Cell type-specific interpretation of noncoding variants using deep learning-based methods.

Interpretation of noncoding genomic variants is one of the most important challenges in human genetics. Machine learning methods have emerged recently as a powerful tool to solve this problem. State-of-the-art approaches allow prediction of transcriptional and epigenetic effects caused by noncoding mutations. However, these approaches require specific experimental data for training and cannot generalize across cell types where required features were not experimentally measured. We show here that available epigenetic characteristics of human cell types are extremely sparse, limiting those approaches that rely on specific epigenetic input. We propose a new neural network architecture, DeepCT, which can learn complex interconnections of epigenetic features and infer unmeasured data from any available input. Furthermore, we show that DeepCT can learn cell type-specific properties, build biologically meaningful vector representations of cell types, and utilize these representations to generate cell type-specific predictions of the effects of noncoding variations in the human genome.

Morphotype analysis of the sibling vole (Microtus rossiaemeridionalis) casually introduced to the Russian Far East.

Here, we present the morphotypic variety of the m1 and M3 teeth diagnostics for the recently formed isolated population of the sibling vole in Far Eastern Russia. In the Far Eastern population, the prevalence of the individuals with m1 with a complicated crown of the forward unpaired loop of the paraconid is characteristic. Namely, m1 in these individuals shows well-expressed sixth exterior and fifth interior salient angles. The structure of the M3 morphotypes is also unique in the sibling voles in Far Eastern Russia. The dominant morphotypes were typica (47 %) and simplex (45 %), whereas the abundance of the duplicata morphotype was 0.08 %. The frequencies of various m1 and M3 morphotypes found in casually introduced sibling voles in the Far East are not typical of any previously studied Microtus rossiaemeridionalis population.

Combined PCR-DGGE fingerprinting and quantitative-PCR indicates shifts in fecal population sizes and diversity of Bacteroides, bifidobacteria and Clostridium cluster IV in institutionalized elderly.

AIMS: This study aimed at determining ageing-related shifts in diversity and composition of key members of the fecal microbiota by comparing institutionalized elderly (n = 17, 78-94 years) and young volunteers (n = 17, 18-31 years). METHODS AND RESULTS: A combination of molecular methods was used to characterize the diversity and relative abundance of total gastro-intestinal flora, along with relevant subsets within the genera Bacteroides, bifidobacteria and Clostridium cluster IV. The institutionalized elderly harbored significantly higher numbers of Bacteroides cells than control (28.5 +/- 8.6%; 21.4 +/- 7.7%; p = 0.016) but contained less bifidobacteria (1.3 +/- 0.9, 2.7 +/- 3.2%, p = 0.026) and Clostridium cluster IV (26.9 +/- 11.7%, 36.36 +/- 11.26%, p = 0.036). The elderly also displayed less total Bacteria diversity and less diversity with the Clostridium cluster IV (p < 0.016) and Bacteroides. CONCLUSION: Despite high individual variations, our analyses indicate the composition of microbiota in the elderly comprises a less diverse subset of young healthy microbiota. SIGNIFICANCE AND IMPACT OF THE STUDY: A better understanding of the individual composition of the human microbiota and the effects of ageing might result in the development of specifically targeted supplementation for elderly citizens in order to support healthy ageing.

Vegetarian diet affects genes of oxidative metabolism and collagen synthesis.

BACKGROUND/AIM: A vegetarian diet is known to prevent a series of diseases but may influence the balance of carbohydrate and fat metabolism as well as collagen synthesis. This study compares expression patterns of relevant genes in oral mucosa of omnivores and vegetarians. METHODS: Quantitative reverse transcriptase polymerase chain reaction was applied for analysis of mRNA levels from carnitine transporter OCTN2, hepatic CPT1A and nonhepatic CPT1B isoforms of carnitine palmitoyltransferase and collagen (CCOL2A1) in oral mucosa. RESULTS: Compared with volunteers with traditional eating habits, carbohydrate consumption was significantly higher (+22%) in vegetarians. This was associated with a significant stimulation of CPT1A (+50%) and OCTN2 (+10%) and a lowered collagen synthesis (-10%). CONCLUSION: These novel findings provide further insight into the association of a changed fat metabolism and reduced collagen synthesis in vegetarians, which could also play a role in the aging process.

[Trans-cultural geriatrics: an incipient challenge]. / Transkulturelle Geriatrie: eine herannahende Herausforderung.

