Short stature diagnosis and referral

The "360° GH in Europe" meeting, which examined various aspects of GH diseases, was held in Lisbon, Portugal, in June 2016. The Merck KGaA (Germany) funded meeting comprised three sessions entitled "Short Stature Diagnosis and Referral, " "Optimizing Patient Management, " and "Managing Transition." Each session had three speaker presentations, followed by a discussion period, and is reported as a manuscript, authored by the speakers. The first session examined current processes of diagnosis and referral by endocrine specialists for pediatric patients with short stature. Requirements for referral vary widely, by country and by patient characteristics such as age. A balance must be made to ensure eligible patients get referred while healthcare systems are not over-burdened by excessive referrals. Late referral and diagnosis of non-GH deficiency conditions can result in increased morbidity and mortality. The consequent delays in making a diagnosis may compromise the effectiveness of GH treatment. Algorithms for growth monitoring and evaluation of skeletal disproportions can improve identification of non-GH deficiency conditions. Performance and validation of guidelines for diagnosis of GH deficiency have not been sufficiently tested. Provocative tests for investigation of GH deficiency remain equivocal, with insufficient information on variations due to patient characteristics, and cutoff values for definition differ not only by country but also by the assay used. When referring and diagnosing causes of short stature in pediatric patients, clinicians need to rely on many factors, but the most essential is clinical experience

Evaluating the usefulness and ease of use of a next-generation–connected drug delivery device for growth hormone therapy: qualitative study of health care professionals’ perceptions

Background: Digital solutions targeting children’s health have become an increasingly important element in the provision of integrated health care. For the treatment of growth hormone deficiency (GHD), a unique connected device is available to facilitate the delivery of recombinant human growth hormone (r-hGH) by automating the daily injection process and collecting injection data such that accurate adherence information is available to health care professionals (HCPs), caregivers, and patients. The adoption of such digital solutions requires a good understanding of the perspectives of HCPs as key stakeholders because they leverage data collection and prescribe these solutions to their patients. Objective: This study aimed to evaluate the third generation of the easypod device (EP3) for the delivery of r-hGH treatment from the HCP perspective, with a focus on perceived usefulness and ease of use. Methods: A qualitative study was conducted, based on a participatory workshop conducted in Zaragoza, Spain, with 10 HCPs experienced in the management of pediatric GHD from 7 reference hospitals in Spain. Several activities were designed to promote discussion among participants about predefined topics based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology to provide their perceptions about the new device. Results: Participants reported 2 key advantages of EP3 over previous easypod generations: the touch screen interface and the real-time data transmission functionality. All participants (10/10, 100%) agreed that the new device should be part of a digital health ecosystem that provides complementary functionalities including data analysis. Conclusions: This study explored the perceived value of the EP3 autoinjector device for the treatment of GHD by HCPs. HCPs rated the new capabilities of the device as having substantial improvements and concluded that it was highly recommendable for clinical practice. EP3 will enhance decision-making and allow for more personalized care of patients receiving r-hGH. JMIR Hum Factors 2023;10:e46893 doi:10.2196/4689

Mutator/Hypermutable Fetal/Juvenile Metakaryotic Stem Cells and Human Colorectal Carcinogenesis

Adult age-specific colorectal cancer incidence rates increase exponentially from maturity, reach a maximum, then decline in extreme old age. Armitage and Doll (1) postulated that the exponential increase resulted from “n” mutations occurring throughout adult life in normal “cells at risk” that initiated the growth of a preneoplastic colony in which subsequent “m” mutations promoted one of the preneoplastic “cells at risk” to form a lethal neoplasia. We have reported cytologic evidence that these “cells at risk” are fetal/juvenile organogenic, then preneoplastic metakaryotic stem cells. Metakaryotic cells display stem-like behaviors of both symmetric and asymmetric nuclear divisions and peculiarities such as bell shaped nuclei and amitotic nuclear fission that distinguish them from embryonic, eukaryotic stem cells. Analyses of mutant colony sizes and numbers in adult lung epithelia supported the inferences that the metakaryotic organogenic stem cells are constitutively mutator/hypermutable and that their contributions to cancer initiation are limited to the fetal/juvenile period. We have amended the two-stage model of Armitage and Doll and incorporated these several inferences in a computer program CancerFit v.5.0. We compared the expectations of the amended model to adult (15–104 years) age-specific colon cancer rates for European-American males born 1890–99 and observed remarkable concordance. When estimates of normal colonic fetal/juvenile APC and OAT gene mutation rates (∼2–5 × 10[superscript −5] per stem cell doubling) and preneoplastic colonic gene loss rates (∼8 × 10[superscript −3]) were applied, the model was in accordance only for the values of n = 2 and m = 4 or 5.United Therapeutics Corporatio

