Evaluation of a near-infrared light ultrasound system as a non-invasive blood glucose monitoring device.

The aim of this study was to evaluate the newly developed non-invasive blood glucose system NIRLUS® (Near-Infra Red Light Ultra Sound; NIRLUS Engineering AG, Lübeck, Germany) under standardized conditions. Seventeen healthy men of normal weight (body mass index 22.4 ± 1.4 kg/m2 ), aged 18 to 45 years, were enrolled in this study. During an intravenous glucose tolerance test, blood glucose profiles were measured simultaneously using the NIRLUS system and a "gold standard" laboratory reference system. Correlation analysis revealed a strong association between NIRLUS and reference values (r = 0.934; P < 0.001). Subsequent Bland-Altman analysis showed a symmetric distribution (r = 0.047; P = 0.395), and 95.5% of the NIRLUS-reference pairs were within the difference (d) of d ± 2 SD. The median deviation of all paired NIRLUS-reference values was 0.5 mmol/L and the mean percent deviation was 11.5%. Error grid analysis showed that 93.6% of NIRLUS-reference pairs are located in the area A, and 6.4% in the area B. No data were allocated in the areas C to E. This proof-of-concept study demonstrates the reproducibility of accurate blood glucose measures obtained by NIRLUS as compared to a gold standard laboratory reference system. The technology of NIRLUS is an important step forward in the development of non-invasive glucose monitoring.

[New technologies in diabetes treatment]. / Neue Technologien in der Diabetestherapie.

Technological progress has led to numerous innovations in diagnostic and therapeutic applications in diabetes and will also improve the treatment of patients with diabetes in the future. The first commercially available hybrid closed-loop system has been available in the USA since 2016 and the next developmental step toward a fully automated artificial pancreas has been made. The automated control of the basal insulin secretion provides a stabilization of blood glucose with a reduction of hypoglycemia and improvement of long-term control as indicated by improved hemoglobin A1c levels. Although closed-loop systems are not yet officially available in Germany, patients with type 1 diabetes mellitus already benefit from a new generation of continuous glucose monitoring (CGM) systems. Apart from the increased accuracy these new devices can be used for up to 180 days and do not require daily calibration. This article provides a short overview of the innovations in CGM systems and the current status in the development of the artificial pancreas.

Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts.

Transplantation of xenogeneic thymus tissue allows xenograft tolerance induction in the highly disparate pig-to-mouse model. Fetal swine thymus (SW THY) can support the generation of a diverse human T cell repertoire that is tolerant of the pig in vitro. We demonstrate that SW THY generates all human T cell subsets, including regulatory T cells (Tregs), in similar numbers as fetal human thymus (HU THY) grafts in immunodeficient mice receiving the same human CD34(+) cells. Peripheral T cells are specifically tolerant to the mouse and to the human and porcine donors, with robust responses to nondonor human and pig Ags. Specific tolerance is observed to pig skin grafts sharing the THY donor MHC. SW THY-generated peripheral Tregs show similar function, but include lower percentages of naive-type Tregs compared with HU THY-generated Tregs. Tregs contribute to donor-pig specific tolerance. Peripheral human T cells generated in SW THY exhibit reduced proportions of CD8(+) T cells and reduced lymphopenia-driven proliferation and memory-type conversion, accelerated decay of memory-type cells, and reduced responses to protein Ags. Thus, SW thymus transplantation is a powerful xenotolerance approach for human T cells. However, immune function may be further enhanced by strategies to permit positive selection by autologous HLA molecules.

Human natural regulatory T cell development, suppressive function, and postthymic maturation in a humanized mouse model.

CD4(+) regulatory T cells (Tregs) control adaptive immune responses and promote self-tolerance. Various humanized mouse models have been developed in efforts to reproduce and study a human immune system. However, in models that require T cell differentiation in the recipient murine thymus, only low numbers of T cells populate the peripheral immune systems. T cells are positively selected by mouse MHC and therefore do not function well in an HLA-restricted manner. In contrast, cotransplantation of human fetal thymus/liver and i.v. injection of CD34(+) cells from the same donor achieves multilineage human lymphohematopoietic reconstitution, including dendritic cells and formation of secondary lymphoid organs, in NOD/SCID mice. Strong Ag-specific immune responses and homeostatic expansion of human T cells that are dependent on peripheral human APCs occur. We now demonstrate that FOXP3(+)Helios(+) "natural" Tregs develop normally in human fetal thymic grafts and are present in peripheral blood, spleen, and lymph nodes of these humanized mice. Humanized mice exhibit normal reversal of CD45 isoform expression in association with thymic egress, postthymic "naive" to "activated" phenotypic conversion, and suppressive function. These studies demonstrate the utility of this humanized mouse model for the study of human Treg ontogeny, immunobiology and therapy.

