Renal cortical necrosis at presentation in a patient with systemic lupus erythematosus: an autopsy case report

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder. Renal involvement has the worst prognosis. However, renal cortical necrosis is extremely unusual in SLE. In this case report, we describe the autopsy findings in a young female patient with SLE presenting with renal failure. At autopsy, there was Libmann–Sacks endocarditis with multiorgan infarcts and renal cortical necrosis. Secondary antiphospholipid antibodies contribute to the cardiac and renal manifestations in SLE. We discuss the incidence and pathogenesis of endocarditis with differential diagnosis for cortical necrosis in a patient of SLE.     

The Iminosugar UV-4 is a Broad Inhibitor of Influenza A and B Viruses ex Vivo and in Mice

Iminosugars that are competitive inhibitors of endoplasmic reticulum (ER) α-glucosidases have been demonstrated to have antiviral activity against a diverse set of viruses. A novel iminosugar, UV-4B, has recently been shown to provide protection against lethal infections with dengue and influenza A (H1N1) viruses in mice. In the current study, the breadth of activity of UV-4B against influenza was examined ex vivo and in vivo. Efficacy of UV-4B against influenza A and B viruses was shown in primary human bronchial epithelial cells, a principal target tissue for influenza. Efficacy of UV-4B against influenza A (H1N1 and H3N2 subtypes) and influenza B was demonstrated using multiple lethal mouse models with readouts including mortality and weight loss. Clinical trials are ongoing to demonstrate safety of UV-4B and future studies to evaluate antiviral activity against influenza in humans are planned.     

Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes

Background

Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion.

The Relationship Between Time Spent Communicating and Communication Outcomes on a Hospital Medicine Service

BACKGROUND  

Quality care depends on effective communication between caregivers, but it is unknown whether time spent communicating is associated with communication outcomes.     

From the Cover: PNAS Plus: Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells

The role of CD8⁺ T cells in dengue virus infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing individuals to severe disease. A comprehensive analysis of CD8⁺ responses in the general population from the Sri Lankan hyperendemic area, involving the measurement of ex vivo IFNγ responses associated with more than 400 epitopes, challenges the original antigenic sin theory. Although skewing of responses toward primary infecting viruses was detected, this was not associated with impairment of responses either qualitatively or quantitatively. Furthermore, we demonstrate higher magnitude and more polyfunctional responses for HLA alleles associated with decreased susceptibility to severe disease, suggesting that a vigorous response by multifunctional CD8⁺ T cells is associated with protection from dengue virus disease.Dengue virus (DENV) is the etiologic agent of dengue fever (DF), the most significant mosquito-borne viral disease in humans. Disease can be caused by any of the four DENV serotypes (DENV1 to -4), which share 67–75% sequence homology with one another (1). DENV transmission occurs in more than 100 countries and is an increasing public health problem in tropical and subtropical regions (2). Demographic changes, urbanization, and international travel contribute to the expansion of geographical areas where transmission occurs, and all four DENV serotypes are now circulating in Asia, Africa, and the Americas (3, 4). Up to 100 million DENV infections occur every year (5), and severity can range from asymptomatic to an acute self-limiting febrile illness (DF). In a small proportion of patients, the disease can exacerbate and progress to dengue hemorrhagic fever (DHF) and/or dengue shock syndrome (DSS), characterized by severe vascular leakage, thrombocytopenia, and hemorrhagic manifestations (4).Although natural infection by any of the four DENV serotypes (primary infection) produces a lasting protective immunity against reinfection by the same serotype, it does not protect against infections with other serotypes (secondary infections) (6, 7). Epidemiologic studies have shown that the majority of individuals that develop DHF/DSS had been previously infected with a different serotype (8). Consequently, the development of DENV vaccines has been hampered by the potential risk of vaccine-related adverse events and the requirement to induce long-lasting protective immune responses against all four DENV serotypes simultaneously (9). The cause for the increased frequency of DHF following secondary infections has not been fully elucidated. One hypothesis is that serotype cross-reactive antibodies exacerbate disease by increasing infection of cells bearing Fcγ receptors, resulting in higher viral loads and more severe disease via this antibody-dependent enhancement (ADE) of infection (10, 11). Indeed, nonhuman primate and murine models have demonstrated that antibodies can lead to enhancement of DENV infection and disease in vivo (12–15).Another hypothesis postulates that T cells raised against the first infecting serotype dominate during a secondary heterologous infection in a phenomenon termed “original antigenic sin” (16, 17). This term was first applied to the humoral response to influenza epidemics (18) but has also been observed in CD8⁺ T-cell responses against lymphocytic choriomeningitis virus (19). This hypothesis postulates that, during secondary infection, expansion of preexisting lower avidity cross-reactive memory T cells dominate the responses over that of naïve T cells that are of higher avidity for the new DENV serotype. This expansion of low avidity T cells results in less efficient elimination of DENV-infected cells.A role for T cells in control of DENV infection is suggested by several studies that implicate HLA associations as a genetic component to variable susceptibility to DENV disease (20–26). However, it has not been addressed whether these associations might indicate a positive or detrimental role for T-cell responses. One major obstacle to the elucidation of the function of T cells is the lack of a comprehensive characterization of HLA-restricted DENV responses in the context of natural infection.Herein, we present a comprehensive analysis of functional T-cell memory against DENV and are able to correlate this with HLA alleles expressed in the very same donors. Collectively, the data suggest an HLA-linked protective role of CD8⁺ T-cell responses and do not support a causative role for CD8⁺ T cells in the induction of severe disease following secondary heterologous infection.     