Transcriptome Analysis Reveals Strain-Specific and Conserved Stemness Genes in Schmidtea mediterranea

The planarian Schmidtea mediterranea is a powerful model organism for studying stem cell biology due to its extraordinary regenerative ability mediated by neoblasts, a population of adult somatic stem cells. Elucidation of the S. mediterranea transcriptome and the dynamics of transcript expression will increase our understanding of the gene regulatory programs that regulate stem cell function and differentiation. Here, we have used RNA-Seq to characterize the S. mediterranea transcriptome in sexual and asexual animals and in purified neoblast and differentiated cell populations. Our analysis identified many uncharacterized genes, transcripts, and alternatively spliced isoforms that are differentially expressed in a strain or cell type-specific manner. Transcriptome profiling of purified neoblasts and differentiated cells identified neoblast-enriched transcripts, many of which likely play important roles in regeneration and stem cell function. Strikingly, many of the neoblast-enriched genes are orthologs of genes whose expression is enriched in human embryonic stem cells, suggesting that a core set of genes that regulate stem cell function are conserved across metazoan species

DNA Repair in Human Pluripotent Stem Cells Is Distinct from That in Non-Pluripotent Human Cells

The potential for human disease treatment using human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells (iPSCs), also carries the risk of added genomic instability. Genomic instability is most often linked to DNA repair deficiencies, which indicates that screening/characterization of possible repair deficiencies in pluripotent human stem cells should be a necessary step prior to their clinical and research use. In this study, a comparison of DNA repair pathways in pluripotent cells, as compared to those in non-pluripotent cells, demonstrated that DNA repair capacities of pluripotent cell lines were more heterogeneous than those of differentiated lines examined and were generally greater. Although pluripotent cells had high DNA repair capacities for nucleotide excision repair, we show that ultraviolet radiation at low fluxes induced an apoptotic response in these cells, while differentiated cells lacked response to this stimulus, and note that pluripotent cells had a similar apoptotic response to alkylating agent damage. This sensitivity of pluripotent cells to damage is notable since viable pluripotent cells exhibit less ultraviolet light-induced DNA damage than do differentiated cells that receive the same flux. In addition, the importance of screening pluripotent cells for DNA repair defects was highlighted by an iPSC line that demonstrated a normal spectral karyotype, but showed both microsatellite instability and reduced DNA repair capacities in three out of four DNA repair pathways examined. Together, these results demonstrate a need to evaluate DNA repair capacities in pluripotent cell lines, in order to characterize their genomic stability, prior to their pre-clinical and clinical use

Loss of amphiregulin reduces myoepithelial cell coverage of mammary ducts and alters breast tumor growth

