BACKGROUND: The main cause of brachioradial pruritus (BRP) is not known but there is evidence to suggest that BRP may arise in the nervous system. Cervical spine disease may be an important contributing factor.
OBJECTIVE: Our aim was to determine whether spine pathology is associated with BRP. METHODS: Medical charts of patients with BRP seen in the Division of Dermatology of the University of Massachusetts Medical Center between the years of 1993 and 2000 were retrospectively analyzed. On the basis of clinical index of suspicion, some patients had undergone radiography of the spine.
RESULTS: Of 22 patients with BRP, 11 had cervical spine radiographs. The radiographs showed cervical nnspine disease that could be correlated with the location of pruritus in each of these 11 patients.
CONCLUSIONS: Patients with BRP may have underlying cervical spine pathology. Whether this association is causal or coincidental remains to be determined.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Case: An otherwise healthy 55-year-old man reports that he has been itchy all over for 6 months. The itch interferes with falling asleep and wakes him repeatedly during the night. Initially, there was no rash, but during the past 4 months, itchy nodules and plaques have developed on his back, arms, and legs. Treatment with sedating and nonsedating oral antihistamines and topical glucocorticoids has had no effect. How would you evaluate and manage this case?
Brachioradial pruritus (BRP) is a form of neuropathic itch characterized by localized itching, burning, stinging, and tingling sensations on the dorsolateral aspect of the forearm and upper arms. Herein we present a case series of 8 patients with BRP-triggered generalized pruritus.
Article snippet: Not all itches arise in the skin. Take, for example, notalgia paraesthetica (NP) and brachioradial pruritus (BRP). Formerly considered rare, these two ‘named itches’ are in fact rather common... It is now generally accepted that BRP and NP arise not in the skin but in the nervous system. NP and BRP are neurogenic in origin,neuropathic in character...
Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. Although adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo.
The Integrated Skin Exam film: an educational intervention to promote early detection of melanoma by medical students
BACKGROUND: Knowledge of the skin cancer examination (SCE) and its practice remain relevant competency gaps among medical students.
OBJECTIVE: We elaborate on a method of SCE known as the Integrated Skin Exam and discuss the development of an instructional film that illustrates its principles. We assess the tool's effect on knowledge, attitudes, and perceptions related to the SCE.
METHODS: Second-year students among 8 randomized schools viewed the film and completed pre-post questionnaires.
RESULTS: After viewing The Integrated Skin Exam film, students demonstrated improved melanoma knowledge, including identification of high-risk demographic groups (61% vs 42.9%, P < .001), high-risk anatomic sites in women (88.6% vs 46.5%, P < .001) and men (92.1% vs 34.8%, P < .001), and the ABCDEs of melanoma (98.4% vs 91.2%, P < .001). Students demonstrated increased confidence in the SCE (66.93% vs 16.40%, P < .001) and augmented intentions to practice it (99.05% vs 13.9%, P < .001). A greater proportion (70.4% vs 41.9%, P < .001) of students thought less than 3 minutes were required to integrate SCE into the routine examination.
LIMITATIONS: Longitudinal impact of the film was not assessed.
CONCLUSION: The Integrated Skin Exam film introduces an integrated approach to the SCE that addresses knowledge gaps, mitigates perceived barriers, and augments intention related to practice of the SCE.
Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and are routinely used for disease diagnosis. Protein citrullination is also increased in cancer and other autoimmune disorders, suggesting that citrullinated proteins may serve as biomarkers for diseases beyond RA. To identify these citrullinated proteins, we developed biotin-conjugated phenylglyoxal (biotin-PG). Using this probe and our platform technology, we identified > 50 intracellular citrullinated proteins. More than 20 of these are involved in RNA splicing, suggesting, for the first time, that citrullination modulates RNA biology. Overall, this chemical proteomic platform will play a key role in furthering our understanding of protein citrullination in rheumatoid arthritis and potentially a wider spectrum of inflammatory diseases.
