Nanoparticle-mediated targeting of autoantigen peptide to cross-presenting liver sinusoidal endothelial cells protects from CD8 T-cell-driven autoimmune cholangitis.

Autoimmune diseases are caused by adaptive immune responses to self-antigens. The development of antigen-specific therapies that suppress disease-related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC-targeting nanoparticles provides effective protection from CD4 T-cell-driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen-specific treatment of a CD8 T-cell-driven autoimmune disease. As a model for CD8 T-cell-mediated autoimmunity, we used OT-1 T-cell-driven cholangitis in K14-OVAp mice expressing the cognate MHC I-restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide-conjugated nanoparticles were administered intravenously one day before transfer of OT-1 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide-conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross-presented the delivered peptide on MHC I molecules. Intriguingly, K14-OVAp mice receiving SIINFEKL-loaded nanoparticles manifested significantly reduced liver damage compared with vehicle-treated K14-OVAp mice. Mechanistically, treatment with LSEC-targeting SIINFEKL-loaded nanoparticles significantly reduced the number of liver-infiltrating OT-1 T cells, which up-regulated expression of the co-inhibitory receptor PD-1 and down-regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross-present nanoparticle-bound peptides on MHC I molecules. Therefore, nanoparticle-mediated autoantigen peptide delivery to LSECs might serve the antigen-specific treatment of CD8 T-cell-driven autoimmune disease.

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression.

BACKGROUND & AIMS: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8+ T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids. METHODS: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes. Cholangitis was induced by the adoptive transfer of transgenic OVA-specific ovalbumin transgene (OT)-1 CD8+ T cells that either had OT-1wt or lacked IL-17A/F (OT-1IL17ko). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro. RESULTS: Transfer of OVA-specific OT-1IL17ko cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1wt T cells. OT-1IL17ko T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1wt CD8+ T cells induced upregulation of the inhibitory molecule programmed cell death ligand 1 (PD-L1) on cholangiocytes, restricting cholangitis by limiting cytotoxicity and proliferation of transferred cells. In contrast, OT-1IL17ko T cells failed to induce PD-L1 on cholangiocytes, resulting in uncontrolled expansion of cytotoxic CD8+ T cells and aggravated cholangitis. Blockade of PD-L1 after transfer of OT-1wt T cells with anti-PD-L1 antibody also resulted in aggravated cholangitis. Using human cholangiocyte organoids, we were able to confirm that IL-17A induces PD-L1 expression in cholangiocytes. CONCLUSIONS: We demonstrate that by upregulating PD-L1 on cholangiocytes, IL-17 has an important role in restricting cholangitis and protecting against CD8+ T cell-mediated inflammatory bile duct injury. Caution should be exercised when targeting IL-17 for the treatment of cholangitis. LAY SUMMARY: IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.

Monocytes as Potential Mediators of Pathogen-Induced T-Helper 17 Differentiation in Patients With Primary Sclerosing Cholangitis (PSC).

BACKGROUND AND AIMS: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T-helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T-cell response toward Th17. APPROACH AND RESULTS: Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes. Cytokine production was measured using flow cytometry, enzyme-linked immunosorbent assay, RNA in situ hybridization, and quantitative real-time PCR. Genetic polymorphisms were obtained from ImmunoChip analysis. Following ex vivo stimulation with phorbol myristate acetate/ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4+ T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1ß and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines chemokine (C-C motif) ligand (CCL)-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hiCD16int and CD14loCD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis, and monocytes were found to be located around bile ducts. CONCLUSIONS: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.

Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis.