Homeostatic expansion and phenotypic conversion of human T cells depend on peripheral interactions with APCs.

Immune recovery in lymphopenic hosts depends largely on homeostatic peripheral expansion, especially when thymopoiesis is insufficient, as is often the case in human adults. Although it has been well studied in mice, the study of homeostatic peripheral expansion of human T cells has been limited by the lack of an appropriate in vivo model. In this study, we use T cell-deficient humanized mice and an adoptive transfer approach to demonstrate that two distinct proliferative responses of autologous T cells occur in vivo in a lymphopenic setting. Human naive CD4 and CD8 T cells that undergo rapid proliferation acquire a memory-like phenotype and the ability to rapidly produce IFN-gamma, whereas those undergoing slow proliferation retain naive phenotypic and functional characteristics. Recovery of both populations depends on the extent of human non-T cell chimerism in the periphery of recipient humanized mice. Furthermore, memory conversion of CD4 and CD8 T cells correlates with the level of human CD14+ and CD19+ chimerism in recipient mice, respectively, suggesting that different types of APCs support memory conversion of CD4 and CD8 T cells. Because lymphopenia affects clinical outcomes, this model, which will allow detailed investigation of the effects of lymphopenia in patients, is of clinical significance.

Chronobiological aspects of sleep restriction modulate subsequent spontaneous physical activity.

PURPOSE: First evidence suggests that chronobiological aspects of sleep restriction affect metabolic conditions. Our aim was to investigate whether spontaneous free-living physical activity likewise is affected by chronobiological timing of short sleep. METHODS: In an experimental randomized, balanced cross-over design, eleven healthy, normal-weight (BMI: 23.9 ± 0.4 kg/m2) men were evaluated. Physical activity was assessed by tri-axial wrist actigraphy after (i) four-hour sleep during the first night-half of the night ('late night sleep loss'), (ii) four-hour sleep during the second night-half ('early night sleep loss'), and (iii) eight-hour regular sleep ('regular sleep'), from 7:00 to 24:00 (17 h). Feelings of tiredness and activity were measured by semi-quantitative questionnaires. RESULTS: Physical activity differed between sleep conditions (P < 0.05) with the lowest physical activity after 'late night sleep loss'. Accordingly, less time was spent in high-intensity physical activity after 'late night sleep loss' as compared to the 'early night sleep loss' and 'regular sleep' conditions (both P < 0.05). Perceived feelings of tiredness were higher after both short sleep conditions as compared to 'regular sleep' (both P < 0.05). CONCLUSIONS: Sleep restriction during the second half of the night elicits stronger effects on spontaneous physical activity than sleep restriction during the first half of the night despite identical sleep duration, but the impact of longer period awake needs to be evaluated in further research. In sum, these data indicate that not only short sleep per se but also chronobiological aspects modulate physical activity pattern.

[Personalized Therapy In Osteoporosis]. / Personalisierte Osteoporose-Therapie.

In Germany, over six million people suffer from osteoporosis. Nearly half of the women over 70 years and nearly 20 % of men at the same age are affected. The clinical and socioeconomical relevance of the disease lies in osteoporotic fractures leading to extensive bone-associated morbidity, increased mortality and health care costs. Fracture risk algorithms and guidelines for the diagnosis and treatment of osteoporosis help to assess the individual fracture risk. By calculating the individual fracture risk, the indication for specific osteoporosis treatment can objectively be determined. A consequent specific osteoporosis therapy is required for patients with a high fracture risk and is essential to prevent osteoporotic fractures and their consequences. As first-line therapy a drug with a proven fracture-reducing effect should be taken. However, for successful osteoporosis therapy, many individual factors have to be considered. A personalized treatment approach should be established according to the severity of the disease, the patient's sex and comorbidities as well as the possible additive and side effects of the drug.

Metabolic Syndrome in Thyroid Disease.

