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The goal of this study was to examine the expression and regulation of aquaporin2 (AQP2), a tonicity-sensitive water channel in nucleus pulposus cells of the intervertebral disc. We found that AQP2 protein was expressed in vivo in both rat and human discs. We determined whether AQP2 promoter expression was regulated by osmolarity in a tonicity enhancer binding protein (TonEBP)-dependent manner.When TonEBP was suppressed under hypertonic conditions or overexpressed under isotonic conditions,AQP2 promoter activity was correspondingly inhibited or induced. The role of TonEBP in controlling AQP2 expression was confirmed using mouse embryonic fibroblasts (MEFs) derived from TonEBP-null mice. We studied whether calcium in addition to osmolarity played a role in regulation of AQP2 in nucleus pulposus cells. We also determined whether both TonEBP and calcineurin-nuclear factor of activated T cells (NFAT)signaling contributed to ionomycin, a calcium ionophore, mediated induction of AQP2. Co-transfection of AQP2 reporter with calcineurin (CnA/B) and/or NFAT1-4 vectors suggested that this pathway did not control AQP2 promoter activity in nucleus pulposus cells. These findings were also validated using MEFs from TonEBP, fibroblasts from CnAalpha- and CnAbeta-null mice, and mutant TonE reporter constructs. Results of these studies suggest that, in nucleus pulposus cells, osmotic pressure and calcium modulate AQP2 expression through TonEBP and are independent of the calcineurin-NFAT pathway. Because calcium flux reflects a change in applied stress, the possibility exists that NFAT5/TonEBP modulate not just water balance in the disc but also accommodate applied biomechanical forces.

Hepatitis C virus (HCV) infection is a major health burden and associated with substantial morbidity and mortality. However, the disease often remains underdiagnosed and untreated. The treatment of HCV infection has evolved dramatically with the introduction of novel, interferon-free therapies that are now able to achieve high cure rates. However, improved and more effective strategies for controlling the high costs of managing patients with HCV, especially in light of the shifting treatment paradigm, need to be developed. This article, the second in a series of 3 focused on hepatitis C, will discuss the diagnosis and management of HCV infection, including treatment recommendations from practice guidelines and emerging agents to treat HCV, and provide suggestions for incorporating these options into treatment algorithms.

Chronic hepatitis C virus (HCV) infection is highly prevalent and associated with a wide range of hepatic and extrahepatic complications. The treatment landscape for HCV infection has evolved to include regimens without interferon formulations and/or ribavirin. This change simplifies therapy, improves tolerability, and decreases therapy duration, while improving virologic response rates. This article, the first in a series of 3, will provide an overview of the hepatitis C disease state, identify populations at risk for HCV, describe testing recommendations for the diagnosis of HCV infection, and distinguish new and emerging HCV therapies.

An 80-year-old woman presented to endocrine clinic with complaints of weight loss, anorexia, and severe bilateral lower extremity pain and numbness. Two years ago she was diagnosed with type 2 diabetes; her BMI was 17 kg/m2, blood pressure (BP) was 100/75 mmHg, and HbA1c was 7.4%. She was treated with metformin 1,000 mg twice daily, but her blood glucose levels remained in the 200s mg/dL (11.1 mmol/L). She had not tried any other medications. She had been told to limit her diet to control her diabetes and her weight decreased from 120 to 80 lb.

OBJECTIVE: To report a case of Corynebacterium striatum endocarditis that was treated successfully with daptomycin plus rifampin following an unsuccessful attempt at vancomycin desensitization and failure of linezolid therapy. CASE SUMMARY: A 46-year-old woman with hemodialysis-dependent chronic renal failure was admitted for a graft-related infection. She presented with C. striatum endocarditis that was treated with daptomycin plus rifampin due to a history of allergies to vancomycin and β-lactam antibiotics and failure of linezolid therapy. The patient received daptomycin and rifampin for a total of 6 weeks. Three months after completion of treatment, no recurrence of endocarditis was evident. DISCUSSION: Daptomycin is a lipopeptide antibiotic, with rapid bactericidal activity. It has demonstrated efficacy in animal models of staphylococcal, streptococcal, and enterococcal endocarditis. Case reports of its activity in methicillin-resistant Staphylococcus aureus endocarditis have also been documented. CONCLUSIONS: Daptomycin, which has shown in vitro activity against C. striatum, may be a viable treatment option for patients with C. striatum endocarditis who are either allergic or refractory to traditional antibiotics.