BACKGROUND & AIMS: T cells are central mediators of liver inflammation and represent potential treatment targets in cholestatic liver disease. Whereas emerging evidence shows that bile acids (BAs) affect T cell function, the role of T cells for the regulation of BA metabolism is unknown. In order to understand this interplay, we investigated the influence of T cells on BA metabolism in a novel mouse model of cholangitis. METHODS: Mdr2-/- mice were crossed with transgenic K14-OVAp mice, which express an MHC class I restricted ovalbumin peptide on biliary epithelial cells (Mdr2-/-xK14-OVAp). T cell-mediated cholangitis was induced by the adoptive transfer of antigen-specific CD8+ T cells. BA levels were quantified using a targeted liquid chromatography-mass spectrometry-based approach. RESULTS: T cell-induced cholangitis resulted in reduced levels of unconjugated BAs in the liver and significantly increased serum and hepatic levels of conjugated BAs. Genes responsible for BA synthesis and uptake were downregulated and expression of the bile salt export pump was increased. The transferred antigen-specific CD8+ T cells alone were able to induce these changes, as demonstrated using Mdr2-/-xK14-OVAp recipient mice on the Rag1-/- background. Mechanistically, we showed by depletion experiments that alterations in BA metabolism were partly mediated by the proinflammatory cytokines TNF and IFN-γ in an FXR-dependent manner, a process that in vitro required cell contact between T cells and hepatocytes. CONCLUSION: Whereas it is known that BA metabolism is dysregulated in sepsis and related conditions, we have shown that T cells are able to control the synthesis and metabolism of BAs, a process which depends on TNF and IFN-γ. Understanding the effect of lymphocytes on BA metabolism will help in the design of combined treatment strategies for cholestatic liver diseases. LAY SUMMARY: Dysregulation of bile acid metabolism and T cells can contribute to the development of cholangiopathies. Before targeting T cells for the treatment of cholangiopathies, it should be determined whether they exert protective effects on bile acid metabolism. Herein, we demonstrate that T cell-induced cholangitis resulted in decreased levels of harmful unconjugated bile acids. T cells were able to directly control synthesis and metabolism of bile acids, a process which was dependent on the proinflammatory cytokines TNF and IFN-γ. Understanding the effect of lymphocytes on bile acid metabolism will help in the design of combined treatment strategies for cholestatic liver diseases.

Dose-response walking activity and physical function in older adults.

The aim of this study was to examine the dose-response relationship between walking activity and physical function (PF) in community-dwelling older adults. Physical activity (PA, pedometry) and PF (self-report [SF-36] and 6-minute walk test [6MWT]) were assessed in 836 individuals. Accumulated PA was categorized into four groups (1 = ≤ 2,500; 2 = 2,501-5,000; 3 = 5,001-7,500; and 4 = ≥ 7,501 steps/day). Across individual groups 1-4, SF-36 scores increased from 66.9 ± 25.0% to 73.5 ± 23.2% to 78.8 ± 19.7% to 81.3 ± 20.6%, and 6MWT increased from 941.7 ± 265.4 ft to 1,154.1 ± 248.2 ft to 1,260.1 ± 226.3 ft to 1,294.0 ± 257.9 ft. Both SF-36 and 6MWT scores were statistically different across all groups, apart from groups 3 and 4. PA and ranks of groups were highly significant predictors (p < .0001) for both SF-36 and 6MWT. There was a positive dose-response relationship evident for both SF-36 and 6MWT with increasing levels of PA. Low levels of PA appear to be an important indicator of poor functionality in older adults.

Telerehabilitation Initiated Early in Post-Stroke Recovery: A Feasibility Study.

BACKGROUND: Enhanced neural plasticity early after stroke suggests the potential to improve outcomes with intensive rehabilitation therapy. Most patients do not get such therapy, however, due to limited access, changing rehabilitation therapy settings, low therapy doses, and poor compliance. OBJECTIVE: To examine the feasibility, safety, and potential efficacy of an established telerehabilitation (TR) program after stroke initiated during admission to an inpatient rehabilitation facility (IRF) and completed in the patient's home. METHODS: Participants with hemiparetic stroke admitted to an IRF received daily TR targeting arm motor function in addition to usual care. Treatment consisted of 36, 70-minute sessions (half supervised by a licensed therapist via videoconference), over a 6-week period, that included functional games, exercise videos, education, and daily assessments. RESULTS: Sixteen participants of 19 allocated completed the intervention (age 61.3 ± 9.4 years; 6 female; baseline Upper Extremity Fugl-Meyer [UEFM] score 35.9 ± 6.4 points, mean ± SD; NIHSS score 4 (3.75, 5.25), median, IQR; intervention commenced 28.3 ± 13.0 days post-stroke). Compliance was 100%, retention 84%, and patient satisfaction 93%; 2 patients developed COVID-19 and continued TR. Post-intervention UEFM improvement was 18.1 ± 10.9 points (P < .0001); Box and Blocks, 22.4 ± 9.8 blocks (P = .0001). Digital motor assessments, acquired daily in the home, were concordant with these gains. The dose of rehabilitation therapy received as usual care during this 6-week interval was 33.9 ± 20.3 hours; adding TR more than doubled this to 73.6 ± 21.8 hours (P < .0001). Patients enrolled in Philadelphia could be treated remotely by therapists in Los Angeles. CONCLUSIONS: These results support feasibility, safety, and potential efficacy of providing intense TR therapy early after stroke. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; NCT04657770.

