Intravaginal contraception with the synthetic progestin, R2010

Four women used polysiloxane vaginal rings of core design containing 50 mg of norgestrienone (17 alpha-ethynyl-17 beta-hydroxy-estra-4,9,11,trien-3-one). The treatment was given in three-week cycles, leaving one treatment-free week between the cycles. The patterns of bleeding were registered and plasma norgestrienone (R2010), estradiol, progesterone, and gonadotropins were determined. Altogether twelve cycles were studied. The patterns of bleeding were unsatisfactory; only one subject had regular bleedings, and two of these were preceded by a luteal phase. The mean plasma concentration of norgestrienone (R2010) produced by the rings was 0.9 ng/ml. Ovulation was observed in 25% of cycles studied. Some follicular activity was present in every subject as judged by estradiol peaks. Excluding LH peaks in subjects who ovulated, mild pituitary suppression was achieved by this treatment. The only side-effect complained of was acne in one subject. The ring was regarded as easy to use.     

Effect of caries in mentally handicapped children of addition of fluoride and bicarbonate-phosphate to dietary sugar products.

Mentally handicapped children, aged 5--15 years and living in institutions, received fluoride supplement in several sugar products of their diet; in candies, marmalades, jams, fruit juices and in sweet desserts corresponding to 10 mg F as NaF per kg of the sugar (sucrose or glucose) of each product. To two of the four daily candies was also added a NaHCO3 + KH2PO4 mixture (mole ratio 9.8/l, resp.) to substitute for 2.5% of the sugar of the candy. The control children received the respective products without the additives. After stepwise exclusions of subjects for various reasons, e.g. for the absence of permanent teeth, low initial caries activity, strong medication, Down's syndrome, etc., the mean DMFS-increment in the remaining 43 control subjects was 4.5 and in the 41 test subjects 2.6 lesions/100 surfaces at risk, i.e. 42% reduction. Caries arrestment had occurred in these test subjects after the first year, while in the respective controls it was continuously increasing. Among numerous oral and body parameters studied, only surface enamel fluoride in primary teeth was increased by the fluoride supplements and urinary phosphate and calcium excretion decreased.     

Pituitary and gonadal function during the use of norgestrel-estradiol vaginal rings

Four women used polysiloxane contraceptive rings (CVR) impregnated with d-Norgestrel and estradiol for contraceptive purposes. The treatment was given in three-week cycles, leaving one treatment-free week between the cycles. Subjects were followed by blood sampling twice a week for three or four treatment cycles. Plasma concentrations of d-Norgestrel, estradiol, progesterone, and gonadotropins were determined by radioimmunoassay.The bleeding patterns were very acceptable. One subject experienced acne and weight gain, but no other side-effects were observed. Furthermore, no local irritation was found during the follow-up period of six or seven months.The individual variation in the mean plasma concentrations of d-norgestrel was between 3.2 and 1.1 ng/ml. Apart from one case, the highest individual levels were observed at the beginning of the first treatment cycle. Plasma estradiol was low during the treatment, but in some cases low post-insertion peaks were observed. No ovulatory progesterone values were found.Plasma LH was generally suppressed, but FSH was not. During the treatment-free week increasing concentrations of both LH and FSH were found, indicating an activation of pituitary function.     

Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights

Cardiac excitation-contraction coupling occurs by a calcium ion-mediated mechanism in which the signal of action potential is converted into Ca2+ influx into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2). RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+ release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and highly malignant, inherited disorder characterized by effort-induced ventricular arrhythmias in the absence of structural alterations of the heart. At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT. Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have proven to be of value in prevention of arrhythmias in CPVT patients, but occasional treatment failures call for alternative measures. There is great interest at present for the development of novel antiarrhythmic drugs for CPVT, as the same approaches may be applied for treatment of more common forms of life-threatening arrhythmias, such as those arising during ischemia and heart failure.     

Familial clustering of beta-cell autoimmunity in initially non-diabetic children

BACKGROUND: Type 1 diabetes is characterised by familial aggregation. We set out to explore whether beta-cell autoimmunity, which is considered to precede clinical disease, also shows familial clustering. METHODS: Tests for HLA DQB1 alleles (*02, *0301, *0302, *0602) and islet cell autoantibodies (ICA) were performed on 5836 children from 2283 families. When a child tested positive for ICA, all his/her previous or subsequent samples that were available were also tested for insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GADA) and antibodies to the IA-2 protein (IA-2A). RESULTS: Forty-four families were observed to have two or more children positive for at least ICA. This proportion (1.9%) was almost five times higher than expected (0.4%; p < 0.001). The frequency of multiple (>/=2) autoantibodies also showed familial aggregation, the observed proportion (0.39%) being three times that expected (0.13%; p < 0.001). In 72.7% of the families with at least two ICA-positive siblings, the children with autoantibodies had the same HLA DQB1 genotype. The median age difference between the ICA-positive children within the same family was 3.3 years (range 0.0-10.5 years), and the median time interval in the appearance of ICA within the family was 1.6 years (range 0.0-3.2). CONCLUSIONS: beta-cell autoimmunity, as defined by the appearance of ICA, demonstrates familial aggregation, although the antibodies do not appear in close temporal proximity or at an identical age within the same family. The HLA-DQB1 genotypes are more often identical in siblings with autoantibodies than in other siblings.     