Ulcerative colitis (UC) is a chronic disease, in which the lining of the colon becomes inflamed and develops ulcers leading to abdominal pain, diarrhea, and rectal bleeding. The extent of these symptoms depends on disease severity. The protein arginine deiminase (PAD) family of enzymes converts peptidyl-Arginine to peptidyl-Citrulline through citrullination. PADs are dysregulated, with abnormal citrullination in many diseases, including UC and colorectal cancer (CRC). We have developed the small molecule, pan-PAD inhibitor, Chlor-amidine (Cl-amidine), with multiple goals, including treating UC and preventing CRC. Building off our recent results showing that: 1) Cl-amidine suppresses colitis in vivo in a dextran sulfate sodium (DSS) mouse model; and 2) Cl-amidine induces microRNA (miR)-16 in vitro causing cell cycle arrest, we tested the hypothesis that Cl-amidine can prevent tumorigenesis and that miR-16 induction, by Cl-amidine, may be involved in vivo. Consistent with our hypothesis, we present evidence that Cl-amidine, delivered in the drinking water, prevents colon tumorigenesis in our mouse model of colitis-associated CRC where mice are given carcinogenic azoxymethane (AOM), followed by multiple cycles of 2% DSS to induce colitis. To begin identifying mechanisms, we examined the effects of Cl-amidine on miR-16. Results show miR-16 suppression during the colitis-to-cancer sequence in colon epithelial cells, which was rescued by drinking Cl-amidine. Likewise, Ki67 and cellular proliferation targets of miR-16 (Cyclins D1 and E1) were suppressed by Cl-amidine. The decrease in cell proliferation markers and increase in tumor suppressor miRNA expression potentially define a mechanism of how Cl-amidine is suppressing tumorigenesis in vivo.
Protein arginine phosphorylation is a post-translational modification (PTM) that is important for bacterial growth and virulence. Despite its biological relevance, the intrinsic acid lability of phosphoarginine (pArg) has impaired studies of this novel PTM. Herein, we report for the first time the development of phosphonate amidines and sulfonate amidines as isosteres of pArg and then use these mimics as haptens to develop the first high-affinity sequence independent anti-pArg specific antibody. Employing this anti-pArg antibody, we further showed that arginine phosphorylation is induced in Bacillus subtilis during oxidative stress. Overall, we expect this antibody to see widespread use in analyzing the biological significance of arginine phosphorylation. Additionally, the chemistry reported here will facilitate the generation of pArg mimetics as highly potent inhibitors of the enzymes that catalyze arginine phosphorylation/dephosphorylation.
Breast Ultrasound Following a Positive Clinical Breast Examination: Does It Have a Role in Low- and Middle-Income Countries?
Purpose: Breast cancer is the most common cancer among women worldwide, with an estimated 1.7 million new cases occurring in 2012. The majority of cases and deaths occur in low- and middle-income countries (LMICs), where population-based mammography screening is not available and countries must rely on clinical breast examination (CBE). Since ultrasound has the potential to reduce unnecessary biopsies by triaging women with palpable or focal breast findings at CBE, we searched for evidence in the literature on the effectiveness of ultrasound in detecting potential breast cancer following positive CBE findings.
Methods: We reviewed the literature from 2000 to 2014 for evidence on the performance of breast ultrasound, in the absence of mammography, used to evaluate women after a positive CBE. From the studies meeting our inclusion/exclusion criteria for our analysis, we extracted data on the study design, location, ultrasound transducer parameters, patient age, method for determining positive and negative cases, and number of malignancies detected/total number of women studied.
Results: We found 15 studies matching our inclusion/exclusion criteria, 9 from high-income countries and 6 from LMICs. Despite considerable variability in study design and patient populations, breast ultrasound consistently showed high sensitivity (median = 94 percent) and specificity (median = 80 percent) for detecting breast cancer and identifying normal and benign findings not requiring a biopsy. Clear patterns related to transducer frequency or income level were not discernible given the variations in patient populations and final diagnostic determinations.