Persistent Salmonella enterica Serovar Typhimurium Infection Induces Protease Expression During Intestinal Fibrosis.

BACKGROUND: Intestinal fibrosis is a common and serious complication of Crohn's disease characterized by the accumulation of fibroblasts, deposition of extracellular matrix, and formation of scar tissue. Although many factors including cytokines and proteases contribute to the development of intestinal fibrosis, the initiating mechanisms and the complex interplay between these factors remain unclear. METHODS: Chronic infection of mice with Salmonella enterica serovar Typhimurium was used to induce intestinal fibrosis. A murine protease-specific CLIP-CHIP microarray analysis was employed to assess regulation of proteases and protease inhibitors. To confirm up- or downregulation during fibrosis, we performed quantitative real-time polymerase chain reaction (PCR) and immunohistochemical stainings in mouse tissue and tissue from patients with inflammatory bowel disease. In vitro infections were used to demonstrate a direct effect of bacterial infection in the regulation of proteases. RESULTS: Mice develop severe and persistent intestinal fibrosis upon chronic infection with Salmonella enterica serovar Typhimurium, mimicking the pathology of human disease. Microarray analyses revealed 56 up- and 40 downregulated proteases and protease inhibitors in fibrotic cecal tissue. Various matrix metalloproteases, serine proteases, cysteine proteases, and protease inhibitors were regulated in the fibrotic tissue, 22 of which were confirmed by quantitative real-time PCR. Proteases demonstrated site-specific staining patterns in intestinal fibrotic tissue from mice and in tissue from human inflammatory bowel disease patients. Finally, we show in vitro that Salmonella infection directly induces protease expression in macrophages and epithelial cells but not in fibroblasts. CONCLUSIONS: In summary, we show that chronic Salmonella infection regulates proteases and protease inhibitors during tissue fibrosis in vivo and in vitro, and therefore this model is well suited to investigating the role of proteases in intestinal fibrosis.

Promoting social capital for the elderly.

The new gold standard has evolved from aging in place to aging in community. Having social capital by being an active member of a community has a positive effect and can decrease vulnerability to health risk. Federal and state monies have been utilized to support community activities for the elderly including the first meal programs and moving to community-based assisted living programs. While staying in the community is the ideal, a community can be created by progressive leadership in a traditional retirement community including a skilled nursing home. Retirement communities based on the six dimensions of wellness can create a nurturing environment. Nurse leaders can meet the challenge of creating strong environments for the elderly.

CD4+ T cells from patients with primary sclerosing cholangitis exhibit reduced apoptosis and down-regulation of proapoptotic Bim in peripheral blood.

The pathogenesis of the progressive liver disease, primary sclerosing cholangitis (PSC), remains largely elusive. The strong genetic association with HLA loci suggests that T cell-dependent, adaptive immune reactions could contribute to disease pathogenesis. Recent studies have indicated that PSC is also associated with polymorphisms in the locus encoding for proapoptotic Bim (BCL2L11). Bim is crucial for the maintenance of immunologic tolerance through induction of apoptosis in activated T cells. Of interest with regard to PSC is the finding that BCL2L11-deficient mice develop periductular infiltrates. We, therefore, investigated, whether defective apoptosis of T cells might contribute to the phenotype of PSC. Thus, we induced apoptosis of T cells from patients with PSC and controls by repeated T cell receptor (TCR) stimulation or cytokine withdrawal. We found that CD4+ T cells, but not CD8+ T cells, from patients with PSC exhibited significantly reduced apoptosis in response to both, TCR restimulation or cytokine withdrawal. This increased apoptosis resistance was associated with significantly reduced up-regulation of proapoptotic Bim in T cells from patients with PSC. However, T cell apoptosis did not seem to be influenced by the previously described BCL2L11 polymorphisms. Reduced CD4+ T cell apoptosis in patients with PSC was not due to reduced cell activation, as indicated by a similar surface expression of the activation markers CD69, CD25, and CD28 in T cells from patients and controls. Thus, decreased apoptosis of activated CD4+ T cells may be part of the immune dysregulation observed in patients with PSC.

Vildagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes.

INTRODUCTION: Vildagliptin is a dipeptidyl peptidase-4 inhibitor targeting the incretin system to improve glycemic control in type 2 diabetes. AREAS COVERED: This review focuses on the pharmacokinetics, drug interactions and use of oral vildagliptin in special populations. Clinical efficacy and vildagliptin's role in the spectrum of therapeutics available are briefly addressed. EXPERT OPINION: Vildagliptin is an effective and well-tolerated oral dipeptidyl peptidase-4 inhibitor. It is dosed orally and can be used safely as monotherapy or in combination with other oral anti-hyperglycemic agents and insulin. It is rapidly absorbed and can be taken without regard to food. It is metabolized by hydrolysis and renally cleared. It has low potential for drug interactions and is well tolerated in elderly patients. Body mass index and gender have no significant pharmacokinetic impact. There is no significant interaction with CYP enzymes. There is a low risk for hypoglycemia and weight gain. Dose adjustment is recommended for renal impairment. Prescribing vildagliptin in the setting of liver dysfunction is not recommended, although pharmacokinetics is minimally (if at all) affected. A variety of patients with type 2 diabetes may benefit from treatment with vildagliptin. Therapy should be individualized but the paucity of data in populations with advanced renal failure and hepatic dysfunction may limit the use in these patients.

Genetic Counseling for Diabetes Mellitus.

Most diabetes is polygenic in etiology, with (type 1 diabetes, T1DM) or without (type 2 diabetes, T2DM) an autoimmune basis. Genetic counseling for diabetes generally focuses on providing empiric risk information based on family history and/or the effects of maternal hyperglycemia on pregnancy outcome. An estimated one to five percent of diabetes is monogenic in nature, e.g., maturity onset diabetes of the young (MODY), with molecular testing and etiology-based treatment available. However, recent studies show that most monogenic diabetes is misdiagnosed as T1DM or T2DM. While efforts are underway to increase the rate of diagnosis in the diabetes clinic, genetic counselors and clinical geneticists are in a prime position to identify monogenic cases through targeted questions during a family history combined with working in conjunction with diabetes professionals to diagnose and assure proper treatment and familial risk assessment for individuals with monogenic diabetes.

Fumonisins in corn (Zea mays L.) from Southern Brazil.

A total of 232 samples of corn commercialised in Santa Catarina state, Southern Brazil (temperate zone climate), were evaluated from 2007 to 2012 for fumonisins (FBs: FB1 and FB2). Before performing this study, a FBs method with liquid chromatography and fluorescence detection (ex. 335; em. 440 nm) was validated first. FBs were detected in 46.6% (108 samples), with values ranging from 66 to 7832 µg kg(-1) for FB1 and 110 to 1201 µg kg(-1) for FB2. The number of contaminated corn samples for FB1 and FB2 varied and often presented contamination of FB1 only. Per year of analysis, the numbers were: n = 22/8(FB1/FB2), 44/5(FB1/FB2), 25/12(FB1/FB2), 4(FB1), 6(FB1) and 7(FB1) in 2007, 2008, 2009, 2010, 2011 and 2012, respectively. The contamination percentage was 42.3/15.4, 59.5/6.8, 43.8/21.1, 36.4, 35.3 and 33.3%, respectively, during these years. Consumers can be exposed to these mycotoxins and their health can be at risk through the consumption of contaminated corn.

Primary thyroid lymphoma: a clinical review.

CONTEXT: Although primary thyroid lymphoma is a rare cause of both thyroid malignancy and extranodal lymphoma, awareness of this disease is important in order to achieve an early diagnosis and implement treatment. We review the epidemiology, clinical presentation, diagnosis, and treatment of this rare disorder. EVIDENCE ACQUISITION: This review is based on a search of PubMed and MDConsult for English language articles containing the term "primary thyroid lymphoma." The authors reviewed original and review articles and case series from all years of publication but focused on those published within the last 5 years. EVIDENCE SYNTHESIS: Primary thyroid lymphoma should be suspected in patients with a rapidly enlarging neck mass, especially in women with Hashimoto's thyroiditis. Certain ultrasound features such as enhanced posterior echoes can suggest the diagnosis, but biopsy for confirmation is ultimately needed. With advances in immunophenotypic analysis, fine-needle aspiration can be used for diagnosis in the hands of experienced physicians. The most common type of primary thyroid lymphoma is diffuse large B-cell lymphoma, which behaves in a more aggressive manner than mucosa-associated lymphoid tissue lymphoma. Radiation therapy can be employed for treatment of localized mucosa-associated lymphoid tissue lymphoma, but a combination of chemotherapy and radiation is needed for disseminated disease or aggressive histological subtypes. CONCLUSIONS: It is important to consider the diagnosis of primary thyroid lymphoma in patients presenting with an enlarging neck mass and a history of Hashimoto's thyroiditis. Advances in both diagnosis and treatment in recent years have altered our approach to the management of this disease.

