PURPOSE: The purpose of this study was to investigate the use of an mHealth application (app), self-management physical activity intervention FOOTFIT with an added patient-provider connectivity feature (FOOTFIT+), that was designed to strengthen the lower extremities of minimally ambulatory individuals with venous leg ulcers (VLUs). DESIGN: Randomized controlled trial. SUBJECTS AND SETTING: Twenty-four adults 18 years and older with VLUs being treated in 2 wound clinics in the Southeastern United States participated in this study. METHODS: Preliminary estimates and 95% confidence intervals for the medians of short-term functional impacts on foot function, strength, ankle range of motion, walking capacity, depression, and physical functioning were obtained pre- and postassessment after the 6-week intervention trial. RESULTS: There were negligible changes in either group for foot function. It is noted that both groups experienced substantial foot and ankle impairment at baseline. The greatest improvement in range of motion was noted in the FOOTFIT group for dorsiflexion of the right ankle (4.6 ± 5.22 lb/in2 over baseline) whereas strength decreased in both ankles for dorsiflexion and plantar flexion in the FOOTFIT+ group. No improvements were noted in walking distance or physical health for FOOTFIT (slight decrease −2.9 ± 5.6) and FOOTFIT+ (slight increase 3.0 ± 6.6) during the 6-week study period. CONCLUSIONS: In a minimally ambulatory population with VLUs, our mHealth FOOTFIT intervention composed of progressive exercise “boosts” demonstrated minimal short-term effects. We recommend engagement with the app for a longer period to determine longer-term outcomes of lower extremity function.

We developed the AJBL6 transforming growth factor-beta 1 (TGF-beta1) heterozygous (HT) mouse by mating A/J mice with C57BL/6 TGF-beta1 HT mice that shows increased carcinogen-induced lung lesions with decreased latency to examine progressive events in lung tumorigenesis. Mouse cDNA macroarrays were used to identify cell cycle genes that are differentially regulated in ethyl carbamate-induced lung adenocarcinomas compared with normal lung tissue in AJBL6 TGF-beta1 HT mice using probes that were generated from tissues isolated using laser capture microdissection. While expression of the genes for cyclin D1, CDK4, and E2F1 increased in lung adenocarcinomas relative to normal lung, expression of p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), p57(Kip2), and pRb genes decreased in comparison. Competitive RT-PCR showed that the levels of cyclin D1 and CDK4 mRNAs were 2- and 3-fold higher, respectively, in lung adenocarcinomas than in normal lung, while the mRNAs for p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), and pRb were 3- to 4-fold lower in adenocarcinomas than in normal lung, thus validating the macroarray findings. Competitive RT-PCR of microdissected lesions also showed that the levels of cyclin D1 and CDK4 mRNAs increased significantly, while the mRNAs for p15(Ink4b) and p27(Kip1) decreased significantly as lung tumorigenesis progressed. Immunohistochemical staining for cyclin D1 and CDK4 showed staining in >80% of nuclei in adenocarcinomas compared with fewer than 20% of nuclei staining positively in normal lung. In contrast, while >60% of normal lung cells showed immunostaining for p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), and pRb, staining for these proteins decreased in hyperplasias, adenomas, and adenocarcinomas. These data show that multiple components of the cyclin D1/CDK4/p16(Ink4a)/pRb signaling pathway are frequently altered early in lung lesions of AJBL6 TGF-beta1 HT mice that are induced by ethyl carbamate as a function of progressive lung carcinogenesis, suggesting that components of this pathway may be potential targets for gene therapy.

Transforming growth factor-␤ (TGF␤) and adrenomedullin (AM) are multifunctional regulatory peptides that are secreted by a variety of normal and malignant cells. The TGF␤s are expressed in developing organs and adults, and their tissue distribution pattern has possible significance for signaling roles in many epithelial-mesenchymal interactions. AM is also expressed in a variety of embryonic and adult tissues. The present study reports a comparison of the patterns of expression of the proteins and messenger RNAs (mRNAs) for TGF␤1 and AM in the developing mouse embryo. Immunohistochemical and in situ hybridization analyses were performed on formalin-fixed paraffin-embedded sections of developing embryonic mouse tissues using specific antibodies and complementary RNA probes for TGF␤1 and AM. The early placenta, including the giant trophoblastic cells, showed high levels of staining and hybridization for TGF␤1 and AM proteins and mRNAs. The heart was the first organ that showed expression of TGF␤1 and AM during embryogenesis. The spatio-temporal patterns of expression of TGF␤1 and AM in cardiovascular, neural, and skeletal-forming tissues as well as in the main embryonic internal organs showed striking similarities. The lung, kidney, and intestine, in which epithelial-mesenchymal interactions occur, showed similar patterns of TGF␤1 and AM expression. These data show colocalization of TGF␤1 and AM in specific cell types associated with several tissues in the developing mouse embryo. Additionally, RT-PCR amplification and Northern blot hybridization showed expression of TGF␤1 and AM mRNAs in all embryonic and adult mouse and rat tissues examined. Our data show that the expression of TGF␤1 and AM is regulated in a spatial and temporal manner such that overlapping patterns of expression of TGF␤1 and AM occur in several tissues at the same stage of development and in the same cellular location in rodent embryogenesis. (Endocrinology 139: 3946 -3957, 1998)

Palliative care approaches that effectively manage distressful symptoms associated with wounds at the end of life remain elusive. This 4-week study examined a topical wound powder RGN107 for reducing pain, odor, and exudate in 50 patients with pressure ulcers, skin tears, and malignant/fungating and vascular wounds receiving hospice or palliative care and explored quality of life for the caregiver. Through an observational design, the outcomes were measured with visual analog scales, 2 pain questionnaires, and a caregiver quality-of-life instrument. Intent-to-treat analyses were used. Statistically significant reductions in pain (P = .001), odor (P = .04), and exudate (P = .00003) were observed. Caregiver quality of life remained unchanged (P = .28); however, improvements were noted in 3 subscales. Findings suggest topical RGN107 reduced pain, odor, and exudate in a highly challenged population with wounds at the end of life. A larger comparative effectiveness trial should be conducted with other wound powder comparators and usual care approaches and should include cost benefits.