Abstract Background Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, is not only essential for proper mammary ductal development, but also associated with breast cancer proliferation and growth. In the absence of AREG, mammary ductal growth is stunted and fails to expand. Furthermore, suppression of AREG expression in estrogen receptor-positive breast tumor cells inhibits in-vitro and in-vivo growth. Methods We crossed AREG-null (AREG−/−) mice with the murine luminal B breast cancer model, MMTV-PyMT (PyMT), to generate spontaneous breast tumors that lack AREG (AREG−/− PyMT). We evaluated tumor growth, cytokeratin-8 (K8)-positive luminal cells, cytokeratin-14 (K14)-positive myoepithelial cells, and expression of AREG, Ki67, and PyMT. Primary myoepithelial cells from nontumor-bearing AREG+/+ mice underwent fluorescence-activated cell sorting and were adapted to culture for in-vitro coculture studies with AT-3 cells, a cell line derived from C57Bl/6 PyMT mammary tumors. Results Intriguingly, PyMT-induced lesions progress more rapidly in AREG−/− mice than in AREG+/+ mice. Quantification of K8+ luminal and K14+ myoepithelial cells in non-PyMT AREG−/− mammary glands showed fewer K14+ cells and a thinner myoepithelial layer. Study of AT-3 cells indicated that coculture with myoepithelial cells or exposure to AREG, epidermal growth factor, or basic fibroblast growth factor can suppress PyMT expression. Late-stage AREG−/− PyMT tumors are significantly less solid in structure, with more areas of papillary and cystic growth. Papillary areas appear to be both less proliferative and less necrotic. In The Cancer Genome Atlas database, luminal-B invasive papillary carcinomas have lower AREG expression than luminal B invasive ductal carcinomas. Conclusions Our study has revealed a previously unknown role of AREG in myoepithelial cell development and PyMT expression. AREG expression is essential for proper myoepithelial coverage of mammary ducts. Both AREG and myoepithelial cells can suppress PyMT expression. We find that lower AREG expression is associated with invasive papillary breast cancer in both the MMTV-PyMT model and human breast cancer

Sovremennye problemy insulinoterapii

Современные препараты инсулина разделяют на группы в зависимости от происхождения (животные и человеческие) и длительности действия. Инсулины от животных - свиные, говяжьи и смешанные (свиной+говяжий). На протяжении 60 лет для лечения СД применяли говяжий и свиной инсулины, которые по составу отличаются от человеческого (на 3 и 1 аминокислоту соответственно). В настоящее время основной проблемой производства инсулинов является абсолютное очищение препарата от малейших примесей; контроль качества наиболее важен при биосинтетическом производстве. Для введения инсулина созданы современные шприц-ручки, гарантирующие точность дозы и безопасность проведения инъекций, удобны в применении, позволяют больному быстро сделать инъекцию в любых условиях и одновременно являются надежным футляром для хранения инсулинового картриджа. Большинство препаратов инсулина в России, странах СНГ и некоторых других странах до сих пор имеет концентрацию 40 МЕ/мл. Международная федерация диабета рекомендовала переход на единую стандартную концентрацию 100 МЕ/мл для всех выпускаемых инсулинов к 2000 г. Главной задачей инсулинотерапии является максимальная имитация секреции инсулина здорового человека. В настоящее время в понятие ?интенсифицированная инсулинотерапия? вкладывается не только особый режим введения инсулина, но и комплекс обучения больных (самоконтроль заболевания, диета, физические упражнения), а также программа профилактики осложнений

Ekonomicheskie aspekty lecheniya sakharnogo diabeta

Анализ стоимости лечения сахарного диабета (СД) является частью фармакоэкономики ? нового направления в здравоохранении. Экономический анализ медицинской помощи зависит от типа затрат, типа прибыли, а также точки зрения части общества, относительно которой проводится анализ. При анализе стоимости лечения СД необходимо различать прямые и непрямые затраты. Прямые затраты включают затраты на лечение диабета и его осложнений, непрямые ? на убытки потери производительности труда. Статистический анализ летальности при СД имеет свои трудности. Данные анализа 606 больных СД на протяжении 8 лет показали, что только в 1 случае диабет являлся прямой причиной смерти. Наиболее частой предшествующей причиной смерти являлась ИБС (70%), которая предшествовала почечной недоста?точности (11%). Большая часть убытков от потери трудоспособности (около 70%) у больных СД обусловлена стойкой нетрудоспособностью. Интенсифицированная терапия позволяет уменьшить риск развития осложнений СД. Проведение оценки интенсифицированной терапии с экономической точки зрения показало, что так как при СД 1 типа частота гипогликемических реакций в 10-20 раз ниже, то интенсифицированная терапия при СД 2 типа даже более выгодна, чем у больных СД 1 типа Современная концепция о СД как особом образе жизни полноценных членов общества диктует необходимость оценки не только клинической, но и экономической эффективности лечения заболевания