A review of the efficacy and safety of oral antidiabetic drugs.

INTRODUCTION: Additional oral antidiabetic agents to metformin, sulfonylureas (SU) and thiazolidinediones (TZD) are approved for the treatment of type 2 diabetes. AREAS COVERED: The efficacy and safety of metformin, SUs, TZDs, dipeptidyl peptidase-IV (DPP-4) inhibitors, meglitinide analogs, α-glucosidase inhibitors (AGIs), bile-acid sequestrants (BAS) and bromocriptine will be reviewed. EXPERT OPINION: Several new oral agents have been approved for type 2 diabetes management in recent years. It is important to understand the efficacy and safety of these medications in addition to the older agents to best maximize oral drug therapy for diabetes. Of the recently introduced oral hypoglycemic/antihyperglycemic agents, the DPP-4 inhibitors are moderately efficacious compared with mainstay treatment with metformin with a low side-effect profile and have good efficacy in combination with other oral agents and insulin. They are a recommended alternative when metformin use is limited by gastrointestinal (GI) side effects or when SU treatment results in significant hypoglycemia or weight gain. Meglitinide analogs are limited by their frequent dosing, expense and hypoglycemia (repaglinide > nateglinide), while AGIs are also limited by their dosing schedule and GI side-effect profile. BAS and bromocriptine have the lowest efficacy with regard to HbA(1c) reduction, also are plagued by GI adverse reactions, but have a low risk of hypoglycemia.

An insight into the recent diabetes trials: what is the best approach to prevent macrovascular and microvascular complications?

Type 2 diabetes mellitus (T2DM) accounts for 90%-95% of all diabetes cases. The overarching goal in caring for patients with T2DM is to prevent microvascular and macrovascular complications with glycemic control. Several studies such as UKPDS, DCCT, and EDIC have been performed to evaluate the effects of glucose control on tissue complications in patients with diabetes. In recent diabetes trials including ACCORD, ADVANCE, VADT, BARI 2D, and ORIGIN, intensive glucose control did not prevent macrovascular complications in older patients with long-standing diabetes with either cardiovascular disease or risk factors for cardiovascular disease. In fact, intensive therapy was associated with increased mortality in the ACCORD trial. Although no clear macrovascular benefit was seen in these trials, analyses of earlier studies in younger patients with type 1 and type 2 diabetes have suggested a significant benefit of intensive glycemic control in patients with a shorter duration of diabetes and less vasculopathy. In the UKPDS, the incidence of microvascular disease, particularly retinopathy, was reduced significantly with intensive glucose control, but in the more recent trials (ACCORD, ADVANCE, VADT, ORIGIN) the benefit was relatively modest and limited to reduced proteinuria. Perhaps the most important message from the above trials is to optimize control of cardiovascular risk factors. Although the goal HbA1c to prevent microvascular and macrovascular complications, per the American Diabetes Association, is less than 7%, hypoglycemia should be avoided as it can increase the risk for severe cardiovascular events.

Combination of glibenclamide-metformin HCl for the treatment of type 2 diabetes mellitus.

INTRODUCTION: Combination of glibenclamide (glyburide in the U.S.) and metformin hydrochloride simultaneously addresses two different but complimentary mechanisms to improve glycemic control in type 2 diabetes. AREAS COVERED: The pharmacokinetics, efficacy, and side effect profile of the oral combination of glibenclamide-metformin are reviewed. EXPERT OPINION: Those patients, uncontrolled with single oral agent sulfonylurea or metformin alone, benefit from combination glibenclamide-metformin. There is improvement in fasting plasma glucose, HbA(1C), and post-prandial glucose control, and patients are more likely to achieve a HbA(1C) < 7%. Initiation should be started at the lowest doses and titrated to get the desired effect. Combination therapy allows for reduced pill burden while treating a multifactorial disease by two different mechanisms. Practitioners should be cognizant of risks of hypoglycemia and the theoretical potential for lactic acidosis in the elderly and those with renal impairment. We caution the use of glibenclamide-metformin in patients at risk for cardiovascular disease. Therapy should be individualized, but overall, combination of glibenclamide-metformin should be considered in patients, without renal or cardiovascular impairment, who are not controlled on monotherapy alone. Alternatively, practitioners may want to weigh the efficacy and safety of available dipeptidyl-peptidase-4 inhibitor-metformin combinations to those of glibenclamide-metformin when considering combination therapy.