Cardiometabolic risk factors like abdominal obesity, hyperglycemia, low high-density lipoprotein (HDL) cholesterol, elevated triglycerides, and hypertension are defined as metabolic syndrome (MetS), which represents one of the most frequent endocrine disorders particularly in a society with increasing weight problems. As more and more evidence is accumulated that thyroid hormones affect components of the MetS, the present review aims to summarize the rapidly expanding knowledge on the pathophysiological interaction between thyroid hormone status and MetS. The review is based on a PubMed search for combinations of thyroid hormone action and MetS, blood pressure, hypertension, hyperlipidemia, cholesterol, HDL cholesterol, glucose, diabetes mellitus, body weight, or visceral fat. A special focus was given for manuscripts published after 2000 but we included seminal papers published before year 2000 as well.

[Diagnostic Approach to Manifestation of Type 1 Diabetes mellitus]. / Zielgerichtete Erstdiagnostik bei Typ-1-Diabetes.

The incidence of type 1 and type 2 diabetes mellitus has been increasing simultaneously. Formerly, these two patients' populations could be differentiated easily, but now, due to the overlapping of both groups, specified diagnostics are necessary. In order to substantiate a suspicion on diabetes, quantifying venous plasma glucose is the gold standard in diagnostics. As a precaution, determination of the HbA1c and OGTT is recommended. It is not necessary to determinate antibodies in every new case of diabetes. In patients with a vague constellation of clinical picture diagnosis can be ensured by findings of uric ketones, BGA, IA-2- and GAD-antibodies and optionally C-peptide. Often T1DM is associated with PGAS. Therefore, once manifestation of diabetes is detected, screening autoimmune disorders is recommended directly and regularly every two years.

The Telomeric Complex and Metabolic Disease.

The attrition of telomeres is believed to be a key event not only in mammalian aging, but also in disturbed nutrient sensing, which could lead to numerous metabolic dysfunctions. The current debate focuses mainly on the question whether telomere shortening, e.g., as a heritable trait, may act as a cause or rather represents a consequence of such chronic diseases. This review discusses the damaging events that ultimately may lead or contribute to telomere shortening and can be associated with metabolic diseases.

Diabetic Retinopathy Screening Ratio Is Improved When Using a Digital, Nonmydriatic Fundus Camera Onsite in a Diabetes Outpatient Clinic.

OBJECTIVE: To evaluate the effect of onsite screening with a nonmydriatic, digital fundus camera for diabetic retinopathy (DR) at a diabetes outpatient clinic. RESEARCH DESIGN AND METHODS: This cross-sectional study included 502 patients, 112 with type 1 and 390 with type 2 diabetes. Patients attended screenings for microvascular complications, including diabetic nephropathy (DN), diabetic polyneuropathy (DP), and DR. Single-field retinal imaging with a digital, nonmydriatic fundus camera was used to assess DR. Prevalence and incidence of microvascular complications were analyzed and the ratio of newly diagnosed to preexisting complications for all entities was calculated in order to differentiate natural progress from missed DRs. RESULTS: For both types of diabetes, prevalence of DR was 25.0% (n = 126) and incidence 6.4% (n = 32) (T1DM versus T2DM: prevalence: 35.7% versus 22.1%, incidence 5.4% versus 6.7%). 25.4% of all DRs were newly diagnosed. Furthermore, the ratio of newly diagnosed to preexisting DR was higher than those for DN (p = 0.12) and DP (p = 0.03) representing at least 13 patients with missed DR. CONCLUSIONS: The results indicate that implementing nonmydriatic, digital fundus imaging in a diabetes outpatient clinic can contribute to improved early diagnosis of diabetic retinopathy.

A substantial level of donor hematopoietic chimerism is required to protect donor-specific islet grafts in diabetic NOD mice.

