2020 ESC Guidelines on acute coronary syndrome without ST-segment elevation : Recommendations and critical appraisal from the Dutch ACS and Interventional Cardiology working groups.

Recently, the European Society of Cardiology (ESC) has updated its guidelines for the management of patients with acute coronary syndrome (ACS) without ST-segment elevation. The current consensus document of the Dutch ACS working group and the Working Group of Interventional Cardiology of the Netherlands Society of Cardiology aims to put the 2020 ESC Guidelines into the Dutch perspective and to provide practical recommendations for Dutch cardiologists, focusing on antiplatelet therapy, risk assessment and criteria for invasive strategy.

What Social, Program, and Behavioral Factors Influence the Healthy Eating Index for EFNEP and SNAP-Ed Adult Participants?

The main objectives of this article were to determine the demographic factors, the program related factors and the behavioral factors that influence Michigan Expanded Food and Nutrition Education Program and Supplemental Nutrition Assistance Program-Education outcomes. Secondarily, we sought to understand the trends and changes in Healthy Eating Index (HEI) scores across the differing baseline score groups. The data were collected by nutrition instructors in a pretest, posttest design to capture change in healthy eating habits through changes in HEI scores. The participants were all low-income program participants during the years of 2011 and 2012, living in Michigan. Findings show that eating habits improved most in households with weekly per-person income within $100 to $500, and with Caucasian females living in cities or suburbs. Improvements were also greater with those who took part in the Expanded Food and Nutrition Education Program, where the participants exhibited higher baseline frequency of planning meals before grocery shopping, comparing prices, and budgeting enough money for food and food related purchases. Overall, the average change in HEI scores increased by 2.3 points, however, the variability between the participants' changes was high, suggesting that more targeted program lessons might increase program efficacy, especially for those participants with high baseline HEI scores.

Follow-up of patients with interventional closure of ventricular septal defects with Amplatzer Duct Occluder II.

Nonsurgical closure of congenital ventricular septal defects (VSD) has become increasingly acceptable with the availability of different occlusion systems. Transcatheter device treatment is used for perimembranous and muscular defects. Atrio-ventricular block remains the most troublesome complication of device closure. The aim of this study was to describe our experience with closure of VSD using the Amplatzer Duct Occluder II (ADO II) as an "off-label" approach in children and adults. Between 2004 and 2012 transcatheter closure of 31 VSD (20 perimembranous, 10 muscular VSD and 1 ruptured sinus valsalva) with ADO II was undertaken in patients between 3 months and 55 years of age and with a body weight ranging from 4 to 105 kg in our institution. In 29 of 31 procedures, the defect was successfully closed (93.5%) without any significant complications. No increase of aortic or tricuspid valve regurgitation was found in any after procedure. Small residual shunts were observed immediately after the device implantation, but disappeared during a median follow-up period of 38 months (0.4-63) in 27 of 31 patients. There was no incidence of AV block or other conductance abnormalities during implantation or follow-up. The ADO II device is safe and effective for transcatheter VSD closure, but this is still an "off-label" use. After long-term follow-up in a large number of patients this device may be approved for VSD closure in the future.

Testosterone stimulates growth of tibial epiphyseal growth plate and insulin-like growth factor-1 receptor abundance in hypophysectomized and castrated rats.

