Sternoclavicular joint arthropathy mimicking radiculopathy in a patient with concurrent C4-5 disc herniation

Background Patients with sternoclavicular joint arthropathy, which can result from septic arthritis, often present with localized sternoclavicular pain as well as shoulder pain. Such pain may be similar to the presenting symptoms of cervical intervertebral disc herniation. Clinical presentation A 47-year-old female presented with 1 month of significant pain in the neck as well as right anterior chest and deltoid. The patient was found to have reduced strength in the right deltoid muscle on physical examination. MRI revealed a C4-C5 herniated nucleus pulposus. The patient underwent successful C4-C5 anterior cervical discectomy, but subsequently developed painful swelling in the region of the right sternoclavicular joint with limited motor strength in the right shoulder and arm. A needle biopsy of the mass yielded negative results, but her erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) numbers did respond to antibiotics, consistent with infection of the sternoclavicular joint. A follow-up CT scan (6.5 months postoperatively) revealed apparent resolution right sternoclavicular joint arthropathy, thought the patient continued to experience pain. 15 months postoperatively, the patient was prescribed methotrexate due to persistent pain and mild weakness arising from a possible rheumatologic inflammation. 19 months postoperatively, the patient had full strength of the right shoulder and arm and visible decrease in swelling at the sternoclavicular joint. More than three years postoperatively, the patient was diagnosed with multiple myeloma, which was appropriately treated. At follow-up four years postoperatively, the patient had an MRI showing new C6-C7 herniated nucleus pulposus, but no longer had any right shoulder or chest pain or associated weakness. Conclusion This case demonstrates that sternoclavicular joint arthropathy results in symptoms that can mimic the presenting symptoms of shoulder or cervical spine pathology, such as shoulder and neck pain, necessitating careful diagnosis and management

TMPRSS2/ERG Promotes Epithelial to Mesenchymal Transition through the ZEB1/ZEB2 Axis in a Prostate Cancer Model

Prostate cancer is the most common non-dermatologic malignancy in men in the Western world. Recently, a frequent chromosomal aberration fusing androgen regulated TMPRSS2 promoter and the ERG gene (TMPRSS2/ERG) was discovered in prostate cancer. Several studies demonstrated cooperation between TMPRSS2/ERG and other defective pathways in cancer progression. However, the unveiling of more specific pathways in which TMPRSS2/ERG takes part, requires further investigation. Using immortalized prostate epithelial cells we were able to show that TMPRSS2/ERG over-expressing cells undergo an Epithelial to Mesenchymal Transition (EMT), manifested by acquisition of mesenchymal morphology and markers as well as migration and invasion capabilities. These findings were corroborated in vivo, where the control cells gave rise to discrete nodules while the TMPRSS2/ERG-expressing cells formed malignant tumors, which expressed EMT markers. To further investigate the general transcription scheme induced by TMPRSS2/ERG, cells were subjected to a microarray analysis that revealed a distinct EMT expression program, including up-regulation of the EMT facilitators, ZEB1 and ZEB2, and down-regulation of the epithelial marker CDH1(E-Cadherin). A chromatin immunoprecipitation assay revealed direct binding of TMPRSS2/ERG to the promoter of ZEB1 but not ZEB2. However, TMPRSS2/ERG was able to bind the promoters of the ZEB2 modulators, IL1R2 and SPINT1. This set of experiments further illuminates the mechanism by which the TMPRSS2/ERG fusion affects prostate cancer progression and might assist in targeting TMPRSS2/ERG and its downstream targets in future drug design efforts

AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases

"The initial Guide to the Primary Prevention of Cardiovascular Diseases was published in 1997 as an aid to healthcare professionals and their patients without established coronary artery disease or other atherosclerotic diseases.1 It was intended to complement the American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines for Preventing Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease (updated2) and to provide the healthcare professional with a comprehensive approach to patients across a wide spectrum of risk. The imperative to prevent the first episode of coronary disease or stroke or the development of aortic aneurysm and peripheral arterial disease remains as strong as ever because of the still-high rate of first events that are fatal or disabling or require expensive intensive medical care. The evidence that most cardiovascular disease is preventable continues to grow. Results of long-term prospective studies consistently identify persons with low levels of risk factors as having lifelong low levels of heart disease and stroke.3,4⇓ Moreover, these low levels of risk factors are related to healthy lifestyles. Data from the Nurses Health Study,5 for example, suggest that in women, maintaining a desirable body weight, eating a healthy diet, exercising regularly, not smoking, and consuming a moderate amount of alcohol could account for an 84% reduction in risk, yet only 3% of the women studied were in that category. Clearly, the majority of the causes of cardiovascular disease are known and modifiable. This 2002 update of the Guide acknowledges a number of advances in the field of primary prevention since 1997. Research continues to refine the recommendations on detection and management of established risk factors, including evidence against the safety and efficacy of interventions once thought promising (eg, antioxidant vitamins).6 This, in turn, has stimulated a large number of additional guidelines for specific demographic groups (eg, women), on individual risk factors (eg, diabetes, smoking), and for the primary prevention of stroke. In all of these guidelines, there is an increasing emphasis on further stratifying patients by level of risk and matching the intensity of interventions to the hazard for cardiovascular disease events.7

RAD50 Is Required for Efficient Initiation of Resection and Recombinational Repair at Random, γ-Induced Double-Strand Break Ends

Resection of DNA double-strand break (DSB) ends is generally considered a critical determinant in pathways of DSB repair and genome stability. Unlike for enzymatically induced site-specific DSBs, little is known about processing of random “dirty-ended” DSBs created by DNA damaging agents such as ionizing radiation. Here we present a novel system for monitoring early events in the repair of random DSBs, based on our finding that single-strand tails generated by resection at the ends of large molecules in budding yeast decreases mobility during pulsed field gel electrophoresis (PFGE). We utilized this “PFGE-shift” to follow the fate of both ends of linear molecules generated by a single random DSB in circular chromosomes. Within 10 min after γ-irradiation of G2/M arrested WT cells, there is a near-synchronous PFGE-shift of the linearized circular molecules, corresponding to resection of a few hundred bases. Resection at the radiation-induced DSBs continues so that by the time of significant repair of DSBs at 1 hr there is about 1–2 kb resection per DSB end. The PFGE-shift is comparable in WT and recombination-defective rad52 and rad51 strains but somewhat delayed in exo1 mutants. However, in rad50 and mre11 null mutants the initiation and generation of resected ends at radiation-induced DSB ends is greatly reduced in G2/M. Thus, the Rad50/Mre11/Xrs2 complex is responsible for rapid processing of most damaged ends into substrates that subsequently undergo recombinational repair. A similar requirement was found for RAD50 in asynchronously growing cells. Among the few molecules exhibiting shift in the rad50 mutant, the residual resection is consistent with resection at only one of the DSB ends. Surprisingly, within 1 hr after irradiation, double-length linear molecules are detected in the WT and rad50, but not in rad52, strains that are likely due to crossovers that are largely resection- and RAD50-independent

Frequent and Efficient Use of the Sister Chromatid for DNA Double-Strand Break Repair during Budding Yeast Meiosis

Studies of DNA double-strand break repair during meiosis reveal that a substantial fraction of recombination occurs between sister chromatids

Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART

Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside of the peripheral blood regarding persistent virus production in tissue reservoirs. Understanding the dynamics of ART-induced reductions in viral RNA (vRNA) levels throughout the body is important for the development of strategies to eradicate infectious HIV from patients. Essential to a successful eradication therapy is a component capable of killing persisting HIV infected cells during ART. Therefore, we determined the in vivo efficacy of a targeted cytotoxic therapy to kill infected cells that persist despite long-term ART. For this purpose, we first characterized the impact of ART on HIV RNA levels in multiple organs of bone marrow-liver-thymus (BLT) humanized mice and found that antiretroviral drug penetration and activity was sufficient to reduce, but not eliminate, HIV production in each tissue tested. For targeted cytotoxic killing of these persistent vRNA+ cells, we treated BLT mice undergoing ART with an HIV-specific immunotoxin. We found that compared to ART alone, this agent profoundly depleted productively infected cells systemically. These results offer proof-of-concept that targeted cytotoxic therapies can be effective components of HIV eradication strategies