Wooden figurines, idols, and scepters are commonly depicted as paraphernalia in Classic-period ritual iconography, but few examples of these objects exist. In 1999, a small wooden figurine was recovered from a cave near the Late Classic center of Muklebal Tzul in the Maya Mountains of southern Belize. It probably represents an ancestral deity or historical figure. Its recovery from a cave is appropriate. Caves functioned as arenas for legitimizing ancestral relationships through mediation with earth-focused deities. Combining analysis and interpretation of the archaeological context with a reading of documentary sources, we review the role of ancestor figurines in Maya society and offer interpretations of how this and similar objects functioned in Classic-period Maya religion and ritual.

Introduction: Current therapies for relapsed/refractory (rel/ref) T-cell lymphomas (TCLs) induce responses in only 25-30% of patients (pts). Phosphoinositide-3-kinases (PI3K) play a pivotal role in cell signaling and PI3K isoforms have distinct roles in the development, function and survival of T cells. A phase I study of the oral PI3K-δ/γ inhibitor duvelisib (DUV) in pts with TCLs showed promising activity in rel/ref TCL (Horwitz, Blood 2014). We assessed mechanisms of response and resistance to DUV in T-cell lymphomas in vitro and in vivo. Based on in vitro evidence of synergy, we initiated a phase I study to evaluate the safety and efficacy of DUV combined with romidepsin or bortezomib in pts with rel/ref TCL. Methods: Preclinical: We characterized the PI3K-signaling pathway across 11 cell lines of TCL by immunoblotting and assessed the in vitro activity of isotype specific PI3K inhibitors, including DUV. A targeted phosphoproteomic approach (P100) was utilized to identify mechanisms of resistance and response of DUV across 6 cell lines in vitro. We assessed the effects of DUV on immune response within the TCL microenvironment in vivo using a patient-derived xenograft (PDX). Clinical: We conducted multicenter, parallel phase I trials of DUV in combination with romidepsin (arm A) or bortezomib (arm B) in rel/ref TCL. For each arm, a standard 3+3 phase I design was used to determine maximum tolerated dose (MTD). DUV was dosed at 25mg, 50mg, or 75mg BID on days 1-28. Romidepsin 10mg/m2 was dosed on days 1, 8, and 15 (arm A) or bortezomib 1mg/m2 on days 1, 4, 8, and 11 (arm B), both on 28-day cycles. All pts received prophylaxis against Varicella and Pneumocystis. Results: Preclinical: DUV potently killed 3 of 4 TCL cell lines that showed constitutive phosphorylation of AKT (pAKT) versus 0 of 7 lines lacking pAKT (p=0.024). Killing by DUV exceeded killing by the PI3K-δ-specific inhibitor idelalisib and was similar to pan-PI3K inhibition. The phosphoproteomic analysis identified resistance through either PI3Kα activation, which was overcome by pan-PI3K inhibition, or by epigenetic reprogramming, which was overcome by co-treatment with romidepsin. Administration of DUV to mice engrafted with a TCL PDX resulted in reprogramming of tumor-infiltrating macrophages from the immunosuppressive M2-like phenotype to the pro-phagocytic M1-like phenotype. Clinical: 12 pts (4 in each dose level [DL]) were treated on arm A (romidepsin+DUV); 8 are evaluable for efficacy. There were no dose limiting toxicities (DLTs), therefore DL 3 was accepted as MTD. 2 serious adverse events (SAEs) possibly related to study drug included grade (Gr) 3 fatigue and Gr 2 aspartate aminotransferase (AST) elevation. 1 fatal event (diffuse alveolar hemorrhage following allogeneic transplant) occurred 31 days after last dose of study drug and was assessed as unrelated to study treatment. Gr 3 or 4 adverse events (AEs) occurring in ≥10% of pts included only neutropenia (Gr 3, n=4, Gr 4, n=2). Overall response rate (ORR) and median time to response (TTR) were 4/8 (50%) and 51 (range 49-54) days. Two of 4 responders proceeded to transplant after 90 and 108 days and 1 remains on treatment for 107+ days. 17 pts were treated on arm B (bortezomib+DUV), including 8 in DL 1, 3 in DL 2, and 6 in DL 3; 15 pts are evaluable for efficacy. 1 out of 6 pts evaluable for DLT on DL 1 experienced DLT (pneumonia). There were no other DLTs, however Gr 3 elevations of alanine aminotransferase (ALT) or AST following cycle 2 were observed for 3 pts treated at DL 2 and 2 treated at DL 3 leading to DL 1 being accepted as MTD. There were 5 SAEs possibly related to study drug including Gr 3 pneumonia (n=2), Gr 3 infectious colitis (n=1), Gr 3 colitis (n=1), and Gr 4 AST/ALT elevation (1). Gr 3 or 4 AEs occurring in ≥10% of pts included only neutropenia (Gr 3, n=3). ORR, complete response (CR), and median time to response (TTR), were 8/15 (53%), 3/15 (20%), and 52 (range 47-57) days. Among the 8 responders, 5 remain on treatment for 103-377+ days. Conclusion: DUV shows activity in T-cell lymphomas with pre-clinical evidence of both tumor cell-autonomous and non-autonomous effects. The combinations of DUV plus romidepsin and DUV plus bortezomib are safe and well tolerated, with limited incidence of AST/ALT elevation from romidepsin+DUV. Promising response rates of at least 50% were observed across TCL histologies with both regimens. Expansion cohorts of pts with peripheral and cutaneous TCL are currently enrolling. Disclosures Moskowitz: ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Mehta-Shah: Celgene: Research Funding; Verastem: Research Funding; Bristol Myers Squibb: Research Funding. Dogan: Roche Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kim: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Soligenix: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Jacobsen: GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Horwitz: Forty-Seven: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy.