Besides extended life expectancy, the globalization, increased mobility and migration are additionally influencing the structural change of the society. Thereafter, the problem of multiculturalism, as known within the school system, will soon also become relevant in the geriatrics. Thus, being in a foreign country as an elderly person can aggravate the common geriatric problem of isolation. Because of better communication, compliance as well as better quality of life, one should strive for empathy between physician and patient. This requires the physician's sensibility for individual aspects of the patient's history, as well as knowledge, or at least a readiness for learning more about other cultures, religions and traditions. Specifically, fundamental aspects of Islam, Eastern Christianity, Judaism and Far-East religious and cultural understanding are presented.

[Why should Byzantium be considered as a cradle of clinical geriatrics?]. / Warum kann ausgerechnet Byzanz als Wiege der klinischen Geriatrie betrachtet werden?

Generally, roots of today's medical ethics are thought to have sprouted from antiquity and from classical Hebraic consciousness, while the origin of hospital medicine and institutional nursing of the elderly was assumed in Middle Age and in modern times, respectively. But even between these two periods, notably in Byzantium (324-1453) there were many famous physicians working with surprising skills in many disciplines such as surgery and ophthalmology. The most important achievement of that time, however, was in public health care. Following the Christian ideal of philanthropy, numerous hospitals (nosokomeia), hospices (xenodocheia) and asylums for the elderly (gerokomeia) of a remarkable organisation and professionalism were founded in many cities of the Byzantine Empire. Concerning the elderly patients, interesting findings were obtained concerning ageing process (eschatogeria), geriatric symptoms, multimorbidity, marasm and typically occurring diseases. Interesting approaches were realized with regard to the nursing care, diet and recommended life style for the elderly. By the end of the Byzantium Empire in 1453 and due to the different cultural development in the West, which was sometimes marked by conflicts between church and science and by the regulations of medicine, the knowledge about the Byzantine health care was almost lost. It survived, however, only in hospitals of occidental monastic orders, which brought their experience from East-Mediterranean area. Their hospitals were than a base for modern health care and for geriatrics.

[Limits and relevance of the laboratory diagnosis of malnutrition in the elderly]. / Grenzen und Bedeutung der Labordiagnostik bei Mangelernährung im Alter.

Despite the widespread interest in malnutrition in the elderly, the utility of laboratory tests is limited. This is because their diagnostic significance can be impaired by undercurrent diseases, pre-analytical effects and unsatisfactory standardization. This survey summarizes the most important parameters of malnutrition. Thus, "nitrogen balance" is considered the golden standard of nutrition status, while the diagnostic significance of serum proteins depends on their biological half-time. Albumin is seen as the most reliable malnutrition marker, but cholinesterase and cholesterol-decrease must also be mentioned. The so-called "low-T3-phenomenon" which is caused by the production of "reverse T3", seems to be the unique parameter for the "catabolic" state of metabolism. Of special interest are also prognostic markers of mortality, such as orosomucoid. Cytokines, other signal peptides, trace elements and vitamins are from the diagnostic point of view of rather limited significance. In sum, the diagnosis and monitoring of malnutrition in the elderly represents an important challenge for laboratory medicine.

Laboratory diagnosis and geriatrics: more than just reference intervals for the elderly...

As he/she approaches the end of life, the healthy elderly person comes to be seen rather as a "biological curiosity" than as a normal case. For laboratory testing it becomes increasingly difficult to determine appropriately stratified and statistically relevant reference groups. More appropriate would be individual monitoring, which, however, requires long-term stable quality in laboratory analyses. Despite "consolidation" in laboratory medicine, the pre-analytical phase, which is especially important in the elderly, remains underestimated. This problem is aggravated by insufficient harmonisation between laboratory tests, especially when point-of-care testing is included. Since in geriatrics, maintenance of life quality is more important than curative therapy, clinicians are forced to undergo therapeutic compromises applying symptomatic, supportive or palliative therapies. In this situation, information on "still remaining functional capacities" of organs is particularly helpful. Diagnostic problems resulting from underestimation of "multi-morbidity" and especially "multi-aetiology" can be complicated by "degradation of clinical information", especially in patients in cognitive and/or physical decline. The specific purpose of "geriatric" laboratory medicine seems to induce a change of paradigms: not only statistically established "evidence", but "individuality" in a single patient will need more profound insight. Not so much differentiation between "physiology" and "pathology", but the consideration of "clinical individuality" as relative risk in dimension of time is of importance.

Soluble transferrin receptor and iron status in elderly patients.

