, the mtDNA content was normal. The liver-specific mtDNA depletion syndrome in this patient manifested itself with features of both a respiratory chain defect and a mitochondrial fatty acid oxidation defect. Syndromes involving depletion of mtDNA can be diagnosed only when the activity of the respiratory chain enzymes and the content of mtDNA are investigated in the most affected tissues.

The pathophysiology of alveolar osteonecrosis of the jaw: Anticardiolipin antibodies, thrombophilia, and hypofibrinolysis

We studied 55 patients (50 women, 5 men) with severe facial pain and biopsy-proven neuralgia-inducing cavitational osteonecrosis (NICO) of the alveolar bone of the jaws. Our aim was to assess the pathophysiologic contributions to NICO of anticardiolipin antibodies (aCLA), thrombophilia (increased tendency to intravascular thrombi), and hypofibrinolysis (reduced ability to lyse thrombi). Of the 55 patients, 43 (78%) had one or more tests positive for thrombophilia or hypofibrinolysis (or both), and only 12 (22%) were normal. Eighteen of 55 (33%) patients had high aCLA (>2 SD above mean value for control subjects); immunoglobulin G (IgG) ( p = 0.01) and immunoglobulin A (IgA)( p = 0.001) levels were higher in patients than in controls. The distribution of elevated aCLA immunoglobulin classes among patients was as follows: IgG alone, 5 (9%); IgA alone, 7 (13%); and IgM alone, 3 (5%). Three patients (5%) had high levels of both IgG and IgA aCLA. Other defects of the thrombotic or fibrinolytic systems in the 55 patients included high lipoprotein(a) in 36% (vs 20% in control subjects ( p = 0.03)), low stimulated tissue plasminogen activator activity (tPA-Fx) in 22% (vs 7% in control subjects ( p = 0.08)), high plasminogen activator inhibitor activity (PAI-Fx) in 18% (vs 8% in control subjects ( p = 0.03)), resistance to activated protein C in 16% (vs 0% in control subjects ( p = 0.007)), low antigenic protein C in 4% (vs 0% in control subjects ( p > 0.2)), and low antigenic protein S in 4% (vs 0% in control subjects ( p > 0.2)). Anticardiolipin antibodies and other defects of the thrombotic and fibrinolytic systems appear to be common, potentially reversible pathogenetic risk factors associated with osteonecrosis of the jaw.

Bone Gla Protein and Sex Hormone-Binding Globulin in Nontoxic Goiter: Parameters for Metabolic Status at the Tissue Level

Several patients with nontoxic goiter have reduced serum TSH levels, as measured with new sensitive assays. Whether this is a sign of subclinical hyperthyroidism, thus having the potential of adverse effects on different organs with time, is not known. We have measured serum levels of 2 markers of thyrometabolic status at the tissue level, bone gamma-carboxyglutamic acid-containing protein (BGP), reflecting the function of osteoblasts, and sex hormone-binding globulin (SHBG), reflecting the function of hepatocytes, in 44 patients (41 women and 3 men) with nontoxic goiter (11 diffuse and 33 nodular goiters; serum T4, T3, free T4, and free T3 levels had been normal and stable for at least 0.5 yr). Serum TSH levels ranged from normal to unmeasurably low values (less than 0.05 mU/L). Serum TSH levels correlated negatively to serum BGP levels (r = -0.60; P less than 0.001). Due to the postmenopausal surge in serum BGP levels, premenopausal women (n = 21) were tested separately without changing the significance (r = -0.53; P less than 0.02). Expressing serum BGP values as a percentage of the mean value in control subjects of the same age and sex did not change the correlation (r = -0.63; P less than 0.001). Six patients had serum BGP levels above the normal range, and patients with reduced serum TSH levels (less than 0.45 mU/L; n = 12) had significantly enhanced serum BGP levels [median, 1.53 nmol/L (range, 1.02-4.24) vs. 1.23 nmol/L (0.62-3.71); P less than 0.05]. Serum TSH also correlated negatively to serum SHBG levels (r = -0.56; P less than 0.001; women alone: r = -0.58; P less than 0.001). Eight patients had serum SHBG levels above the normal range, and patients with reduced serum TSH levels had significantly enhanced serum SHBG levels, expressed as a percentage of the mean control value for the relevant sex [203% (range, 75-288) vs. 120% (42-317); P less than 0.01]. It is concluded that the lower serum TSH levels in patients with nontoxic goiter, the higher are serum BGP and SHBG levels. This suggests a progressively generalized (not only pituitary) tissue overexposure to thyroid hormones, the lower the serum TSH levels. Therefore, the finding of a reduced serum TSH level in patients with nontoxic goiter might reflect supraphysiological levels of T4 and/or T3, which could possibly be harmful.

Effect of gonadectomy on growth hormone, IGF-I and sex steroids in children with complete and incomplete androgen insensitivity.