Contracting and monitoring relationships for adolescents with type 1 diabetes: a pilot study.

BACKGROUND: Adolescents are developmentally in a period of transition-from children cared for by their parents to young adults capable of self-care, independent judgment, and self-directed problem solving. We wished to develop a behavioral contract for adolescent diabetes management that addresses some negotiable points of conflict within the parent-child relationship regarding self-monitoring and then assess its effectiveness in a pilot study as part of a novel cell phone-based glucose monitoring system. METHODS: In the first phase of this study we used semistructured interview techniques to determine the major sources of diabetes-related conflict in the adolescent-parent relationship, to identify factors that could facilitate or inhibit control, and to determine reasonable goals and expectations. These data were then used to inform development of a behavioral contract that addressed the negotiable sources of conflict between parents and their adolescent. The second phase of this research was a 3-month pilot study to measure how a novel cell phone glucose monitoring system would support the contract and have an effect on glucose management, family conflict, and quality of life. RESULTS: Interviews were conducted with 10 adolescent-caregiver pairs. The major theme of contention was nagging about diabetes management. Two additional themes emerged as points of negotiation for the behavioral contract: glucose testing and contact with the diabetes clinical team. Ten adolescent-parent pairs participated in the pilot test of the system and contract. There was a significant improvement in the Diabetes Self-Management Profile from 55.2 to 61.1 (P < 0.01). A significant reduction in hemoglobin A1c also occurred, from 8.1% at the start of the trial to 7.6% at 3 months (P < 0.04). CONCLUSIONS: This study confirms previous findings that mobile technologies do offer significant potential in improving the care of adolescents with type 1 diabetes. Moreover, behavioral contracts may be an important adjunct to reduce nagging and improve outcomes with behavioral changes.

Using a cell phone-based glucose monitoring system for adolescent diabetes management.

INTRODUCTION: Mobile technology may be useful in addressing several issues in adolescent diabetes management. PURPOSE: To assess the feasibility and acceptability of a cell phone glucose monitoring system for adolescents with type 1 diabetes and their parents. METHODS: The authors recruited patients with type 1 diabetes who had been diagnosed for at least 1 year. Each adolescent used the system for 6 months, filling out surveys every 3 months to measure their usability and satisfaction with the cell phone glucose monitoring system, as well as how use of the system might affect quality of family functioning and diabetes management. RESULTS: Adolescents reported positive feelings about the technology and the service, even though a concerning number of them had significant technical issues that affected continued use of the device. Nearly all thought that the clinic involvement in monitoring testing behavior was quite acceptable. The use of the Glucophone™ did not, however, significantly change the quality of life of the adolescents, their level of conflict with their parents, their reported self-management of diabetes, or their average glycemic control within the short time frame of the study. CONCLUSIONS: As a feasibility study of the technology, this work was successful in demonstrating that cell phone glucose monitoring technology can be used in an adolescent population to track and assist in self-monitoring behavior. The authors speculate that explicitly attempting to change behavior, perhaps with the use of behavioral contracts, would enhance the technology's ability to improve outcomes.

Screening for thyroid disease: defining high-risk populations.

The pros and cons of population screening for thyroid disease have been hotly debated over the past several decades. This article addresses the issue from the point of view of the potential benefit of screening, that is, disease detection. Earlier diagnoses of hypothyroidism, hyperthyroidism, thyroid nodules, thyroid cancer and so on, with implementation of the indicated diagnostic and therapeutic interventions, avoid the adverse consequences of unrecognized and untreated progressive disease. Arguments against screening and case-finding often focus on cost considerations. To achieve the greatest yield at the lowest cost, our emphasis is on vulnerable populations with associated risk factors, and special situations such as pregnancy.