Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57

BackgroundTransient neonatal diabetes mellitus 1 (TNDM1) is a rare imprinting disorder characterized by intrautering growth retardation and diabetes mellitus usually presenting within the first six weeks of life and resolves by the age of 18 months. However, patients have an increased risk of developing diabetes mellitus type 2 later in life. Transient neonatal diabetes mellitus 1 is caused by overexpression of the maternally imprinted genes PLAGL1 and HYMAI on chromosome 6q24. One of the mechanisms leading to overexpression of the locus is hypomethylation of the maternal allele of PLAGL1 and HYMAI. A subset of patients with maternal hypomethylation at PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2 (PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57, a transcription factor involved in establishment and maintenance of methylation of imprinted loci. Our objective was to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers.MethodsGenome-wide DNA methylation analysis was performed on four individuals with homozygous or compound heterozygous ZFP57 mutations, three relatives with heterozygous ZFP57 mutations and five controls. Methylation status of selected regions showing aberrant methylation in the patients was verified using bisulfite-sequencing.ResultsWe found large variability among the patients concerning the number and identity of the differentially methylated regions, but more than 60 regions were aberrantly methylated in two or more patients and a novel region within PPP1R13L was found to be hypomethylated in all the patients. The hypomethylated regions in common between the patients are enriched for the ZFP57 DNA binding motif.ConclusionsWe have expanded the epimutational spectrum of TNDM1 associated with ZFP57 mutations and found one novel region within PPP1R13L which is hypomethylated in all TNDM1 patients included in this study. Functional studies of the locus might provide further insight into the etiology of the disease.<br/

Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia

Epidemiological studies have consistently shown elevated rates of breast cancer among female blood relatives of patients with ataxia telangiectasia (AT), a rare autosomal recessive disease. A large proportion of the members of AT families are carriers of AT-causing gene mutations in ATM (Ataxia Telangiectasia Mutated), and it has been hypothesised that these otherwise healthy carriers are predisposed to breast cancer. This is an extended and enlarged follow-up study of cancer incidence in blood relatives of 75 patients with verified AT in 66 Nordic families. Blood relatives were identified through population registry linkages, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. The ATM mutation carrier probabilities of relatives were assigned from the combined information on location in family, consanguinity, if any, and supplementary carrier screening in some families. Among the 1445 blood relatives of AT patients, 225 cancers were observed, with 170.4 expected, yielding a standardised incidence ratio (SIR) of 1.3 (95% confidence interval (CI), 1.1–1.4). Invasive breast cancer occurred in 34 female relatives (SIR, 1.7; 95% CI, 1.2–2.4) and was diagnosed in 21 women before the age of 55 years (SIR, 2.9; 95% CI, 1.8–4.5), including seven mothers of probands (SIR, 8.1; 95% CI, 3.3–17). When the group of mothers was excluded, no clear relationship was observed between the allocated mutation carrier probability of each family member and the extent of breast cancer risk. We concluded that the increased risk for female breast cancer seen in 66 Nordic AT families appeared to be restricted to women under the age of 55 years and was due mainly to a very high risk in the group of mothers. The findings of breast cancer risk in mothers, but not other likely mutation carriers, in this and other studies raises questions about the hypothesis of a simple causal relationship with ATM heterozygosity