Puberty is associated with an increase in the plasma concentration of sex steroids, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Gonadal steroid hormones are important for the normal pubertal growth spurt and skeletal growth. The mechanism by which gonadal steroids induces skeletal growth is still not fully understood. To study the GH-independent effect of testosterone on growth, we investigated the effect of testosterone injections on the tibial epiphyseal growth plate (EGP) in an in vivo model of hypophysectomized and castrated male rats. Four groups (six animals each) of 28-d-old male rats were studied. Groups A, B, and C were hypophysectomized and castrated and received 500 microg/(kg x d) of hydrocortisone and 15 microg/(kg x d) of levothyroxine sodium. Groups A and B were also treated with daily sc injections of 10 microg of testosterone/100 g of body wt and 100 microg of testosterone/100 g of body wt, respectively, for 7 d. Group C was injected with vehicle alone. Group D were intact animals injected with saline (controls). Animals were sacrificed on 8 d. As expected, serum GH levels were found to be very low (1.13+/-0.1 ng/mL) in the hypophysectomized animals (group C, hypopit), and testosterone treatment did not change them significantly. Serum IGF-1 decreased from 502.9+/-13 ng/mL in group D to 167+/-41.4 ng/mL in group C (p < 0.001). Testosterone therapy had no stimulatory effect on serum IGF-1 levels in the hypopit + low-dose group (A) (220+/-94.8 ng/mL) and had an inhibitory effect in the hypopit + high-dose group (B) (39.3+/-17.5). Histomorphometric determinations demonstrated an EGP width of 472.3+/-39 microm in the intact animals but only 336.9+/-1.6 microm in the hypopit group (C) (p < 0.01). High-dose testosterone treatment (group B) significantly increased the EGP width (to 438.8+/-27.8), (p < 0.001), whereas low-dose testosterone (group A) did not. Immunohistochemistry studies revealed that the levels of IGF-1 in the EGP of the control animals were almost negligible and that testosterone did not change them. However, testosterone increased in a dose-dependent manner the abundance of IGF-1 receptor EGP. We conclude that testosterone has a direct, local, GH-independent effect on the EGP growth and IGF-1 receptor abundance.

Neonatal pig islets induce a lower T-cell response than adult pig islets in IDDM patients.

BACKGROUND: Pancreatic pig islets may provide a substitute in the future for difficult to obtain human islets for transplantation in insulin-dependent diabetes millitus (IDDM) patients. However, the immune response to xenografts may significantly hamper this approach. Because neonatal tissue is believed to be less immunogenic, we examined whether the T-cell response to neonatal pig islets differs from the response to adult islets. METHODS: The T-cell proliferative response to different concentrations of sonicated neonatal and adult pig islets, as well as to insulin and mitogens, was tested in 21 recent onset IDDM patients and 21 healthy controls. We determined the presence of various circulating islet autoantibodies and their association with the T-cell response in IDDM patients. RESULTS: In the IDDM patients, sonicated adult pig islets (at 1 microg protein/ml) induced a significantly higher frequency (12 of 21 vs. 1 of 21, p<0.001) and magnitude (2.58+/-0.44 vs. 1.38+/-0.13, p<0.02) of positive T-cell responses than neonatal islets at the same concentration. Similar results were obtained with a 10-fold higher concentration of islet sonicate. There was no significant association between the individual T-cell responses and the presence of circulating autoantibodies in IDDM patients. CONCLUSION: These results indicate that neonatal pig islets induce a lower T-cell reactivity than adult islets, suggesting that the neonatal tissue may be immunologically more suitable for future islet xenotransplantation.

Induction of the hsp70 Gene Promoter by Various Anticancer Drugs.

HeLa cells containing the chloramphenicol acetyl transferase (CAT) gene under the control of the hsp70 promoter have been exposed in vitro to various anticancer drugs. Cisplatin induced CAT production with a dose-effect relationship at a non-cytotoxic dose, whereas no induction was detected with carboplatin. Etoposid induced a significant response at a cytotoxic concentration. The limited positive response with doxorubicin, daunomycin and mitoxantrone was not statistically significant. These chemicals are known to produce reactive oxygen species and induce apoptosis. No induction of the hsp70 promoter could be detected with the other cytostatic compounds that have been tested such as base analogues (5-fluorouracil, cytosine arabinoside 3'-MP), inhibitors of DNA synthesis (amethopterin, aminopterin), antimitotics (vinblastine, colchicine), and alkylating (streptozotocine, carboplatin, melphalan) or intercalating agents (bleomycin). In addition, the role of the transcription inhibitory activity of doxorubicin in this model is evidenced and the consequent question of the suitability of the reporter gene system is discussed. Our results suggest that specific genotoxic compounds are not able to induce the hsp70 promoter, and are in agreement with the concept that stimulation of HSP70 synthesis occurs through a biochemical process involving proteotoxicity.

D-penicillamine-induced pancreatic islet autoantibody production is independent of the immunogenetic background: a lesson from patients with Wilson's disease.