This review aims to evaluate the literature on the safety and efficacy of novel toxoid vaccines for the prophylaxis of Clostridium difficile infections (CDI) in healthy adults. Literature searches for clinical trials were performed through MEDLINE, ClinicalTrials.gov, and Web of Science using the keywords bacterial vaccines, Clostridium difficile, and vaccine. English-language clinical trials evaluating the efficacy and/or safety of Clostridium difficile toxoid vaccines that were completed and had results posted on ClinicalTrials.gov or in a published journal article were included. Six clinical trials were included. The vaccines were associated with mild self-reported adverse reactions, most commonly injection site reactions and flu-like symptoms, and minimal serious adverse events. Five clinical trials found marked increases in antibody production in vaccinated participants following each dose of the vaccine. Clinical trials evaluating C. difficile toxoid vaccines have shown them to be well tolerated and relatively safe. Surrogate markers of efficacy (seroconversion and geometric mean antibody levels) have shown significant immune responses to a vaccination series in healthy adults, indicating that they have the potential to be used as prophylaxis for CDI. However, more research is needed to determine the clinical benefits of the vaccines.

Most acute heart failure (AHF) patients have dyspnea but their most bothersome (worst) symptom (WS) may vary. We hypothesized that improvement in a patient's WS over time would be associated with decongestion efficacy and outcomes in AHF. Patients with AHF enrolled (< 24 hr from admission) in ROSE

Background: The incidence of skin and soft tissue abscesses (SSTAs) has increased owing to the emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Some of these patients are treated as outpatients (OPs) and some as inpatients (IPs). Objective: To review the microbiology and clinical features of SSTAs and the clinical parameters that may have influenced clinicians to treat patients as IPs. Methods: The study was conducted in a 673-bed teaching hospital between January and December 2005. A retrospective chart review of patients identified from a microbiology culture log was conducted. Data were collected for demographics, underlying disease, SSTA number and site, recurrence rates, and clinical presentation. Results: One hundred thirty-eight patients were identified; 76 (55%) were female, with a mean age of 42 years (range 18–80 years); 76 (55.5%) had no underlying disease, 27 (19.6%) had diabetes, 20 (14.5%) had human immunodeficiency virus (HIV) infection, and 13 (9.4%) were intravenous drug users. Common SSTA sites involved were the perineal area (43; 31.2%), upper extremities (35; 25.4%), lower extremities (19; 13.8%), head and neck (14; 10.1%), chest (13; 9.4%), and abdomen (8; 5.8%). Conclusions: CA-MRSA was the most commonly isolated organism overall and in patients treated as OPs. The decision to treat SSTA patients as IPs seems to be influenced by SSTA number and site and the presence of fever at presentation. SSTA number and site (variables that led to the decision to treat patients as IPs) were confirmed by demonstrating statistical significance in the analysis between the IP and OP groups, but the other determinant of admission, the presence of fever at presentation, was based on chart review statements and not confirmed by statistical analysis between the IP and OP groups.