IGF-I, testosterone and estradiol levels were evaluated in 8 girls with androgen insensitivity immediately before and from 1 to 3 months after bilateral gonadectomy. In 6 patients GH secretion was evaluated before and after gonadectomy by means of an arginine test and in 3 a sleep test was also performed. Mean IGF-I level before surgery was significantly higher than that of normal controls (2850 +/- 1230 vs 1680 +/- 1040 U/l, p less than 0.025). After gonadectomy a significant decrease was evident for testosterone, estradiol and IGF-I levels. A positive correlation between IGF-I and estradiol levels was present before surgery (p less than 0.005). The presence of a correlation with estradiol, but not with testosterone, and the knowledge that this syndrome is due to an insensitivity to androgens, but not to estradiol, support the hypothesis that the estradiol level is the major determinant for the control of IGF-I values in these patients. After gonadectomy, a substantial decrease of the 12-h nocturnal GH secretion was evident. Comparison of the nocturnal GH levels before surgery of the 3 patients with those of normal subjects of the same age showed hormonal values higher than 1 SD over the mean values of control subjects. Even if the number of patients studied is too small to draw any definitive conclusion, these data may suggest that sex hormones play a role in the control of IGF-I levels, a function which seems to be mediated through GH secretion.

115 EFFECT OF GONADECTOMY ON GROWTH FACTORS IN TESTICULAR FENINIZED CHILDREN

Sm-C increase during puberty or sex hormones treatment. Whether this increase is mediated by GH is still unclear. Children with testicular feminization submitted to gonadectomy provide a good model to assess the role of sex steroids on GH secretion. we evaluated Sm-C, T and E2 in 9 testicular feminized girls (mean age 11.6±1 yrs) immediately before and after gonadectomy. In 3 subjects GH release was evaluated by means of a sleep test. Hean Sm-C before surgery (2.85 UI ± 1.23) was significantly higher than that after gonadectomy (1.39±0.9, p<0.025) and than that of normal controls (n 83) (1.68±1.04, p<0.025). In all 3 patients the sleep test showed GH values higher before surgery by 1 SD over the mean value of control subjects and a GH decrease after gonadectomy (see table). Though the number of subjects studied is small, the fact that all showed the same Gil behaviour allows us to hypothesize that the higher Sm-C values before surgery, in spite of androgen insensitivity, are the expression of the high testosterone (or estradiol) levels oF these subjects and the Sm-C increase seems mediated through enhanced GH secretion.

Low A-esterase activity in serum of patients with fish-eye disease.

The activity of HDL-associated paraoxonase in the lipoprotein fraction of serum from two patients with fish-eye disease (FED) was only 11% of the mean value for control subjects. Similarly, concentrations of apolipoproteins A-I and A-II in the serum of FED subjects were only 10% of those in normal subjects. Thus the ratio of enzyme activity to A-I and A-II is virtually the same in these two groups of subjects. This suggests that paraoxonase activity of the lipoprotein fraction is associated with one or both of these apolipoproteins.

Sister chromatid exchange in lymphocytes from renal transplant recipients with and without cancer.

The frequency of sister chromatid exchange (SCE) was measured in peripheral blood lymphocytes from control, healthy subjects and immunosuppressed recipients of cadaveric donor kidneys with and without skin cancer. The mean SCE frequency in 43 control subjects was 9.2 per cell (range 5.4-12.3). In 30 transplant recipients with no history or evidence of cancer the mean SCE rate was 10.3 per cell (range 5.8-24.5); four (13%) of these patients had a mean SCE frequency outside the control range. In 7 transplant recipients with skin cancer, the mean SCE frequency was 14.3 per cell (range 9.1-19.9). This was significantly (P less than 0.01) higher than the mean value of control subjects. The mean SCE frequencies in 3 of these 7 patients fell within the control range and in 4 of these patients was above the control range. These results suggest that some immunosuppressed kidney transplant recipients are liable to chromosomal damage.

Plasma progesterone in normal subjects and patients with benign essential hypertension on normal, low, and high sodium intake.

Plasma progesterone determined by a protein-binding method was significantly higher (p < 0.001) in 27 patients with stable BEH (79.0 ± 56.0 sd ng/100 ml) than in 21 healthy subjects (35.0 ± 14 sd ng/100 ml). Four out of 11 patients with labile hyperkinetic BEH had markedly increased plasma progesterone. However, the mean (59.0 ± 54.0 sd ng/100 ml) was statistically not different (p < 0.1) from control. Sodium restriction induced a marked increase in plasma progesterone in seven (out of eight) control subjects and in six out of 13 patients with BEH. The remaining one control and seven hypertensive patients showed a blunted response. Plasma progesterone in two of the control subjects returned to normal after sodium loading. Plasma cortisol determined by a protein-binding method remained the same after sodium depletion in eight normal and 15 patients with BEH. When patients with BEH were kept on normal diet, 13 of 15 determinations were below the mean value for control subjects. From comparison of these find...