Conclusion: Our systematic review suggests that breast ultrasound following a positive CBE may be a powerful diagnostic test to determine those who do or do not need biopsy. We encourage further research in breast ultrasound use after a positive CBE in LMICs to assess the accuracy of ultrasound in these settings and the feasibility of widespread implementation.
Falls remain one of the most reportable, serious and costly type of adverse events costing an estimated $3,500 to $27,000 depending on the injury. The research often focuses on the elderly and their risk for falls and injury. Increasingly higher rates of falls are being reported in the middle-age inpatient 45 to 64 years of age. While predictors of falls and injuries have been studied across all adult inpatients, research has not specifically addressed fall risk characteristics in the middle-age. The World Health Organization’s (WHO), “Risk factor model for fall in older age”, framework was adapted for the middle-age inpatient. This framework identifies extrinsic and intrinsic variables from four risk factor groupings of biological, socioeconomic, behavioral, environmental and related outcomes to describe characteristics of the middle-age inpatient’s fall injury risk. Hitcho et al. (2004) seminal article was also used to identify pertinent inpatient characteristics. The purpose of this exploratory retrospective quantitative study described fall risk factors specific to the middle-age inpatient. The aims: (1) described risk factors of falls and fall injury; (2) described unit specific data, fall numbers with type of falls, injuries from falls, and prevention strategies (3) compare the incidence of fall and injury rates in the middle-age (45- 64) patients to the other hospital adult age-groups (ages 21-44 and 65-90). This study used Retrospective hospital occurrence data to identify middle-age inpatient falls and related characteristics reported by staff. Chart review of inpatient falls identified 439 individual falls occurring from January 2012 through July 2014. The study sample included inpatients that fell either one-time or had a repeat fall during the study period. Analysis for data included use of descriptive statistics, crosstabs, and Poisson regression. Outcomes collected included demographics, admitting diagnosis, chief complaints, cormorbities, and discharge status, type of falls and areas of falls. There was no significant difference in rates of falls between units or in staffing ratios that had a bearing on the middle-age inpatient. Fall prevention interventions were found to be universally applied, not specific to the individual, nor based on outcomes of risk screening of anticipated physiological risk factors. In comparison of the middle-age inpatient population with those age 65 -90 years of age the rates per 1000 patient days for both falls (p=.637) and injuries (p=.626) had no significant difference. Males fell at a significantly higher rate (p=.000) than females in the middle-age inpatient and those aged 64-90 years. The middleage inpatient fell at an alarming rate of 42% of all falls.
staffing ratios that had a bearing on the middle-age inpatient. Fall prevention interventions were found to be universally applied, not specific to the individual, nor based on outcomes of risk screening of anticipated physiological risk factors. In comparison of the middle-age inpatient population with those age 65 -90 years of age the rates per 1000 patient days for both falls (p=.637) and injuries (p=.626) had no significant difference. Males fell at a significantly higher rate (p=.000) than females in the middle-age inpatient and those aged 64-90 years. The middle age inpatient fell at an alarming rate of 42% of all falls.
This research provided insight into a population with acute and multiple chronic disease conditions and comorbidities that contribute to altered mental status, abnormal gait and frequently awaking at night to void. This population often overestimates their limitations and strives to maintain their autonomy. The age of the patient should not influence staff assessment of alertness and orientation. The findings of the characteristics in this research provide rich information for further research in how to include the middle-age patient in clinical decision making and education of this age group.
This qualitative descriptive (QD) study examined the experience of the woman newly diagnosed with obstructive sleep apnea (OSA). The study employed Leventhal’s Self- Regulatory Theory to understand women’s illness representation of OSA, cognitive and emotional coping, and situational appraisal skills in coming to terms with OSA. The specific aims were to: 1) Describe the illness representation of women with a recent diagnosis (within one year) of OSA; 2) Describe the cognitive perceptions and emotional response to diagnosis and treatment of OSA in this sample of women; and, 3) Describe the meaning of OSA and the coping strategies used by this sample of women.