A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system

BACKGROUND: This paper proposes a novel model for homeopathic remedy action on living systems. Research indicates that homeopathic remedies (a) contain measurable source and silica nanoparticles heterogeneously dispersed in colloidal solution; (b) act by modulating biological function of the allostatic stress response network (c) evoke biphasic actions on living systems via organism-dependent adaptive and endogenously amplified effects; (d) improve systemic resilience. DISCUSSION: The proposed active components of homeopathic remedies are nanoparticles of source substance in water-based colloidal solution, not bulk-form drugs. Nanoparticles have unique biological and physico-chemical properties, including increased catalytic reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum effects different from bulk-form materials. Trituration and/or liquid succussions during classical remedy preparation create “top-down” nanostructures. Plants can biosynthesize remedy-templated silica nanostructures. Nanoparticles stimulate hormesis, a beneficial low-dose adaptive response. Homeopathic remedies prescribed in low doses spaced intermittently over time act as biological signals that stimulate the organism’s allostatic biological stress response network, evoking nonlinear modulatory, self-organizing change. Potential mechanisms include time-dependent sensitization (TDS), a type of adaptive plasticity/metaplasticity involving progressive amplification of host responses, which reverse direction and oscillate at physiological limits. To mobilize hormesis and TDS, the remedy must be appraised as a salient, but low level, novel threat, stressor, or homeostatic disruption for the whole organism. Silica nanoparticles adsorb remedy source and amplify effects. Properly-timed remedy dosing elicits disease-primed compensatory reversal in direction of maladaptive dynamics of the allostatic network, thus promoting resilience and recovery from disease. SUMMARY: Homeopathic remedies are proposed as source nanoparticles that mobilize hormesis and time-dependent sensitization via non-pharmacological effects on specific biological adaptive and amplification mechanisms. The nanoparticle nature of remedies would distinguish them from conventional bulk drugs in structure, morphology, and functional properties. Outcomes would depend upon the ability of the organism to respond to the remedy as a novel stressor or heterotypic biological threat, initiating reversals of cumulative, cross-adapted biological maladaptations underlying disease in the allostatic stress response network. Systemic resilience would improve. This model provides a foundation for theory-driven research on the role of nanomaterials in living systems, mechanisms of homeopathic remedy actions and translational uses in nanomedicine

Segmentierung sprachlicher Information während der Entwicklung

The following study measured the processing of different phonemes in dependence on different gap durations between two consonant-vowel items. Event related potentials (ERPs) were recorded to a phoneme change occurring during the iterative presentation of /da-da/, occasionally interrupted by a stimulus /da-ba/. The pre-attentive detection of the change is measured by the difference between the ERPs of the frequently presented standard stimulus and the rarely presented deviant stimulus. The experiment was conducted during the first year of life to describe the maturation. The results showed that the phoneme change including a short gap can only be detected in the later maturational stadium, whereas a long gap is detected already in the age of four weeks. The greater mask effect in younger infants can be seen to be induced by a slower neural processing in early infancy.Der kontinuierliche Sprachschall setzt sich aus vielfältigen Variationen akustischer Parameter zusammen. Gemessen an der Vielzahl akustischer Merkmale ist nicht genau klar, woran sich das auditorische System orientiert, um eine Segmentierung und Identifizierung einzelner Wörter zu bewerkstelligen. Die Verarbeitung von akustischen Merkmalen der Sprache kann mit Hilfe von Ereignis Korrelierten Potenzialen (EKP) sichtbar gemacht werden. In der folgenden Studie wurde die Verarbeitung von Phonemkategorien in Abhängigkeit von unterschiedlich langen Silbengrenzen (50ms und 150 ms) im Alter von 4 Wochen, fünf Monaten und 13 Monaten getestet. Um die Detektion einer Phonemänderung zu messen wurde der Reiz /da-da/ iterativ präsentiert. Die so angelegte neuronale Gedächtnisspur soll durch eine Abweichung der Phonemkategorie /da-ba/ unterbrochen werden. Die prä-attentive Detektion zeigt sich erwiesenermaßen in der Differenz der EKP beider Reize (Näätänen, R. 1992).Die Ergebnisse zeigen, dass eine kurze Silbengrenze erst im Alter von 13 Monaten identifiziert wird. Die langsame Verarbeitung der ersten Silbe scheint hier die Verarbeitung der zweiten Silbe zu überlagern. Eine lange Silbengrenze vereinfacht die Verarbeitung und kann schon im Alter von 4 Wochen genutzt werden, um Silben zu segmentieren. Darüberhinaus zeigen die morphologischen Veränderungen anhand von Amplitude und Latenz eine deutliche Entwicklung des auditorischen Systems innerhalb des ersten Lebensjahres