D-penicillamine (d-PA) was reported to induce various immunological abnormalities including production of autoantibodies to insulin. These abnormalities were mainly described in patients with primary immunological disorders such as rheumatoid arthritis. In order to clarify whether d-PA-induced immune disorders are restricted to patients genetically prone to develop autoimmune diseases or to a direct drug effect, we tested for the presence of various autoantibodies and for molecular HLA typing in 17 patients with Wilson's disease treated with this drug. In 2/17 patients, low-titer (10 JDFU) circulating islet cell autoantibodies (ICA) were detected, while another patient was positive for the presence of insulin autoantibodies. None of the sera tested showed reactivity for glutamic acid decarboxylase or ICA512. Five of twelve patients were positive for anti-single-stranded DNA autoantibody. Molecular HLA typing of the autoantibody-positive subjects showed that they carry HLA haplotypes not associated with insulin-dependent diabetes. The insulin response to intravenous glucose tolerance test in two patients with autoantibodies was found to be normal. A second blood testing of the autoantibody-positive patients 5 months following initial evaluation revealed conversion to negativity in all three. Our results suggest that d-PA-induced autoantibodies in patients with Wilson's disease are independent of the immunogenetic background characteristics of diabetes.

HLA class II immunogenetics of IDDM in Yemenite Jews.

The association between HLA-DR and DQ and insulin dependent diabetes mellitus (IDDM) was analyzed in 47 patients and 76 controls of Yemenite Jewish origin. The IDDM susceptibility alleles DRB1*03011, DQA1*0501, DQB1*02 and DRB1*0402, DQA1*0301, DQB1*0302 found in Caucasians had a very strong predisposing effect also in the Yemenite IDDM group. The DRB1*07, DQA1*0201 and DQB1*02 alleles were found to have a strong negative association with IDDM. None of the patients carried DRB1*07 and DQA1*0201 compared with healthy controls (43.7%). Our analysis revealed that the DRB1*03011 DQA1*0501 DQB1*02/DRB1*04 DQA1*03 DQB1*0302 heterozygous genotype confers the highest susceptibility (59.6% in patients vs. 0% in controls). The homozygous DRB1*03 and DRB1*04 genotypes were also found to be positively associated with the disease. 81% of the patients compared to 1.3% of controls carried the susceptibility alleles on both haplotypes. In conclusion, the development of IDDM in Yemenite Jews is strongly dependent on the presence of the susceptibility HLA alleles and on the absence of the DRB1*07 haplotype. The Yemenite Jewish group is uniquely homogenous with regard to genetic susceptibility factors involved in the process of IDDM, and may thus be an ideal model for further genetic studies.

[Islet autoantibody assays in type I diabetes: superiority of passage from use of ICA to traditional tests].

Islet cell antibodies (ICA) continue to serve as the basis of the principal serological test for definition of active autoimmunity of beta-cells. Its disadvantages are the need for human pancreatic tissue and difficulty in obtaining quantitative results. In the past decade biochemically-defined beta-cell antigens were described, leading to the development of sensitive and specific autoantibody assays, to predict insulin-dependent diabetes mellitus (IDDM). We examined the value of combined biochemically-based serological assays, such as autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and ICA512 (ICA512A) to replace the traditional ICA assay. Blood samples of 114 newly diagnosed IDDM patients, aged 12 +/- 5 yrs (range 2 months-29 years) were tested for ICA (indirect immunofluorescence), IAA, GADA and ICA512A (radiobinding assay). The latter 2 assays were performed using recombinant human [35S]-labeled antigen produced by in vitro transcription/translation. We found that fewer sera scored positive for ICA and/or IAA (80.7%, 92/114) than for 1 or more of IAA, GAD, or ICA512 (88.6%, 101/114). We conclude that combined testing for IAA, GAD and ICA512 can replace the traditional ICA/IAA test to predict IDDM and is helpful in the differential diagnosis of insulin-dependent and noninsulin-dependent diabetes.

Mathematical formulae for the prediction of the residual beta cell function during the first two years of disease in children and adolescents with insulin-dependent diabetes mellitus.