Clostridial bacteremia (CB) is a rare clinical entity, accounting for less than 2-3% of all blood cultures. CB is frequently associated with intra-abdominal infections and underlying malignancy, particularly colon cancer or leukemia.Clostridiumspecies are commonly isolated from blood cultures as a part of polymicrobial bacteremia. The mortality rate among patients with CB has been reported to be as high as 50%. The presentation and outcome of CB depends on underlying host defenses and the type ofClostridiumspecies causing infection. A favorable outcome for CB appears to depend on the prompt initiation of appropriate antibiotics and surgical intervention. All patients with positive blood cultures forClostridiumspecies, from January 1995 to December 2003, were included in this study. Medical records of these patients were reviewed for age, sex, underlying diseases (such as malignancy and diabetes), antibiotic use, and outcome. Antimicrobial therapy was defined as either “appropriate” or “insufficient” based on its activity againstClostridiumspecies. In-hospital, postdiagnosis survival was examined by Kaplan-Meier methodology and comparisons made by the Mantel-Cox Log-Rank test. Ninety-two percent of the patients had monomicrobial CB. C. perfringens was the most frequently isolated pathogen, seen in 60% of cases. The most common underlying conditions were genitourinary and gastrointestinal malignancies, and diabetes. The overall mortality was 48%. Patients with malignancy had a significantly higher 2-day mortality rate (54%) compared to patients without malignancy (8%, p = 0.023). The mortality rates varied according to type ofClostridiumspecies. Patients with C. innocuum bacteremia had a significantly higher 2-day mortality rate (100%) compared to patients with C. septicum (67%), and to patients with C. perfringens (27%) (p = 0.004). “appropriate” antibiotics were given to 64% of the patients, 16% were on antibiotics with “insufficient” coverage, and 20% were not given any antibiotics. Patients receiving “insufficient” antibiotic therapy had a significantly higher 2-day mortality rate (75%) compared to patients on “appropriate” antibiotics forClostridium(12.5%) (p = 0.011). CB is associated with high and rapid mortality, especially in patients with malignancy. Early mortality was significantly lower in patients receiving antibiotics with adequate coverage forClostridiumspecies.

We assessed the rates of influenza vaccine acceptance and the reasons for acceptance or refusal among medical residents in different disciplines during the 2004-2005 influenza season. Rates varied among disciplines; emergency department residents had the lowest acceptance rate (24%). The perception of a low risk of contracting influenza was the most common reason reported for vaccine refusal.

We examined the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) database to understand the impact and pathophysiology of renal dysfunction in patients hospitalized with advanced decompensated heart failure (HF).Baseline renal insufficiency (RI) (estimated glomerular filtration rate [eGFR]60 ml/min) and worsening renal function (WRF) (upward arrow serum creatinine [SCr]or=0.3 mg/dl) during treatment of decompensated HF are associated with adverse outcomes.We used a Cox proportional hazards model to evaluate the impact of renal function on 6-month outcomes. Renal parameters were correlated with hemodynamic measurements. The impact of a strategy using pulmonary artery catheter (PAC) guidance on WRF and outcomes in patients with baseline RI was compared with treatment based on clinical assessment alone.Baseline and discharge RI, but not WRF, were associated with an increased risk of death and death or rehospitalization. Among the hemodynamic parameters measured in patients randomized to the PAC arm (n = 194), only right atrial pressure correlated weakly with baseline SCr (r = 0.165, p = 0.03). There was no correlation between baseline hemodynamics or change in hemodynamics and WRF. A PAC-guided strategy was associated with less average increase in creatinine but did not decrease the incidence of defined WRF during hospitalization or affect renal function after discharge relative to clinical assessment alone.Among patients with advanced decompensated HF, baseline RI impacts outcomes more than WRF. Poor forward flow alone does not appear to account for the development of RI or WRF in these patients. The addition of hemodynamic monitoring to clinical assessment does not prevent WRF or improve renal function after discharge.