Soluble adhesion molecules in young children with signs of beta-cell autoimmunity--prospective follow-up from birth

BACKGROUND: This study aimed at evaluating the relationship between the circulating concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and sL-selectin and the appearance of beta-cell autoimmunity, and at assessing whether these molecules could assist in the identification of environmental factors implicated in the immune process damaging the pancreatic beta-cells. METHODS: Serum levels of soluble adhesion molecules were measured with enzyme-linked immunosorbent assays over the first 2 years of life in 65 children seroconverting to positivity for autoantibodies and 65 control children, all with HLA-conferred susceptibility to type 1 diabetes (T1D). RESULTS: The total integrated concentrations of soluble adhesion molecules were comparable between the two groups. The autoantibody-positive children tended to have higher sL-selectin concentrations during the 3-month seroconversion (SC) period than did the control children during the corresponding period (P = 0.07), the difference being significant (P = 0.03) after excluding subjects with signs of a concurrent enterovirus infection. Autoantibody-positive children had higher concentrations of sL-selectin in the 3-month period when an enterovirus infection was detectable than did the control children (P = 0.018). No significant difference could, however, be seen after excluding the children with concomitant seroconversion to autoantibody positivity. CONCLUSIONS: Elevated concentrations of sL-selectin are temporally associated with seroconversion to autoantibody positivity suggesting that leukocyte activation might coincide with the appearance of beta-cell autoimmunity. Early-onset progressive beta-cell autoimmunity, on the other hand, is not reflected in overall increased concentrations of soluble adhesion molecules in the peripheral circulation during the first 2 years of life in children carrying increased HLA-conferred disease susceptibility. Enterovirus infections (EVIs) are not independently associated with increased circulating sL-selectin concentrations in young children with enhanced HLA-conferred susceptibility to T1D.     

Common candidate gene variants are associated with QT interval duration in the general population

Objectives. QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30–40% of the QT‐interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population‐based sample. Methods. We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI‐TOF mass spectrometry. ECG parameters were measured from digital 12‐lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. Results. The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT_Nc interval (P = 3.6 × 10^?11) in gender‐pooled analysis. In agreement with previous studies, we replicated the association with QT_Nc interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P = 4.7 × 10^?5], KCNH2 K897T [?2.6 ms (SE 0.5) or ?0.14 SD, P = 2.1 × 10^?7] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P = 3.2 × 10^?24] under additive models. Conclusions. We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age‐, gender‐ and heart rate‐adjusted QT interval and could thus modulate repolarization‐related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.     

Prevalence of early stages of chronic kidney disease in healthy army personnel

Introduction: Chronic kidney disease (CKD) is associated with significant morbidity and mortality. Screening and detection of early stages of CKD can help institute interventions that may delay the progression of the disease. One aim was to study the prevalence of early stages of CKD in the Army.Methods: A cross-sectional study ofArmy Personnel in an Army cantt in Central India was carried out. All participants filled a structured questionnaire and anthropometric data was collected. Investigative profile included routine urine exam, semi-quantitative microalbuminuria (MAU), serum creatinine, lipid profile and fasting blood glucose. Glomerular Filteration rate (eGFR) was calculated using the Modification of Diet in Renal Diseases (MDRD) study equation.Result: A total of 1920 subjects were examined with 731 (38.07%) from Arms and 1189 (6I.93%) from Services. 348 were excluded and of the remaining 1572 subjects, 141 (8.97%) had MAU and 157 (9.99%) had deranged Albumin Creatinine Ratio (ACR). Mean eGFR by MDRD equation was 102 ± 25.84 ml/min/1.73m². Early CKD was seen in 150 (9.54%) with 84 (5.34%) in stage I CKD, 55 (3.5%) in stage II and 11 (0.7%) in stage III. Multiple logistic regression showed BMI > 23, the presence of DM and HTN were independent risk factors for CKD.Conclusion: 9.54 % of healthy army personnel were found to have early stages of CKD. Institution of screening programs can result in early detection of CKD.