Thrombopoietin serum levels in patients with aplastic anaemia: correlation with platelet count and persistent elevation in remission

In an attempt to evaluate the role of thrombopoietin (TPO) in the pathobiology of aplastic anaemia (AA), we have examined TPO levels in sera from 54 AA patients and 119 healthy controls. A total of 92 samples were collected from AA patients: 43 samples were harvested at diagnosis, 23 samples in the cytopenic period after treatment, and 26 samples when patients were in partial (n = 10) or complete remission (n = 16) following immunosuppressive treatment. TPO serum levels were assessed by a sandwich-antibody ELISA that utilized a polyclonal rabbit antiserum for both capture and signal. Serum samples from normal donors revealed a mean TPO level of 95.3 ± 54.0 pg/ml (standard deviation). Mean TPO levels in AA sera collected at diagnosis and before onset of treatment were 2728 ± 1074 pg/ml (P < 0.001 compared to normal controls; mean platelet count at that time: 27 × 10⁹/l). TPO serum levels of AA patients in partial or complete remission after immunosuppressive treatment were significantly lower than TPO levels at diagnosis (P < 0.001). However, despite normal platelet counts (mean 167 × 10⁹/l), TPO levels remained significantly elevated in complete remission (mean TPO 1009 ± 590 pg/ml, P < 0.001 compared to normal controls). There was a significant inverse correlation between serum TPO levels and platelet counts in AA patients who were not transfused for at least 2 weeks prior to sample collection (coefficient of correlation (r) = ?0.70, P < 0.0001). In summary, TPO levels were highly elevated in sera of patients with AA. Thus there is no evidence to suggest an impaired TPO response contributing to thrombocytopenia in AA. Thrombopoietin did not return to normal levels in remission, indicating a persisting haemopoietic defect in remission of AA. We hypothesize that elevated levels of TPO may be required to maintain normal or near normal platelet counts in remission of AA.     

Professional accountability in restructured contexts of occupational therapy practice

Professional standards for accountability establish essential competencies for clinical practices and provide strategies for professional advancement. This study examines the perspectives of a sample of occupational therapists on their capacity to engage in continuing education, to provide evidence-based practices and to have confidence in the effectiveness of available quality assurance mechanisms within restructured contexts of occupational therapy practice. The analysis of in-depth interviews with participants from program management, managed competition and private practice suggested three urgent needs: the development of strategies to assist therapists' translation of research evidence into clinical practices, research to determine the effectiveness of models of professional leadership within the workplace that promote professional accountability and alliances to advance policies that eliminate workplace barriers to professional accountability.     

Single agent gefitinib as first line therapy in patients with advanced non-small cell lung cancer: Washington University experience

Gefitinib has modest activity with an overall response rate of 11-18% in patients with metastatic non-small cell lung cancer (NSCLC) who have had progressive disease following platinum containing chemotherapy. However, the efficacy of gefitinib in previously untreated metastatic NSCLC is not known. We retrospectively analyzed the efficacy of gefitinib as a first line therapy in 26 patients with advanced NSCLC enrolled in the expanded access program. Patients received gefitinib 250 mg a day orally if they had a poor performance status (PS) or if they refused cytotoxic chemotherapy. Treatment was continued as long as there was no evidence of disease progression or unacceptable treatment related toxicities. The characteristics of 25 evaluable patients enrolled between the period of May 2001 and August 2002 include: 15 women, 10 men; median age 73 years (range 56-86), 81% had an ECOG performance status of two. Only one patient had a partial response and 32% had stable disease as their best response for a disease control rate of 36%; 32% of patients had disease control lasting 5 months or longer. The median overall survival and progression-free survival (PFS) were 14.1 and 2.9 months, respectively. Toxicities were minimal and included rash and diarrhea. Gefitinib was well tolerated and had interesting activity in previously untreated patients with advanced NSCLC.     

CT findings of a unicameral calcaneal bone cyst containing a fluid-fluid level.

Calcaneal unicameral bone cysts often contain fluid, but rarely contain fluid-fluid levels. We present a case focusing on the CT findings of a large calcaneal bone cyst with a fluid-fluid level and a review of the literature.