Objective Inefficiencies in clinical trial data collection cause delays, increase costs, and may reduce clinician participation in medical research. In this proof-of-concept study, we examine the feasibility of using point-of-care data capture for both the medical record and clinical research in the setting of a working clinical trial. We hypothesized that by doing so, we could increase reuse of patient data, eliminate redundant data entry, and minimize disruption to clinic workflow. Design We developed and used a point-of-care electronic data capture system to record data during patient visits. The standards-based system was used for clinical research and to generate the clinic note for the medical record. The system worked in parallel with data collection procedures already in place for an ongoing multicenter clinical trial. Our system was iteratively designed after analyzing case report forms and clinic notes, and observing clinic workflow patterns and business procedures. Existing data standards from CDISC and HL7 were used for database insertion and clinical document exchange. Results Our system was successfully integrated into the clinic environment and used in two live test cases without disrupting existing workflow. Analyses performed during system design yielded detailed information on practical issues affecting implementation of systems that automatically extract, store, and reuse healthcare data. Conclusion Although subject to the limitations of a small feasibility study, our study demonstrates that electronic patient data can be reused for prospective multicenter clinical research and patient care, and demonstrates a need for further development of therapeutic area standards that can facilitate researcher use of healthcare data.

A recent study reported a higher than expected prevalence of hypothyroidism among patients with cutaneous melanoma. To further characterize and validate those findings, we conducted a retrospective review of the prevalence of hypothyroidism among all consecutive patients diagnosed with cutaneous melanoma in the dermatology clinic at the Michael E. DeBakey VA Medical Center (VAMC) in Houston, Texas. To accomplish this task, the electronic medical records of all patients diagnosed with cutaneous melanoma at the VAMC from January 2001 through October 2004 were examined for signs of hypothyroidism. Data regarding the site of melanoma and age at diagnosis were obtained for these hypothyroid cases and for age- and gender-matched euthyroid controls from the same melanoma cohort. Among 156 cutaneous melanoma patients (151 male and 5 female), 8 (5.1 %) showed a history of hypothyroidism [7 of 151 male (4.6 %) and 1 of 5 female (20 %)]. The prevalence of hypothyroidism among the male melanoma patients was significantly higher than that reported for the general population. The prevalence data concerning hypothyroidism among our female patients was not considered evaluable due to the primarily male distribution of our study population. We conclude that hypothyroidism (excluding iatrogenic etiologies) is frequent among male patients with cutaneous melanoma. Our results further suggest that a subset of melanoma tumors may respond to hormones of the hypothalamus-pituitary-thyroid axis, raising many questions that could influence the diagnosis, care, and treatment of a subset of melanoma patients.

Two Maya-period sites, Las Pacayas and Aguateca, have recently yielded fragments composed of a previously unknown material -- a laminate formed from multiple layers of woven cloth and clay slip. On-site and laboratory conservation efforts enabled the Aguateca finds to be identified as ceremonial headdress elements. Materials analysis and replication experimentation have elucidated technological aspects of this medium, and demonstrate its suitability for fabricating elaborate, lightweight items such as these.

Intestinal endometriosis mimics a wide variety of inflammatory, infectious, or neoplastic digestive diseases. To alert clinicians to its diverse manifestations, we describe nine patients who required laparotomy. The underlying diagnosis was elusive initially. In no case were symptoms clearly cyclic or temporally related to phases of the menstrual cycle. Presenting complaints included acute or subacute lower abdominal pain (three patients), hematochezia (two patients), signs or symptoms of small-bowel obstruction (two patients), peritonitis (one patient), and a partially obstructing sigmoid lesion (one patient). The findings of barium enema were nondiagnostic in the five cases in which it was performed. Surgery was needed in each case; indications included inability to exclude carcinoma (two patients), small-bowel obstruction (two patients), diffuse peritonitis (one patient), persistent colonic obstruction (one patient), pericolonic abscess (one patient), and intractable pain (one patient). Intestinal endometriosis has a diverse clinical spectrum, with nonspecific features in many patients. This disease should be considered during the evaluation of unexplained digestive complaints in women of childbearing years. (Arch Intern Med. 1995;155:977-980)

Dyspnea relief is a regulatory benchmark in acute heart failure (AHF) and typically assessed by a dyspnea visual analog scale (DVAS). We hypothesized that a provocative dyspnea score (PDS) assessing dyspnea under incrementally more difficult conditions is a more sensitive metric of change (Δ) in