BACKGROUND: Mixed chimerism can induce tolerance to alloantigens and restore self-tolerance to autoantigens, thereby permitting islet transplantation. However, the minimal level of donor chimerism that is required to prevent islet allograft rejection and recurrence of autoimmune diabetes has not been established. METHODS: We investigated whether allogeneic Balb/c donor chimerism can be induced in C57BL/6 mice, in prediabetic NOD mice, and in diabetic NOD mice after transplantation of a modest dose of bone marrow by using purine nucleoside analogue, fludarabine phosphate and cyclophosphamide conditioning therapy, followed by short-term anti-CD40 ligand monoclonal antibody and rapamycin posttransplant treatment. We also investigated whether the induced donor chimerism is sufficient to prevent the onset of diabetes in prediabetic NOD mice and protect donor islet grafts in diabetic NOD mice. RESULTS: Allogeneic donor chimerism could be induced under the authors' approach that is nonmyeloablative and radiation-free. Diabetes onset was prevented in chimeric prediabetic NOD mice. The induction of mixed chimerism protected donor-specific islet grafts in diabetic NOD mice. At 60 days after islet transplantation, all donor Balb/c islet grafts survived in diabetic NOD mice whose level of donor-derived lymphocytes was higher than 30% at the time of islet transplantation (n=8). In contrast, Balb/c islet grafts were rejected in five of seven diabetic NOD mice whose level was lower than 30%. CONCLUSIONS: Our data demonstrate that a donor lymphocyte chimerism (>30%) at the time of islet transplantation is required to protect donor-specific islet grafts, and indicate that a strictly non-irradiation-based protocol can be used to achieve this goal.

Blockade of the CD40/CD154 pathway enhances T-cell-depleted allogeneic bone marrow engraftment under nonmyeloablative and irradiation-free conditioning therapy.

BACKGROUND: T-cell-depleted bone marrow transplantation (TDBMT) can prevent graft-versus-host disease (GvHD). However, depleting T cells from allogeneic bone marrow often results in failure of bone marrow engraftment under irradiation conditioning. It is not know whether donor T cells are essential for bone marrow engraftment and whether blocking the CD40/CD154 pathway promotes allogeneic TDBM engraftment under nonmyeloablative and irradiation-free fludarabine phosphate and cyclophosphamide conditioning therapy. METHODS: Using fully major histocompatibility complex (MHC)-matched mouse models, we investigated whether donor T cells are essential for bone marrow engraftment under fludarabine phosphate and cyclophosphamide conditioning therapy. We also determined whether the barrier of allogeneic TDBM could be overcome by blocking the CD40/CD154 pathway. Donor chimerism was detected by flow cytometric analysis. Donor-specific tolerance through establishing mixed chimerism was tested in vivo by skin transplantation and in vitro by mixed leukocyte reaction and enzyme-linked immunospot (ELISPOT) assay. RESULTS: Compared with unmodified bone marrow, TDBM resulted in poor engraftment when fully MHC-mismatched donors were used. However, anti-CD154 monoclonal antibody (mAb) treatment significantly enhanced donor TDBM engraftment. TDBM engraftment was also seen in CD154 knockout mice. A stable and high level of multilinage donor chimerism was achieved. Recovery of host CD3 T cells was suppressed, and recovery of donor CD3 T cells was promoted, after TDBMT and anti-CD154 mAb treatment. Donor chimerism was established by TDBMT induced donor-specific tolerance in vivo and in vitro. CONCLUSION: Donor T cells facilitate bone marrow engraftment under nonmyeloablative and irradiation-free conditioning therapy, and the blocking the CD40/CD154 pathway can replace donor T cells to promote TDBM engraftment.

A model for personalized in vivo analysis of human immune responsiveness.

Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies. Immunodeficient mice receiving human fetal thymus grafts and fetal CD34(+) cells intravenously produce robust human immune systems, allowing analysis of human T cell development and function. However, to use humanized mice to study human immune-mediated disorders, immune systems must be generated from adult hematopoietic cells. Here, we demonstrated robust immune reconstitution in mice with hematopoietic stem cells (HSCs) aspirated from bone marrow of adults with type 1 diabetes (T1D) and healthy control volunteers. In these humanized mice, cryopreservation of human leukocyte antigen allele-matched fetal thymic tissue prevented allogeneic adult HSC rejection. Newly generated T cells, which included regulatory T cells (T(regs)), were functional and self-tolerant and had a diverse repertoire. The immune recognition of these mice mimicked that of the adult CD34(+) cell donor, but the T cell phenotypes were more predominantly "naïve" than those of the adult donors. HSCs from T1D and control donors generated similar numbers of natural T(regs) intrathymically; however, peripheral T cells from T1D subjects showed increased proportions of activated or memory cells compared to controls, suggesting possible HSC-intrinsic differences in T cell homeostasis that might underlie immune pathology in T1D. This "personalized immune" mouse provides a new model for individualized analysis of human immune responses that may provide new insights into not only T1D but also other forms of immune function and dysfunction as well.