The measurement of soluble transferrin receptor (sTfR) has been proposed as a novel approach to the diagnosis of iron deficiency, especially in anaemia of chronic diseases (ACD). Our aim was to study the utility of sTfR under 'everyday conditions' as seen in a geriatric hospital in the following groups of patients: First, in a pilot group of 99 multimorbid geriatric patients (85 women, 14 men; 82.00 +/- 6.32 years) admitted for rehabilitation after recent surgical treatment of a bone fracture; second, in 677 geriatric patients (506 women, 171 men; 79.17 +/- 11.47 years) with different diagnoses admitted to a department of internal medicine; third, in some remarkable clinical cases in order to illustrate the diagnostic limits of sTfR. In general, both genders showed a remarkable age-dependent decrease in erythropoiesis. In patients with haemoglobin levels below 12.0 mg/dL, this parameter correlated significantly with sTfR. However, this was seen only in women, not in men. Moreover, an age-dependent increase in sTfR was seen in women, while in men it remained almost constant. Based on these findings, we conclude that there is a different, gender-specific aetiology of iron deficiency in the elderly. About 30% of patients of both genders simultaneously had low haemoglobin levels and low sTfR. This was interpreted as 'adaptation' or 'tolerance' to the iron deficiency. This was illustrated by a clinical case of megaloblastic anaemia: Initially low sTfR rose only during the vitamin B12 substitution and normalized after recovery. We conclude that sTfR provides an insight into the 'dynamics' of iron metabolism: A rise in sTfR indicates an 'acute readiness to refill iron stores', while a low (non-stimulated) sTfR level corresponds to the quite frequent adaptation to iron deficiency and/or inhibition of resorption. Finally, extremely high sTfR levels were observed in some cases of malignancy such as in acute leukaemia and in hypernephroma. Thus, increased sTfR levels can be caused by paraneoplastic effects.

Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes.

Changes in key enzymes of oxidative metabolism at the mitochondrial level are known to be associated with the aging process, apoptosis, and many diseases. Considering the risk of acquiring a myelodysplastic syndrome (MDS) with age, the aim of this study was to quantify mRNA synthesis of the carnitine palmitoyltransferases (CPT1 and CPT2), carnitine acetyltransferase (CRAT), human specific microsomal CPT, and OCTN2 (organic cation transporter) in mononuclear cells of healthy humans of different age groups and MDS patients. Using quantitative reverse transcriptase real-time PCR we compared mRNA synthesis of the above mentioned enzymes in mononuclear cells from peripheral blood of 23 healthy persons (mean age 45 years), 9 blood and 22 bone marrow samples of 31 MDS patients with varying proportions of apoptotic cells (mean age 78 years), and blood samples of 30 age-matched controls. In addition, plasma carnitine levels were determined. Compared to younger adults, there was a 50% downregulation of CPT1 in elderly persons and in MDS patients. Reduction in CRAT, CPT 2, and OCTN2 was more than 85%. Reduction in microsomal CPT was more pronounced in MDS patients than in age-matched controls (96% vs. 43%). In MDS bone marrow cells there was a negative correlation of CPT1 and CRAT with the relative proportion of apoptotic cells. Plasma carnitine values were similar in all groups. The described reduction in transcription of different genes in blood cells which is well known in different tissues may reflect a systemic signaling process, associated with aging, apoptosis, and MDS.

Serum androgen levels in men: impact of health status and age.

OBJECTIVES: To investigate the impact of health status on androgen levels in men and to assess the age-related changes in androgen levels. METHODS: Sera were obtained from 526 men (age 20 to 89 years) participating in a health screening project and 35 men selected according to the SENIEUR protocol, which excludes those with underlying disease. The health screening project participants were divided into two groups: healthy men (n = 133; group 1) and the remainder (n = 393; group 2). The total testosterone and sex hormone-binding globulin levels were quantified, and the amount of free testosterone (cfT) was calculated. RESULTS: The lowest annual declines in androgen level were observed in group 3 (testosterone 0.2%; cfT 0.4%), followed by group 1 (testosterone 0.4%; cfT 0.8%) and group 2 (testosterone 0.8%; cfT 0.9%). Body mass index and levels of cholesterol, triglycerides, and glucose correlated negatively (P <0.01) with testosterone and cfT. Decade-adjusted reference values (mean +/- 2 standard deviations) for testosterone and cfT were defined. The proposed lower testosterone reference value declined gradually from 3.1 ng/mL (20 to 29 years) to 1.7 ng/mL (70 years or older). CONCLUSIONS: In this cross-sectional study, serum androgens declined in aging men, and the extent of this decrease correlated with health status. A fixed, non-age-adjusted reference value does not adequately reflect this and might lead to a false diagnosis of androgen deficiency, particularly in elderly men. The clinical value of age-related reference values, however, needs to be determined in prospective studies.