On the basis of a retrospective study of 71 children followed for 24 months after diagnosis of type I insulin dependent diabetes a fitted mathematical model was constructed for the prediction of the course of beta cell function from the time of diagnosis. Two equations were derived, one for the maximal basal (B-max) and the other for the maximal i.v. glucagon stimulated peak C-peptide (P-max) levels reached during the remission period. The prognostic variables selected for analysis were: peak C-peptide levels at diagnosis (Po), age sex, degree of obesity, pubertal rating, the presence of islet cell antibodies (ICA) and levels of GHb. Multivariate analysis of the data showed that Po (p = 0.0006), puberty (p = 0.041). obesity (p = 0.0021), sex (p = 0.031), ICA (p = 0.0045) and GHb(p = 0.0066) significantly contributed to the prediction formula obtained for B-max whereas the contribution of the above variables for P-max were: Po (p = 0.0019), puberty (p = 0.0187), obesity (p = 0.0058), sex (p = 0.0598), ICA (p = 0.0187) and GHb (p = 0.0027). The residuals of the observed values from the values fitted by the predicted equations served to define two separate groups demonstrating distinct differences in the natural course of beta cell function in type I diabetes. This fitted model may thus be useful in distinguishing between newly diagnosed young patients who will undergo remission, requiring lower insulin doses, and those who have little chance for remission. It might also be helpful in the selection of patients most likely to benefit from immunosuppression or modulation, to maximize the benefit to risk ratio for such patients.

Insulin antibody assay: a statistical evaluation of sensitivity, precision and reproducibility in healthy subjects.

Eighty-seven sera from healthy non-diabetic subjects, negative for islet cell antibodies, were analysed for 125I-insulin serum binding capacity by a commercial radioimmunoassay. In order to define the detection limit of the assay for insulin antibodies we used the corrected binding capacity to 125I-insulin of the normal sera obtained by competitive inhibition with excess of unlabelled insulin. To test the reproducibility of the results as a function of the tracer decay the sera were re-examined after intervals of 17 and 37 days, when a drift of more than 1% was found in the period investigated. Using the corrected bindings improved reproducibility considerably. The extra variation between the three assays, taking into account the decay of the tracer, was negligible. The main component of error contributing to these variations among individuals was found to be the precision, defined as the mean standard deviation among the replicates, which is SD(c) = 0.325%. We conclude that this assay is suitable for the screening of positive insulin autoantibodies in pre-diabetic subjects, and recommend that the estimate of precision from the replicates with excess insulin be used and that the detection limit be set at three times the estimated SD(c).

Elevated serum placental isoferritin in newly diagnosed type 1 (insulin-dependent) diabetes mellitus. A possible marker for identification of high risk subjects.

Placental isoferritin is produced by activated T lymphocytes and may, therefore, be considered as a manifestation of T cell involvement. Placental isoferritin is measured using CM-H-9 monoclonal antibody which binds exclusively to placental isoferritin. Placental isoferritin has been determined in the serum of 80 patients with Type I (insulin-dependent) diabetes mellitus, 100 healthy first degree relatives and 81 healthy children. Serum levels which were measured in Type 1 diabetic patients, (24.0-140 U/ml; median and range) were significantly higher than those of family members (0,0-73; median and range; p less than 0.0001) and normal control subjects (0,0-48; median and range; p less than 0.0001). Using 0-10 U/ml as the upper limit of normal, it was found that 31 of 50 (62%) of Type 1 diabetic patients, 25 of 100 (25%) family members and 7 of 81 (8.6%) healthy control subjects had abnormal placental isoferritin levels. Islet cell antibodies were positive in 31 of 44 tested diabetic patients and, in 8 of 71 tested family members, and among them 54.8% and 50% respectively also had elevated placental isoferritin levels. However, no statistically significant correlation was found between islet cell antibodies and placental isoferritin levels. Treatment of Type 1 diabetic patients with insulin was accompanied by a significant decrease (p less than 0.002) of serum placental isoferritin within 2-4 weeks of treatment. It is noteworthy that placental isoferritin was below detection in 34 of 35 Type 2 (non-insulin-dependent) diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of short-term estrogen replacement therapy (ERT) on the blood pressure and daily urinary catecholamine excretion in a small group of post-menopausal women.

The blood pressure and daily urinary catecholamine excretion were examined in nineteen non-smoking post-menopausal women, receiving estrogen replacement therapy for a period of 4 months. The estrogens administered consisted of 17 beta-estradiol combined with estriol and norethisterone acetate administered sequentially (Trisequens, Novo, Denmark). Before the institution of treatment, the blood pressure and urinary catecholamine excretion were normal. After a period of 4 months, no change in blood pressure was observed. However, a marked and significant increase in daily urinary catecholamine excretion was noticed (72.3 +/- 18.96 micrograms/day to 102.0 +/- 26.0 micrograms: p less than 0.01). The pathogenetic implications of this increase are discussed.