The overarching theme of this study of a life-altering diagnosis required participants to process the health threatening information in both a conceptual and concrete process for dealing with both the physical and emotional aspects. The first two subthemes that emerged were Making sense of it, and Making it work as the women came to terms with their symptoms, diagnosis, and adapted to their treatment. For this sample of women, both acceptance (acknowledging the diagnosis of OSA and embracing treatment), and denial (not convinced of diagnosis or need for treatment, seeking alternatives) were factors in how they made sense of the situation. The making it work subtheme dealt with the women’s experiences adapting to treatment both physically and emotionally, including the appraisal, reconsideration and adjustments when they encountered difficulties and delays. A fluid iterative process included women participants describing how they appraised their situation often moving back and forth between acceptance, denial, seeking alternatives, struggling with treatment and moving forward. In both of these subthemes, family support and the stigma of OSA and CPAP were involved in how the women accepted and adapted to treatment. The third subtheme that emerged was Paying it forward as many women felt the obligation to help themselves by adapting a healthier lifestyle for themselves, their families and to assist others impacted by OSA. Women spoke of paying it forward by offering information and support to others not yet diagnosed, or are struggling with diagnosis and treatment. Many of these women were staunch advocates for other women to be tested, for HCPs to be more aware, to be more attuned to women’s sleep history, and to refer women for treatment. Implications of these findings include enhancing recognition and awareness by women of OSA symptoms, the need for diagnostic evaluation, and partner awareness as an important component of diagnosis and successful treatment for women.
Study findings support recognition of women’s presentation of OSA including unusual symptoms for earlier diagnosis and treatment. Sleep partner awareness and support appear to be relevant to women in acceptance of a life altering diagnosis. Further exploration of modifiable factors such as prompt diagnosis and individualized treatment of women with OSA could also impact potential co-morbidities. Provision of further education and awareness by HCPs and insurance companies that women may not present with classic symptoms of OSA is also needed. Targeted interventions specific to women’s experiences with OSA include development of screening tools, care guidelines and treatments that enhance applicability, acceptability, and patient satisfaction. Future advocacy work will also require supporting women in “paying it forward” to help other women diagnosed with OSA.
IMP3 (insulin-like growth factor-2 mRNA binding protein 3) is an oncofetal protein whose expression is prognostic for poor outcome in several cancers. Although IMP3 is expressed preferentially in triple-negative breast cancer (TNBC), its function is poorly understood. We observed that IMP3 expression is significantly higher in tumor initiating than in non-tumor initiating breast cancer cells and we demonstrate that IMP3 contributes to self-renewal and tumor initiation, properties associated with cancer stem cells (CSCs). The mechanism by which IMP3 contributes to this phenotype involves its ability to induce the stem cell factor SOX2. IMP3 does not interact with SOX2 mRNA significantly or regulate SOX2 expression directly. We discovered that IMP3 binds avidly to SNAI2 (SLUG) mRNA and regulates its expression by binding to the 5' UTR. This finding is significant because SLUG has been implicated in breast CSCs and TNBC. Moreover, we show that SOX2 is a transcriptional target of SLUG. These data establish a novel mechanism of breast tumor initiation involving IMP3 and they provide a rationale for its association with aggressive disease and poor outcome.
A new model for imaging and radiation therapy quality assurance in the National Clinical Trials Network of the National Cancer Institute
In March 2014, the National Cancer Institute (NCI) will consolidate the current cooperative group clinical trials program and establish a National Clinical Trials Network (NCTN).