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The transforming growth factor-betas (TGF-beta s) are multifunctional proteins that inhibit the proliferation of many epithelial cells through a set of cell protein receptors that includes the TGF-beta type I (RI) and type II (RII) receptors. Loss of growth inhibition by TGF-beta is thought to contribute to the development of many types of tumors. In the present study, we have examined expression of the proteins and mRNAs for TGF-beta 1, TGF-beta RI, and TGF-beta RII in normal human lung, well-characterized non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens. Immunohistochemical staining for TGF-beta 1, TGF-beta RI, and TGF-beta RII using specific antibodies in normal human lung showed expression of the 3 proteins in the epithelium of bronchi and bronchioles as well as in alveoli. Differential expression of TGF-beta RI and TGF-beta RII proteins was detected in 5 NSCLC cell lines using Western blot analysis, with reduced levels in 3 cell lines. A panel of 45 formalin-fixed and paraffin-embedded NSCLC specimens showed positive immunostaining for TGF-beta 1, TGF-beta RI, and TGF-beta RII, with reduced TGF-beta RII in poorly differentiated adenocarcinomas and squamous cell carcinomas and some moderately differentiated adenocarcinomas. In situ hybridization studies conducted with specific riboprobes for TGF-beta 1, TGF-beta RI, and TGF-beta RII showed corresponding localization of expression of the mRNAs in the specimens that showed positive immunostaining for the proteins. To investigate the roles of TGF-beta 1, TGF-beta RI, and TGF-beta RII in chemically induced mouse lung tumorigenesis, we examined the expression of their proteins and mRNAs in 2 mouse model systems. Whereas expression of the proteins and mRNAs for TGF-beta 1 and TGF-beta RI was comparable in lung adenomas and bronchioles of A/J mice treated with benzo(alpha)pyrene, decreased immunostaining and hybridization for TGF-beta RII protein and mRNA was detected in 50% of lung adenomas in these mice. Interestingly, expression of TGF-beta 1 and the TGF-beta receptor proteins was similar to that of bronchioles in C57B1/6 mice and their littermates heterozygous for deletion of the TGF-beta 1 gene treated with diethylnitrosamine. These data show that reduced levels of expression of TGF-beta RII occur in some, but not all, human and mouse lung tumors. This suggests that different mechanisms of action, some of which may involve the TGF-beta signaling pathway, may contribute to the progression of lung tumorigenesis.

BackgroundFor intervention studies that require the use of participant self-reports, the quality and accuracy of recorded data and variability in participant adherence rates to the treatment can cause significant outcome bias.PurposeTo assess the quality and accuracy of participant documentation of daily self-monitoring of leg skin temperature, adherence to a graduated cooling treatment protocol to prevent venous leg ulcers, and the potential for bias in treatment effect in a randomized controlled trial that included a population with chronic venous disease.MethodsIndividuals were randomized to a leg cooling intervention or placebo treatment group to daily self-monitor and record lower leg skin temperature over a 9-month period on monthly paper study logs. Returned study logs for the first 100 completed participants (n=54 cooling intervention, n=46 control) were reviewed for quality and accuracy. Adherence was determined from evaluating the accuracy of participant documentation. To examine potential outcome bias in treatment effect, mean between group and within group comparisons of the before and after treatment differences were conducted using an intention-to-treat (ITT) versus a modified intention-to-treat (mITT) analysis approach with an 85% accuracy cut-off rate. Data were collected in 2011–2014.ResultsOf the expected 900 study logs, 91.8% (826/900) were returned and 8.2% (74/900) were not. Non-mutually exclusive main error types in returned documentation included: 59.2% (489/826) white-outs, cross-off and/or overwrites, 34.9% (288/826) entries omitted, 29.4% (243/826) no performance of daily self-monitoring, 28.7% (237/826) no performance of the treatment intervention per the prescribed protocol regime, 26.8% (221/826) extraneous data, 8.6% (71/826) suspected fabrication, and 7.6% (63/826) questionable validity. Under ITT analysis, 38.4% (346/900) of all returned logs were <85% accurate, 25.0% (225/900) were 85%–99% accurate, and 36.6% (329/900) were 100% accurate. Mean overall participant adherence rates were: 22.0% at <85% accuracy, 53.0% at 85%–99% accuracy, and 25.0% at 100% accuracy. Under the mITT analysis, 54.0% (483/900) of returned logs were deemed adherent with ≥85% accuracy.ConclusionThis study found good rates of adherence. Under ITT analysis, 78.0% of participants were deemed adherent to the study protocol with ≥85% accuracy in documenting daily self-monitoring of skin temperatures in response to a topically applied experimental cooling cuff intervention for the prevention of venous leg ulcers.

Pain was reduced in both groups while self-efficacy did not change. Findings suggest that strictly implemented standard of CVeD care in each study group, with or without cooling, improved pain while there were no effects on self-efficacy.