Trends in urolithiasis in various ethnic groups and by age, in Israel.

A survey of upper urinary tract stone composition was carried out over 8 years (1974-1982) in 1147 patients, following a previous survey (1966-1974). Trends in the development of stone formation were found. The most obvious differences were fewer pure calcium oxalate (0.75 versus 5.50%) and uric acid stones (6.11 versus 13.30%) and more mixed stones than in our previous study. In most ethnic groups urinary stones were composed of calcium oxalate/calcium phosphate. A higher prevalence of stones in Israeli-born Jews was noted, in comparison with our previous survey. Age group analysis showed this increase to be limited to the 21-50-year-old group, in contradistinction to a clear decrease in stone formation in Israeli-born Arabs and Jews under the age of 20 years.

Cytoplasmic islet cell antibodies in type I diabetics in Israel and their first-degree relatives.

The prevalence of islet cell antibodies (ICA) was studied in 172 newly diagnosed juveniles with Type I diabetes and in 300 unaffected first-degree relatives of 93 of these patients. Approximately 60% of the juvenile diabetics were ICA-positive at onset. Most of these patients gradually lost their antibodies, although two patients remained positive for ICA for periods up to 5 years. Complement-fixing ICA (CF-ICA) were found in 20% of the patients having ICA at onset. Disappearance of CF-ICA was rapid, with all patients showing negative values by the end of the second year. In 19 patients ICA intermittently disappeared and reappeared. ICA were found in 17 healthy family members (7 parents and 10 siblings). Although Type I diabetes is relatively rare in both the Jewish and Arab populations in Israel, these findings indicate that it has a similar autoimmune pathogenesis to that found in other populations around the world. The percentage of patients with ICA was as reported elsewhere, but that of CF-ICA was lower; its similarity with that reported for a Mediterranean population in France suggests a possible link with ethnic origin.

Delayed puberty and hypoplastic uterus associated with hyperprolactinemia: successful treatment with bromocriptine.

A 15-year-old girl referred because of primary amenorrhea was found to have a hypoplastic uterus and persistent hyperprolactinemia (72-110 ng/ml). The gonadotrophin-dependent pubertal signs, i.e. breast and vulvar development, were significantly retarded (Tanner stage 2-3) while sexual hair was well developed; bone age was 13 years. The endocrinological evaluation revealed gonadotrophin secretion (LH-basal: 0.85-1.25; peak after LH-RH: 10.4 mIU/ml; FSH-basal: 1.63-2.5; peak: 8.2 mIU/ml) and E2 levels (26-68 pg/ml) which were appropriate for Tanner stage 3. The high basal levels of PRL were nonresponsive to either stimulatory (TRH) or inhibitory (nomifensine) agents. CT scan of the brain suggested the presence of a pituitary microadenoma. Following therapy with bromocriptine (2.5 mg/day) plasma PRL levels dropped to normal (5-6.8 ng/ml) with an accompanying catch-up of pubertal development and linear growth and a marked increase in size of the uterus as documented by repeated ultrasonographic examinations. Menarche occurred 5 months after initiation of therapy, followed by regular menses thereafter. Repeated CT scan of the brain showed a decrease in the density and size of the still persisting lesion. This patient demonstrates that hyperprolactinemia can cause delayed puberty with a particular inhibitory effect on uterine growth and development.

Unusual association of insulin-dependent diabetes mellitus with congenital myasthenia gravis and autoimmune thyroid disease.

A 26-year-old woman with congenital myasthenia gravis and antibodies to the acetylcholine receptor developed overt insulin-dependent diabetes with positive islet cell antibodies and thyroid microsomal and gastric parietal cell antibodies. Her younger sister has been an insulin-dependent diabetic since the age of 7 years, and the mother has nongoitrous hypothyroidism. In the same period the woman in question developed a transient chemical hyperthyroidism. HLA typing of the family members showed that the diabetes was probably associated with an HLA AW30, BW38, DR4 haplotype, found in both sisters and in their father, and that the thyroid disease was associated with the A29, B7, DR6 haplotype found in the patient and in her mother. This familial HLA pattern may indicate that each autoimmune manifestation in the patient is due to a different susceptible gene associated with the HLA system.