The molecular circuitries controlling osseous prostate metastasis are known to depend on the activity of multiple pathways, including integrin signaling. Here, we demonstrate that the alphavbeta6 integrin is upregulated in human prostate cancer bone metastasis. In prostate cancer cells, this integrin is a functionally active receptor for fibronectin and latency-associated peptide-TGF-beta1; it mediates attachment and migration upon ligand binding and is localized in focal contacts. Given the propensity of prostate cancer cells to form bone metastatic lesions, we investigated whether the alphavbeta6 integrin promotes this type of metastasis. We show for the first time that alphavbeta6 selectively induces matrix metalloproteinase 2 (MMP2) in vitro in multiple prostate cancer cells and promotes osteolysis in vivo in an immunodeficient mouse model of bone metastasis through upregulation of MMP2, but not MMP9. The effect of alphavbeta6 on MMP2 expression and activity is independent of androgen receptor in the analyzed prostate cancer cells. Increased levels of parathyroid hormone-related protein (PTHrP), known to induce osteoclastogenesis, were also observed in alphavbeta6-expressing cells. However, by using MMP2 short hairpin RNA, we demonstrate that the alphavbeta6 effect on bone loss is due to upregulation of soluble MMP2 by the cancer cells, not due to changes in tumor growth rate. Another related alphav-containing integrin, alphavbeta5, fails to show similar responses, underscoring the significance of alphavbeta6 activity. Overall, these mechanistic studies establish that expression of a single integrin, alphavbeta6, contributes to the cancer cell-mediated program of osteolysis by inducing matrix degradation through MMP2. Our results open new prospects for molecular therapy for metastatic bone disease.
Bending the cost curve: a unique collaboration between radiation oncologists and Blue Cross Blue Shield of Massachusetts to optimize the use of advanced technology
PURPOSE: Intensity-modulated radiation therapy (IMRT) limits the dose of radiation to critical normal tissue structures and can be applied to the management of most cancers treated with radiation therapy. Because of increased treatment planning time and quality assurance, IMRT is costly. Blue Cross Blue Shield of Massachusetts (BCBSMA) and the Massachusetts Radiation Oncology Physicians Advisory Council (PAC) developed a strategy to develop standards for the appropriate use of IMRT.
METHODS: Normal tissue volume guidelines were established in multiple oncology disease areas and body site regions. Guidelines were activated in September 2011, and the use of IMRT per case was tracked quarterly by BCBSMA staff.
RESULTS: During the first year of activation of the volume-based guidelines, use of IMRT decreased by 17% in Massachusetts, in contrast to a 20% increase during the previous year.
CONCLUSIONS: The normal tissue-based guidelines have decreased the use of IMRT in Massachusetts; increased the use of 3D treatment; continued communication between treating radiation oncologists and an insurance organization responsible for cost and quality in medicine; increased cost savings; enabled an efficient appeal process; and provided optimal, cost-effective patient care. This may prove to be an effective model for other disciplines and other developing and maturing radiation technologies.
Dosimetric impact of the AeroForm tissue expander in postmastectomy radiation therapy: an ex vivo analysis
PURPOSE: To evaluate the effect of the AeroForm (AirXpanders Inc, Palo Alto, CA) tissue expander on the dose distribution in a phantom from a simulated postmastectomy radiation treatment for breast cancer.
METHODS AND MATERIALS: Experiments were conducted to determine the effect on the dose distribution with the metallic reservoir irradiated independently and with the entire AeroForm tissue expander placed on a RANDO phantom (The Phantom Laboratory, Salem, NY). The metallic reservoir was irradiated on a block of solid water with film at various depths ranging from 0 to 8.2 cm from the surface. The intact 400 cc AeroForm was inflated to full capacity and irradiated while positioned on a RANDO phantom, with 12 optically stimulated luminescent dosimeters (OSLDs) placed at clinically relevant expander-tissue interface points.
RESULTS: Film dosimetry with the reservoir perpendicular to film reveals 40% transmission at a depth of 0.7 cm, which increases to 60% at a depth of 8.2 cm. In the parallel position, the results vary depending on which area under the reservoir is examined, indicating that the reservoir is not a uniformly dense object. Testing of the intact expander on the phantom revealed that the average percent difference (measured vs expected dose) was 2.7%, sigma = 6.2% with heterogeneity correction and 3.7%, sigma = 2.4% without heterogeneity correction. The only position where the OSLD readings were consistently higher than the calculated dose by > 5% was at position 1, just deep to the canister at the expander-phantom interface. At this position, the readings varied from 5.2% to 14.5%, regardless of heterogeneity correction.
CONCLUSIONS: Film dosimetry demonstrated beam attenuation in the shadow of the metallic reservoir in the expander. This decrease in dose was not reproduced on the intact expander on the phantom designed to replicate a clinical setup. Inc.
A wealth of physical interaction data between transcription factors (TFs) and DNA has been generated, but these interactions often do not have apparent regulatory consequences. Thus, equating physical interaction data with gene regulatory networks (GRNs) is problematic. Here, we comprehensively assay TF activity, rather than binding, to construct a network of gene regulatory interactions in the C. elegans intestine. By manually observing the in vivo tissue-specific knockdown of 921 TFs on a panel of 19 fluorescent transcriptional reporters, we identified a GRN of 411 interactions between 19 promoters and 177 TFs. This GRN shows only modest overlap with physical interactions, indicating that many regulatory interactions are indirect. We applied nested effects modeling to uncover information flow between TFs in the intestine that converges on a small set of physical TF-promoter interactions. We found numerous cell nonautonomous regulatory interactions, illustrating tissue-to-tissue communication. Altogether, our study illuminates the complexity of gene regulation in the context of a living animal.
Mammalian interphase chromosomes interact with the nuclear lamina (NL) through hundreds of large lamina-associated domains (LADs). We report a method to map NL contacts genome-wide in single human cells. Analysis of nearly 400 maps reveals a core architecture consisting of gene-poor LADs that contact the NL with high cell-to-cell consistency, interspersed by LADs with more variable NL interactions. The variable contacts tend to be cell-type specific and are more sensitive to changes in genome ploidy than the consistent contacts. Single-cell maps indicate that NL contacts involve multivalent interactions over hundreds of kilobases. Moreover, we observe extensive intra-chromosomal coordination of NL contacts, even over tens of megabases. Such coordinated loci exhibit preferential interactions as detected by Hi-C. Finally, the consistency of NL contacts is inversely linked to gene activity in single cells and correlates positively with the heterochromatic histone modification H3K9me3. These results highlight fundamental principles of single-cell chromatin organization.
Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells
BACKGROUND: Higher-order chromatin structure is often perturbed in cancer and other pathological states. Although several genetic and epigenetic differences have been charted between normal and breast cancer tissues, changes in higher-order chromatin organization during tumorigenesis have not been fully explored. To probe the differences in higher-order chromatin structure between mammary epithelial and breast cancer cells, we performed Hi-C analysis on MCF-10A mammary epithelial and MCF-7 breast cancer cell lines.
RESULTS: Our studies reveal that the small, gene-rich chromosomes chr16 through chr22 in the MCF-7 breast cancer genome display decreased interaction frequency with each other compared to the inter-chromosomal interaction frequency in the MCF-10A epithelial cells. Interestingly, this finding is associated with a higher occurrence of open compartments on chr16-22 in MCF-7 cells. Pathway analysis of the MCF-7 up-regulated genes located in altered compartment regions on chr16-22 reveals pathways related to repression of WNT signaling. There are also differences in intra-chromosomal interactions between the cell lines; telomeric and sub-telomeric regions in the MCF-10A cells display more frequent interactions than are observed in the MCF-7 cells.
CONCLUSIONS: We show evidence of an intricate relationship between chromosomal organization and gene expression between epithelial and breast cancer cells. Importantly, this work provides a genome-wide view of higher-order chromatin dynamics and a resource for studying higher-order chromatin interactions in two cell lines commonly used to study the progression of breast cancer.